Therapeutic polypeptides, nucleic acids encoding same, and methods of use

Info

Publication number: 20040029150
Type: Application
Filed: Mar 31, 2003
Publication Date: Feb 12, 2004
Inventors: John Alsobrook (Madison, CT), David Anderson (Plantsville, CT), Ferenc Boldog (North Haven, CT), Catherine Burgess (Wethersfield, CT), Stacie Casman (North Haven, CT), Shlomit R. Edinger (New Haven, CT), Valerie Gerlach (Branford, CT), William Grosse (Branford, CT), Xiaojia Guo (Branford, CT), Vladimir Gusev (Madison, CT), Weizhen Ji (Branford, CT), William LaRochelle (Madison, CT), Denise Lepley (Branford, CT), Li Li (Branford, CT), Xiaohong Liu (Branford, CT), John R. MacDougall (Hamden, CT), Uriel M. Malyankar (Branford, CT), Isabelle Millet (Milford, CT), Muralidhara Padigaru (Branford, CT), Meera Patturajan (Branford, CT), John A. Peyman (New Haven, CT), Luca Rastelli (Guilford, CT), Daniel Rieger (Branford, CT), Mark E. Rothenberg (Clinton, CT), Richard Shimkets (Guilford, CT), David J. Stone (Guilford, CT), Raymond Taupier (East Haven, CT), Corine Vernet (North Branford, CT), Bryan Zerhusen (Branford, CT)
Application Number: 10403676

Abstract

Disclosed herein are nucleic acid sequences that encode novel polypeptides. Also disclosed are polypeptides encoded by these nucleic acid sequences, and antibodies that immunospecifically bind to the polypeptide, as well as derivatives, variants, mutants, or fragments of the novel polypeptide, polynucleotide, or antibody specific to the polypeptide. The invention further discloses therapeutic, diagnostic and research methods for diagnosis, treatment, and prevention of disorders involving any one of these novel human nucleic acids and proteins.

Description

Description

RELATED APPLICATIONS

[0001] This application is a continuation-in-part of U.S. Ser. No. 09/520,781, filed Mar. 8, 2000, which claims priority to U.S. S No. 60/123,667, filed Mar. 9, 1999; U.S. Ser. No. 09/957,187, filed Sep. 19, 2001; U.S. Ser. No. 09/538,092, filed Mar. 29, 2000, which claims priority to U.S. S No. 60/127,352, filed Apr. 1, 1999; U.S. Ser. No. 09/604,286, filed Jun. 22, 2000, which claims priority to U.S. S No. 60/140,584, filed Jun. 23, 1999; U.S. Ser. No. 09/898,994, filed Jul. 3, 2001, which claims priority to U.S. S No. 60/216,722, filed Jul. 7, 2000; U.S. Ser. No. 09/954,342, filed Sep. 17, 2001, which claims priority to U.S. S No. 60/233,798, filed Sep. 19, 2000; U.S. Ser. No. 09/995,514, filed Nov. 28, 2001, which claims priority to U.S. S No. 60/250,926, filed Nov. 30, 2000; U.S. Ser. No. 10/044,564, filed Jan. 11, 2002, which claims priority to U.S. S No. 60/261,018, filed Jan. 11, 2001; and U.S. Ser. No. 10/072,013, filed Feb. 8, 2002, which claims priority to U.S. S No. 60/265,395, filed Jan. 31, 2001 and U.S. S No. 60/266,767, filed Feb. 5, 2001; and this application claims priority to the following provisional patent applications: U.S. S No. 60/368,996, filed Apr. 1, 2002; U.S. S No. 60/369,980, filed Apr. 4, 2002; U.S. S No. 60/370,381, filed Apr. 5, 2002; U.S. S No. 60/370,969, filed Apr., 8, 2002; U.S. S No. 60/371,002, filed Apr. 9, 2002; U.S. S No. 60/372,002, filed Apr. 12, 2002; U.S. S No. 60/384,297, filed May 30, 2002; U.S. S No. 60/386,816, filed Jun. 7, 2002; U.S. S No. 60/389,123, filed Jun. 13, 2002; U.S. S No. 60/402,207, filed Aug. 9, 2002; and U.S. S No. 60/420,860, filed Oct. 24, 2002; each of which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

[0002] The present invention relates to novel polypeptides, and the nucleic acids encoding them, having properties related to stimulation of biochemical or physiological responses in a cell, a tissue, an organ or an organism. More particularly, the novel polypeptides are gene products of novel genes, or are specified biologically active fragments or derivatives thereof. Methods of use encompass diagnostic and prognostic assay procedures as well as methods of treating diverse pathological conditions.

BACKGROUND OF THE INVENTION

[0003] Eukaryotic cells are characterized by biochemical and physiological processes, which under normal conditions are exquisitely balanced to achieve the preservation and propagation of the cells. When such cells are components of multicellular organisms such as vertebrates or, more particularly, organisms such as mammals, the regulation of the biochemical and physiological processes involves intricate signaling pathways. Frequently, such signaling pathways involve extracellular signaling proteins, cellular receptors that bind the signaling proteins and signal transducing components located within the cells.

[0004] Signaling proteins may be classified as endocrine effectors, paracrine effectors or autocrine effectors. Endocrine effectors are signaling molecules secreted by a given organ into the circulatory system, which are then transported to a distant target organ or tissue. The target cells include the receptors for the endocrine effector, and when the endocrine effector binds, a signaling cascade is induced. Paracrine effectors involve secreting cells and receptor cells in close proximity to each other, for example, two different classes of cells in the same tissue or organ. One class of cells secretes the paracrine effector, which then reaches the second class of cells, for example by diffusion through the extracellular fluid. The second class of cells contains the receptors for the paracrine effector; binding of the effector results in induction of the signaling cascade that elicits the corresponding biochemical or physiological effect. Autocrine effectors are highly analogous to paracrine effectors, except that the same cell type that secretes the autocrine effector also contains the receptor. Thus the autocrine effector binds to receptors on the same cell, or on identical neighboring cells. The binding process then elicits the characteristic biochemical or physiological effect.

[0005] Signaling processes may elicit a variety of effects on cells and tissues including, by way of nonlimiting example, induction of cell or tissue proliferation, suppression of growth or proliferation, induction of differentiation or maturation of a cell or tissue, and suppression of differentiation or maturation of a cell or tissue.

[0006] Many pathological conditions involve dysregulation of expression of important effector proteins. In certain classes of pathologies the dysregulation is manifested as diminished or suppressed level of synthesis and secretion of protein effectors. In other classes of pathologies the dysregulation is manifested as increased or up-regulated level of synthesis and secretion of protein effectors. In a clinical setting a subject may be suspected of suffering from a condition brought on by altered or mis-regulated levels of a protein effector of interest. Therefore there is a need to assay for the level of the protein effector of interest in a biological sample from such a subject, and to compare the level with that characteristic of a nonpathological condition. There also is a need to provide the protein effector as a product of manufacture. Administration of the effector to a subject in need thereof is useful in treatment of the pathological condition. Accordingly, there is a need for a method of treatment of a pathological condition brought on by a diminished or suppressed levels of the protein effector of interest. In addition, there is a need for a method of treatment of a pathological condition brought on by a increased or up-regulated levels of the protein effector of interest.

[0007] Antibodies are multichain proteins that bind specifically to a given antigen, and bind poorly, or not at all, to substances deemed not to be cognate antigens. Antibodies are comprised of two short chains termed light chains and two long chains termed heavy chains. These chains are constituted of immunoglobulin domains, of which generally there are two classes: one variable domain per chain, one constant domain in light chains, and three or more constant domains in heavy chains. The antigen-specific portion of the immunoglobulin molecules resides in the variable domains; the variable domains of one light chain and one heavy chain associate with each other to generate the antigen-binding moiety. Antibodies that bind immunospecifically to a cognate or target antigen bind with high affinities. Accordingly, they are useful in assaying specifically for the presence of the antigen in a sample. In addition, they have the potential of inactivating the activity of the antigen.

[0008] Therefore there is a need to assay for the level of a protein effector of interest in a biological sample from such a subject, and to compare this level with that characteristic of a nonpathological condition. In particular, there is a need for such an assay based on the use of an antibody that binds immunospecifically to the antigen. There further is a need to inhibit the activity of the protein effector in cases where a pathological condition arises from elevated or excessive levels of the effector based on the use of an antibody that binds immunospecifically to the effector. Thus, there is a need for the antibody as a product of manufacture. There further is a need for a method of treatment of a pathological condition brought on by an elevated or excessive level of the protein effector of interest based on administering the antibody to the subject.

SUMMARY OF THE INVENTION

[0009] The invention is based in part upon the discovery of isolated polypeptides including amino acid sequences selected from mature forms of the amino acid sequences selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 64. The novel nucleic acids and polypeptides are referred to herein as NOVX, or NOV1, NOV2, NOV3, etc., nucleic acids and polypeptides. These nucleic acids and polypeptides, as well as derivatives, homologs, analogs and fragments thereof, will hereinafter be collectively designated as “NOVX” nucleic acid or polypeptide sequences.

[0010] The invention also is based in part upon variants of a mature form of the amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 64, wherein any amino acid in the mature form is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence of the mature form are so changed. In another embodiment, the invention includes the amino acid sequences selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 64. In another embodiment, the invention also comprises variants of the amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 64, wherein any amino acid specified in the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence are so changed. The invention also involves fragments of any of the mature forms of the amino acid sequences selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 64, or any other amino acid sequence selected from this group. The invention also comprises fragments from these groups in which up to 15% of the residues are changed.

[0011] In another embodiment, the invention encompasses polypeptides that are naturally occurring allelic variants of the sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 64. These allelic variants include amino acid sequences that are the translations of nucleic acid sequences differing by a single nucleotide from nucleic acid sequences selected from the group consisting of SEQ ID NOS: 2n-1, wherein n is an integer between 1 and 64. The variant polypeptide where any amino acid changed in the chosen sequence is changed to provide a conservative substitution.

[0012] In another embodiment, the invention comprises a pharmaceutical composition involving a polypeptide with an amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 64, and a pharmaceutically acceptable carrier. In another embodiment, the invention involves a kit, including, in one or more containers, this pharmaceutical composition.

[0013] In another embodiment, the invention includes the use of a therapeutic in the manufacture of a medicament for treating a syndrome associated with a human disease, the disease being selected from a pathology associated with a polypeptide with an amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 64, wherein said therapeutic is the polypeptide selected from this group.

[0014] In another embodiment, the invention comprises a method for determining the presence or amount of a polypeptide with an amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 64, in a sample, the method involving providing the sample; introducing the sample to an antibody that binds immunospecifically to the polypeptide; and determining the presence or amount of antibody bound to the polypeptide, thereby determining the presence or amount of polypeptide in the sample.

[0015] In another embodiment, the invention includes a method for determining the presence of or predisposition to a disease associated with altered levels of a polypeptide with an amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 64, in a first mammalian subject, the method involving measuring the level of expression of the polypeptide in a sample from the first mammalian subject; and comparing the amount of the polypeptide in this sample to the amount of the polypeptide present in a control sample from a second mammalian subject known not to have, or not to be predisposed to, the disease, wherein an alteration in the expression level of the polypeptide in the first subject as compared to the control sample indicates the presence of or predisposition to the disease.

[0016] In another embodiment, the invention involves a method of identifying an agent that binds to a polypeptide with an amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 64, the method including introducing the polypeptide to the agent; and determining whether the agent binds to the polypeptide. The agent could be a cellular receptor or a downstream effector.

[0017] In another embodiment, the invention involves a method for identifying a potential therapeutic agent for use in treatment of a pathology, wherein the pathology is related to aberrant expression or aberrant physiological interactions of a polypeptide with an amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 64, the method including providing a cell expressing the polypeptide of the invention and having a property or function ascribable to the polypeptide; contacting the cell with a composition comprising a candidate substance; and determining whether the substance alters the property or function ascribable to the polypeptide; whereby, if an alteration observed in the presence of the substance is not observed when the cell is contacted with a composition devoid of the substance, the substance is identified as a potential therapeutic agent.

[0018] In another embodiment, the invention involves a method for screening for a modulator of activity or of latency or predisposition to a pathology associated with a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 64, the method including administering a test compound to a test animal at increased risk for a pathology associated with the polypeptide of the invention, wherein the test animal recombinantly expresses the polypeptide of the invention; measuring the activity of the polypeptide in the test animal after administering the test compound; and comparing the activity of the protein in the test animal with the activity of the polypeptide in a control animal not administered the polypeptide, wherein a change in the activity of the polypeptide in the test animal relative to the control animal indicates the test compound is a modulator of latency of, or predisposition to, a pathology associated with the polypeptide of the invention. The recombinant test animal could express a test protein transgene or express the transgene under the control of a promoter at an increased level relative to a wild-type test animal The promoter may or may not b the native gene promoter of the transgene.

[0019] In another embodiment, the invention involves a method for modulating the activity of a polypeptide with an amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 64, the method including introducing a cell sample expressing the polypeptide with a compound that binds to the polypeptide in an amount sufficient to modulate the activity of the polypeptide.

[0020] In another embodiment, the invention involves a method of treating or preventing a pathology associated with a polypeptide with an amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 64, the method including administering the polypeptide to a subject in which such treatment or prevention is desired in an amount sufficient to treat or prevent the pathology in the subject. The subject could be human.

[0021] In another embodiment, the invention involves a method of treating a pathological state in a mammal, the method including administering to the mammal a polypeptide in an amount that is sufficient to alleviate the pathological state, wherein the polypeptide is a polypeptide having an amino acid sequence at least 95% identical to a polypeptide having the amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 64, or a biologically active fragment thereof.

[0022] In another embodiment, the invention involves an isolated nucleic acid molecule comprising a nucleic acid sequence encoding a polypeptide having an amino acid sequence selected from the group consisting of a mature form of the amino acid sequence given SEQ ID NO:2n, wherein n is an integer between 1 and 64, a variant of a mature form of the amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 64, wherein any amino acid in the mature form of the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence of the mature form are so changed; the amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 64, a variant of the amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 64, in which any amino acid specified in the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence are so changed; a nucleic acid fragment encoding at least a portion of a polypeptide comprising the amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 64, or any variant of the polypeptide wherein any amino acid of the chosen sequence is changed to a different amino acid, provided that no more than 10% of the amino acid residues in the sequence are so changed; and the complement of any of the nucleic acid molecules.

[0023] In another embodiment, the invention comprises an isolated nucleic acid molecule having a nucleic acid sequence encoding a polypeptide comprising an amino acid sequence selected from the group consisting of a mature form of the amino acid sequence given SEQ ID NO:2n, wherein n is an integer between 1 and 64, wherein the nucleic acid molecule comprises the nucleotide sequence of a naturally occurring allelic nucleic acid variant.

[0024] In another embodiment, the invention involves an isolated nucleic acid molecule including a nucleic acid sequence encoding a polypeptide having an amino acid sequence selected from the group consisting of a mature form of the amino acid sequence given SEQ ID NO:2n, wherein n is an integer between 1 and 64, that encodes a variant polypeptide, wherein the variant polypeptide has the polypeptide sequence of a naturally occurring polypeptide variant.

[0025] In another embodiment, the invention comprises an isolated nucleic acid molecule having a nucleic acid sequence encoding a polypeptide comprising an amino acid sequence selected from the group consisting of a mature form of the amino acid sequence given SEQ ID NO:2n, wherein n is an integer between 1 and 64, wherein the nucleic acid molecule differs by a single nucleotide from a nucleic acid sequence selected from the group consisting of SEQ ID NOS: 2n-1, wherein n is an integer between 1 and 64.

[0026] In another embodiment, the invention includes an isolated nucleic acid molecule having a nucleic acid sequence encoding a polypeptide including an amino acid sequence selected from the group consisting of a mature form of the amino acid sequence given SEQ ID NO:2n, wherein n is an integer between 1 and 64, wherein the nucleic acid molecule comprises a nucleotide sequence selected from the group consisting of the nucleotide sequence selected from the group consisting of SEQ ID NO:2n-1, wherein n is an integer between 1 and 64, a nucleotide sequence wherein one or more nucleotides in the nucleotide sequence selected from the group consisting of SEQ ID NO:2n-1, wherein n is an integer between 1 and 64, is changed from that selected from the group consisting of the chosen sequence to a different nucleotide provided that no more than 15% of the nucleotides are so changed; a nucleic acid fragment of the sequence selected from the group consisting of SEQ ID NO:2n-1, wherein n is an integer between 1 and 64, and a nucleic acid fragment wherein one or more nucleotides in the nucleotide sequence selected from the group consisting of SEQ ID NO:2n-1, wherein n is an integer between 1 and 64, is changed from that selected from the group consisting of the chosen sequence to a different nucleotide provided that no more than 15% of the nucleotides are so changed.

[0027] In another embodiment, the invention includes an isolated nucleic acid molecule having a nucleic acid sequence encoding a polypeptide including an amino acid sequence selected from the group consisting of a mature form of the amino acid sequence given SEQ ID NO:2n, wherein n is an integer between 1 and 64, wherein the nucleic acid molecule hybridizes under stringent conditions to the nucleotide sequence selected from the group consisting of SEQ ID NO:2n-1, wherein n is an integer between 1 and 64, or a complement of the nucleotide sequence.

[0028] In another embodiment, the invention includes an isolated nucleic acid molecule having a nucleic acid sequence encoding a polypeptide including an amino acid sequence selected from the group consisting of a mature form of the amino acid sequence given SEQ ID NO:2n, wherein n is an integer between 1 and 64, wherein the nucleic acid molecule has a nucleotide sequence in which any nucleotide specified in the coding sequence of the chosen nucleotide sequence is changed from that selected from the group consisting of the chosen sequence to a different nucleotide provided that no more than 15% of the nucleotides in the chosen coding sequence are so changed, an isolated second polynucleotide that is a complement of the first polynucleotide, or a fragment of any of them.

[0029] In another embodiment, the invention includes a vector involving the nucleic acid molecule having a nucleic acid sequence encoding a polypeptide including an amino acid sequence selected from the group consisting of a mature form of the amino acid sequence given SEQ ID NO:2n, wherein n is an integer between 1 and 64. This vector can have a promoter operably linked to the nucleic acid molecule. This vector can be located within a cell.

[0030] In another embodiment, the invention involves a method for determining the presence or amount of a nucleic acid molecule having a nucleic acid sequence encoding a polypeptide including an amino acid sequence selected from the group consisting of a mature form of the amino acid sequence given SEQ ID NO:2n, wherein n is an integer between 1 and 64, in a sample, the method including providing the sample; introducing the sample to a probe that binds to the nucleic acid molecule; and determining the presence or amount of the probe bound to the nucleic acid molecule, thereby determining the presence or amount of the nucleic acid molecule in the sample. The presence or amount of the nucleic acid molecule is used as a marker for cell or tissue type. The cell type can be cancerous.

[0031] In another embodiment, the invention involves a method for determining the presence of or predisposition for a disease associated with altered levels of a nucleic acid molecule having a nucleic acid sequence encoding a polypeptide including an amino acid sequence selected from the group consisting of a mature form of the amino acid sequence given SEQ ID NO:2n, wherein n is an integer between 1 and 64, in a first mammalian subject, the method including measuring the amount of the nucleic acid in a sample from the first mammalian subject; and comparing the amount of the nucleic acid in the sample of step (a) to the amount of the nucleic acid present in a control sample from a second mammalian subject known not to have or not be predisposed to, the disease; wherein an alteration in the level of the nucleic acid in the first subject as compared to the control sample indicates the presence of or predisposition to the disease.

[0032] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting.

[0033] Other features and advantages of the invention will be apparent from the following detailed description and claims.

DETAILED DESCRIPTION OF THE INVENTION

[0034] The present invention provides novel nucleotides and polypeptides encoded thereby. Included in the invention are the novel nucleic acid sequences, their encoded polypeptides, antibodies, and other related compounds. The sequences are collectively referred to herein as “NOVX nucleic acids” or “NOVX polynucleotides” and the corresponding encoded polypeptides are referred to as “NOVX polypeptides” or “NOVX proteins.” Unless indicated otherwise, “NOVX” is meant to refer to any of the novel sequences disclosed herein. Table A provides a summary of the NOVX nucleic acids and their encoded polypeptides. 1 TABLE A Sequences and Corresponding SEQ ID Numbers SEQ ID SEQ ID NO NO NOVX Internal (nucleic (amino Assignment Identification acid) acid) Homology NOV1a CG50907-03 1 2 Human extracellular matrix and cell adhesion molecule-4 (XMAD-4) - Homo sapiens NOV1b CG50907-04 3 4 Human extracellular matrix and cell adhesion molecule-4 (XMAD-4) - Homo sapiens NOV1c CG50907-02 5 6 Human extracellular matrix and cell adhesion molecule-4 (XMAD-4) - Homo sapiens NOV1d 170645595 7 8 Human extracellular matrix and cell adhesion molecule-4 (XMAD-4) - Homo sapiens NOV1e 170645599 9 10 Human extracellular matrix and cell adhesion molecule-4 (XMAD-4) - Homo sapiens NOV1f CG50907-01 11 12 Human extracellular matrix and cell adhesion molecule-4 (XMAD-4) - Homo sapiens NOV2a CG51896-04 13 14 Human semaphorin 6A-1 - Homo sapiens NOV2b 271674560 15 16 Human semaphorin 6A-1 - Homo sapiens NOV2c 267441133 17 18 Human semaphorin 6A-1 - Homo sapiens NOV2d 267441137 19 20 Human semaphorin 6A-1 - Homo sapiens NOV2e 262254987 21 22 Human semaphorin 6A-1 - Homo sapiens NOV2f 260565761 23 24 Human semaphorin 6A-1 - Homo sapiens NOV2g 252324008 25 26 Human semaphorin 6A-1 - Homo sapiens NOV2h 252323542 27 28 Human semaphorin 6A-1 - Homo sapiens NOV2i 252323483 29 30 Human semaphorin 6A-1 - Homo sapiens NOV2j CG51896-01 31 32 Human semaphorin 6A-1 - Homo sapiens NOV2k CG51896-02 33 34 Human semaphorin 6A-1 - Homo sapiens NOV2l CG51896-03 35 36 Human semaphorin 6A-1 - Homo sapiens NOV2m CG51896-05 37 38 Human semaphorin 6A-1 - Homo sapiens NOV2n CG51896-06 39 40 Human semaphorin 6A-1 - Homo sapiens NOV2o CG51896-07 41 42 Human semaphorin 6A-1 - Homo sapiens NOV2p CG51896-08 43 44 Human semaphorin 6A-1 - Homo sapiens NOV2q CG51896-09 45 46 Human semaphorin 6A-1 - Homo sapiens NOV2r CG51896-10 47 48 Human semaphorin 6A-1 - Homo sapiens NOV2s CG51896-11 49 50 Human semaphorin 6A-1 - Homo sapiens NOV2t CG51896-12 51 52 Human semaphorin 6A-1 - Homo sapiens NOV2u CG51896-13 53 54 Human semaphorin 6A-1 - Homo sapiens NOV2v CG51896-14 55 56 Human semaphorin 6A-1 - Homo sapiens NOV3a CG52324-01 57 58 Phosphatidylethanolamine binding protein - Homo sapiens NOV3b 249357821 59 60 Phosphatidylethanolamine binding protein - Homo sapiens NOV3c 249357798 61 62 Phosphatidylethanolamine binding protein - Homo sapiens NOV3d 248644954 63 64 Phosphatidylethanolamine binding protein - Homo sapiens NOV3e 248644962 65 66 Phosphatidylethanolamine binding protein - Homo sapiens NOV3f 248645004 67 68 Phosphatidylethanolamine binding protein - Homo sapiens NOV3g 249420987 69 70 Phosphatidylethanolamine binding protein - Homo sapiens NOV3h 248486005 71 72 Phosphatidylethanolamine binding protein - Homo sapiens NOV3i 249421046 73 74 Phosphatidylethanolamine binding protein - Homo sapiens NOV3j CG52324-02 75 76 Phosphatidylethanolamine binding protein - Homo sapiens NOV3k CG52324-03 77 78 Phosphatidylethanolamine binding protein - Homo sapiens NOV4a CG53054-02 79 80 WNT-14 protein precursor - Homo sapiens NOV4b 170251039 81 82 WNT-14 protein precursor - Homo sapiens NOV4c 170251076 83 84 WNT-14 protein precursor - Homo sapiens NOV4d CG53054-01 85 86 WNT-14 protein precursor - Homo sapiens NOV4e CG53054-03 87 88 WNT-14 protein precursor - Homo sapiens NOV4f CG53054-04 89 90 WNT-14 protein precursor - Homo sapiens NOV5a CG54818-01 91 92 Semaphorin 3E precursor - Homo sapiens NOV5b CG54818-02 93 94 Semaphorin 3E precursor - Homo sapiens NOV5c CG54818-03 95 96 Semaphorin 3E precursor - Homo sapiens NOV5d CG54818-04 97 98 Semaphorin 3E precursor - Homo sapiens NOV6a CG55023-01 99 100 Epigen protein precursor - Mus musculus NOV6b 248209521 101 102 Epigen protein precursor - Mus musculus NOV6c 317459649 103 104 Epigen protein precursor - Mus musculus NOV6d 317459665 105 106 Epigen protein precursor - Mus musculus NOV6e 317459901 107 108 Epigen protein precursor - Mus musculus NOV6f 317459910 109 110 Epigen protein precursor - Mus musculus NOV6g CG55023-02 111 112 Epigen protein precursor - Mus musculus NOV6h CG55023-03 113 114 Epigen protein precursor - Mus musculus NOV6i CG55023-04 115 116 Epigen protein precursor - Mus musculus NOV6j CG55023-05 117 118 Epigen protein precursor - Mus musculus NOV6k CG55023-06 119 120 Epigen protein precursor - Mus musculus NOV7a CG56136-01 121 122 Interleukin 1 family member 6 (IL-1F6) (Interleukin-1 epsilon) (IL-1 epsilon) (FIL1 epsilon) - Homo sapiens NOV7b CG56136-02 123 124 Interleukin 1 family member 6 (IL-1F6) (Interleukin-1 epsilon) (IL-1 epsilon) (FIL1 epsilon) - Homo sapiens NOV7c CG56136-03 125 126 Interleukin 1 family member 6 (IL-1F6) (Interleukin-1 epsilon) (IL-1 epsilon) (FIL1 epsilon) - Homo sapiens NOV7d CG56136-04 127 128 Interleukin 1 family member 6 (IL-1F6) (Interleukin-1 epsilon) (IL-1 epsilon) (FIL1 epsilon) - Homo sapiens

[0035] Table A indicates the homology of NOVX polypeptides to known protein families. Thus, the nucleic acids and polypeptides, antibodies and related compounds according to the invention corresponding to a NOVX as identified in column 1 of Table A will be useful in therapeutic and diagnostic applications implicated in, for example, pathologies and disorders associated with the known protein families identified in column 5 of Table A.

[0036] Pathologies, diseases, disorders, conditions and the like that are associated with NOVX sequences include, but are not limited to, e.g., cardiomyopathy, atherosclerosis, hypertension, congenital heart defects, aortic stenosis, atrial septal defect (ASD), atrioventricular (A-V) canal defect, ductus arteriosus, pulmonary stenosis, subaortic stenosis, ventricular septal defect (VSD), valve diseases, tuberous sclerosis, scleroderma, obesity, metabolic disturbances associated with obesity, transplantation, adrenoleukodystrophy, congenital adrenal hyperplasia, prostate cancer, diabetes, metabolic disorders, neoplasm; adenocarcinoma, lymphoma, uterus cancer, fertility, hemophilia, hypercoagulation, idiopathic thrombocytopenic purpura, immunodeficiencies, graft versus host disease, AIDS, bronchial asthma, Crohn's disease; multiple sclerosis, treatment of Albright Hereditary Ostoeodystrophy, infectious disease, anorexia, cancer-associated cachexia, cancer, neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders, hematopoietic disorders, and the various dyslipidemias, the metabolic syndrome X and wasting disorders associated with chronic diseases and various cancers, as well as conditions such as transplantation and fertility.

[0037] NOVX nucleic acids and their encoded polypeptides are useful in a variety of applications and contexts. The various NOVX nucleic acids and polypeptides according to the invention are useful as novel members of the protein families according to the presence of domains and sequence relatedness to previously described proteins. Additionally, NOVX nucleic acids and polypeptides can also be used to identify proteins that are members of the family to which the NOVX polypeptides belong.

[0038] Consistent with other known members of the family of proteins, identified in column 5 of Table A, the NOVX polypeptides of the present invention show homology to, and contain domains that are characteristic of, other members of such protein families. Details of the sequence relatedness and domain analysis for each NOVX are presented in Example A.

[0039] The NOVX nucleic acids and polypeptides can also be used to screen for molecules, which inhibit or enhance NOVX activity or function. Specifically, the nucleic acids and polypeptides according to the invention may be used as targets for the identification of small molecules that modulate or inhibit diseases associated with the protein families listed in Table A.

[0040] The NOVX nucleic acids and polypeptides are also useful for detecting specific cell types. Details of the expression analysis for each NOVX are presented in Example C. Accordingly, the NOVX nucleic acids, polypeptides, antibodies and related compounds according to the invention will have diagnostic and therapeutic applications in the detection of a variety of diseases with differential expression in normal vs. diseased tissues, e.g., detection of a variety of cancers.

[0041] Additional utilities for NOVX nucleic acids and polypeptides according to the invention are disclosed herein.

[0042] NOVX Clones

[0043] NOVX nucleic acids and their encoded polypeptides are useful in a variety of applications and contexts. The various NOVX nucleic acids and polypeptides according to the invention are useful as novel members of the protein families according to the presence of domains and sequence relatedness to previously described proteins. Additionally, NOVX nucleic acids and polypeptides can also be used to identify proteins that are members of the family to which the NOVX polypeptides belong.

[0044] The NOVX genes and their corresponding encoded proteins are useful for preventing, treating or ameliorating medical conditions, e.g., by protein or gene therapy. Pathological conditions can be diagnosed by determining the amount of the new protein in a sample or by determining the presence of mutations in the new genes. Specific uses are described for each of the NOVX genes, based on the tissues in which they are most highly expressed. Uses include developing products for the diagnosis or treatment of a variety of diseases and disorders.

[0045] The NOVX nucleic acids and proteins of the invention are useful in potential diagnostic and therapeutic applications and as a research tool. These include serving as a specific or selective nucleic acid or protein diagnostic and/or prognostic marker, wherein the presence or amount of the nucleic acid or the protein are to be assessed, as well as potential therapeutic applications such as the following: (i) a protein therapeutic, (ii) a small molecule drug target, (iii) an antibody target (therapeutic, diagnostic, drug targeting/cytotoxic antibody), (iv) a nucleic acid useful in gene therapy (gene delivery/gene ablation), and (v) a composition promoting tissue regeneration in vitro and in vivo (vi) a biological defense weapon.

[0046] In one specific embodiment, the invention includes an isolated polypeptide comprising an amino acid sequence selected from the group consisting of: (a) a mature form of the amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 64, (b) a variant of a mature form of the amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 64, wherein any amino acid in the mature form is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence of the mature form are so changed; (c) an amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 64, (d) a variant of the amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 64, wherein any amino acid specified in the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence are so changed; and (e) a fragment of any of (a) through (d).

[0047] In another specific embodiment, the invention includes an isolated nucleic acid molecule comprising a nucleic acid sequence encoding a polypeptide comprising an amino acid sequence selected from the group consisting of: (a) a mature form of the amino acid sequence given SEQ ID NO:2n, wherein n is an integer between 1 and 64; (b) a variant of a mature form of the amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 64, wherein any amino acid in the mature form of the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence of the mature form are so changed; (c) the amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 64; (d) a variant of the amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 64, in which any amino acid specified in the chosen sequence is changed to a different amino acid, provided that no more than 15% of the amino acid residues in the sequence are so changed; (e) a nucleic acid fragment encoding at least a portion of a polypeptide comprising the amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 64, or any variant of said polypeptide wherein any amino acid of the chosen sequence is changed to a different amino acid, provided that no more than 10% of the amino acid residues in the sequence are so changed; and (f) the complement of any of said nucleic acid molecules.

[0048] In yet another specific embodiment, the invention includes an isolated nucleic acid molecule, wherein said nucleic acid molecule comprises a nucleotide sequence selected from the group consisting of: (a) the nucleotide sequence selected from the group consisting of SEQ ID NO:2n-1, wherein n is an integer between 1 and 64; (b) a nucleotide sequence wherein one or more nucleotides in the nucleotide sequence selected from the group consisting of SEQ ID NO:2n-1, wherein n is an integer between 1 and 64, is changed from that selected from the group consisting of the chosen sequence to a different nucleotide provided that no more than 15% of the nucleotides are so changed; (c) a nucleic acid fragment of the sequence selected from the group consisting of SEQ ID NO:2n-1, wherein n is an integer between 1 and 64; and (d) a nucleic acid fragment wherein one or more nucleotides in the nucleotide sequence selected from the group consisting of SEQ ID NO:2n-1, wherein n is an integer between 1 and 64, is changed from that selected from the group consisting of the chosen sequence to a different nucleotide provided that no more than 15% of the nucleotides are so changed.

[0049] NOVX Nucleic Acids and Polypeptides

[0050] One aspect of the invention pertains to isolated nucleic acid molecules that encode NOVX polypeptides or biologically active portions thereof. Also included in the invention are nucleic acid fragments sufficient for use as hybridization probes to identify NOVX-encoding nucleic acids (e.g., NOVX mRNAs) and fragments for use as PCR primers for the amplification and/or mutation of NOVX nucleic acid molecules. As used herein, the term “nucleic acid molecule” is intended to include DNA molecules (e.g., cDNA or genomic DNA), RNA molecules (e.g., mRNA), analogs of the DNA or RNA generated using nucleotide analogs, and derivatives, fragments and homologs thereof. The nucleic acid molecule may be single-stranded or double-stranded, but preferably is comprised double-stranded DNA.

[0051] A NOVX nucleic acid can encode a mature NOVX polypeptide. As used herein, a “mature” form of a polypeptide or protein disclosed in the present invention is the product of a naturally occurring polypeptide, precursor form, or proprotein. The naturally occurring polypeptide, precursor or proprotein includes, by way of nonlimiting example, the full-length gene product encoded by the corresponding gene. Alternatively, it may be defined as the polypeptide, precursor or proprotein encoded by an ORF described herein. The product “mature” form arises, by way of nonlimiting example, as a result of one or more naturally occurring processing steps that may take place within the cell (e.g., host cell) in which the gene product arises. Examples of such processing steps leading to a “mature” form of a polypeptide or protein include the cleavage of the N-terminal methionine residue encoded by the initiation codon of an ORF or the proteolytic cleavage of a signal peptide or leader sequence. Thus a mature form arising from a precursor polypeptide or protein that has residues 1 to N, where residue 1 is the N-terminal methionine, would have residues 2 through N remaining after removal of the N-terminal methionine. Alternatively, a mature form arising from a precursor polypeptide or protein having residues 1 to N, in which an N-terminal signal sequence from residue 1 to residue M is cleaved, would have the residues from residue M+1 to residue N remaining. Further as used herein, a “mature” form of a polypeptide or protein may arise from a post-translational modification step other than a proteolytic cleavage event. Such additional processes include, by way of non-limiting example, glycosylation, myristylation or phosphorylation. In general, a mature polypeptide or protein may result from the operation of only one of these processes, or a combination of any of them.

[0052] The term “probe”, as utilized herein, refers to nucleic acid sequences of variable length, preferably between at least about 10 nucleotides (nt), about 100 nt, or as many as approximately, e.g., 6,000 nt, depending upon the specific use. Probes are used in the detection of identical, similar, or complementary nucleic acid sequences. Longer length probes are generally obtained from a natural or recombinant source, are highly specific, and much slower to hybridize than shorter-length oligomer probes. Probes may be single- or double-stranded and designed to have specificity in PCR, membrane-based hybridization technologies, or ELISA-like technologies.

[0053] The term “isolated” nucleic acid molecule, as used herein, is a nucleic acid that is separated from other nucleic acid molecules which are present in the natural source of the nucleic acid. Preferably, an “isolated” nucleic acid is free of sequences which naturally flank the nucleic acid (i.e., sequences located at the 5′- and 3′-termini of the nucleic acid) in the genomic DNA of the organism from which the nucleic acid is derived. For example, in various embodiments, the isolated NOVX nucleic acid molecules can contain less than about 5 kb, about 4 kb, about 3 kb, about 2 kb, about 1 kb, about 0.5 kb, or about 0.1 kb, of nucleotide sequences which naturally flank the nucleic acid molecule in genomic DNA of the cell/tissue from which the nucleic acid is derived (e.g., brain, heart, liver, spleen, etc.). Moreover, an “isolated” nucleic acid molecule, such as a cDNA molecule, can be substantially free of other cellular material, or culture medium, or of chemical precursors or other chemicals.

[0054] A nucleic acid molecule of the invention, e.g., a nucleic acid molecule having the nucleotide sequence of SEQ ID NOS: 2n-1, wherein n is an integer between 1 and 64, or a complement of this nucleotide sequence, can be isolated using standard molecular biology techniques and the sequence information provided herein. Using all or a portion of the nucleic acid sequence of SEQ ID NOS:2n-1, wherein n is an integer between 1 and 64, as a hybridization probe, NOVX molecules can be isolated using standard hybridization and cloning techniques (e.g., as described in Sambrook, et al., (eds.), MOLECULAR CLONING: A LABORATORY MANUAL 2nd Ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989; and Ausubel, et al., (eds.), CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, New York, N.Y., 1993).

[0055] A nucleic acid of the invention can be amplified using cDNA, mRNA or, alternatively, genomic DNA as a template with appropriate oligonucleotide primers according to standard PCR amplification techniques. The nucleic acid so amplified can be cloned into an appropriate vector and characterized by DNA sequence analysis. Furthermore, oligonucleotides corresponding to NOVX nucleotide sequences can be prepared by standard synthetic techniques, e.g., using an automated DNA synthesizer.

[0056] As used herein, the term “oligonucleotide” refers to a series of linked nucleotide residues. A short oligonucleotide sequence may be based on, or designed from, a genomic or cDNA sequence and is used to amplify, confirm, or reveal the presence of an identical, similar or complementary DNA or RNA in a particular cell or tissue. Oligonucleotides comprise a nucleic acid sequence having about 10 nt, 50 nt, or 100 nt in length, preferably about 15 nt to 30 nt in length. In one embodiment of the invention, an oligonucleotide comprising a nucleic acid molecule less than 100 nt in length would further comprise at least 6 contiguous nucleotides of SEQ ID NOS:2n-1, wherein n is an integer between 1 and 64, or a complement thereof. Oligonucleotides may be chemically synthesized and may also be used as probes.

[0057] In another embodiment, an isolated nucleic acid molecule of the invention comprises a nucleic acid molecule that is a complement of the nucleotide sequence shown in SEQ ID NOS:2n-1, wherein n is an integer between 1 and 64, or a portion of this nucleotide sequence (e.g., a fragment that can be used as a probe or primer or a fragment encoding a biologically-active portion of a NOVX polypeptide). A nucleic acid molecule that is complementary to the nucleotide sequence of SEQ ID NOS:2n-1, wherein n is an integer between 1 and 64, is one that is sufficiently complementary to the nucleotide sequence of SEQ ID NOS:2n-1, wherein n is an integer between 1 and 64, that it can hydrogen bond with few or no mismatches to a nucleotide sequence of SEQ ID NOS:2n-1, wherein n is an integer between 1 and 64, thereby forming a stable duplex.

[0058] As used herein, the term “complementary” refers to Watson-Crick or Hoogsteen base pairing between nucleotides units of a nucleic acid molecule, and the term “binding” means the physical or chemical interaction between two polypeptides or compounds or associated polypeptides or compounds or combinations thereof. Binding includes ionic, non-ionic, van der Waals, hydrophobic interactions, and the like. A physical interaction can be either direct or indirect. Indirect interactions may be through or due to the effects of another polypeptide or compound. Direct binding refers to interactions that do not take place through, or due to, the effect of another polypeptide or compound, but instead are without other substantial chemical intermediates.

[0059] A “fragment” provided herein is defined as a sequence of at least 6 (contiguous) nucleic acids or at least 4 (contiguous) amino acids, a length sufficient to allow for specific hybridization in the case of nucleic acids or for specific recognition of an epitope in the case of amino acids, and is at most some portion less than a full length sequence. Fragments may be derived from any contiguous portion of a nucleic acid or amino acid sequence of choice.

[0060] A full-length NOVX clone is identified as containing an ATG translation start codon and an in-frame stop codon. Any disclosed NOVX nucleotide sequence lacking an ATG start codon therefore encodes a truncated C-terminal fragment of the respective NOVX polypeptide, and requires that the corresponding full-length cDNA extend in the 5′ direction of the disclosed sequence. Any disclosed NOVX nucleotide sequence lacking an in-frame stop codon similarly encodes a truncated N-terminal fragment of the respective NOVX polypeptide, and requires that the corresponding full-length cDNA extend in the 3′ direction of the disclosed sequence.

[0061] A “derivative” is a nucleic acid sequence or amino acid sequence formed from the native compounds either directly, by modification or partial substitution. An “analog” is a nucleic acid sequence or amino acid sequence that has a structure similar to, but not identical to, the native compound, e.g. they differs from it in respect to certain components or side chains. Analogs may be synthetic or derived from a different evolutionary origin and may have a similar or opposite metabolic activity compared to wild type. A “homolog” is a nucleic acid sequence or amino acid sequence of a particular gene that is derived from different species.

[0062] Derivatives and analogs may be full length or other than full length. Derivatives or analogs of the nucleic acids or proteins of the invention include, but are not limited to, molecules comprising regions that are substantially homologous to the nucleic acids or proteins of the invention, in various embodiments, by at least about 70%, 80%, or 95% identity (with a preferred identity of 80-95%) over a nucleic acid or amino acid sequence of identical size or when compared to an aligned sequence in which the alignment is done by a computer homology program known in the art, or whose encoding nucleic acid is capable of hybridizing to the complement of a sequence encoding the proteins under stringent, moderately stringent, or low stringent conditions. See e.g. Ausubel, et al., CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, New York, N.Y., 1993, and below.

[0063] A “homologous nucleic acid sequence” or “homologous amino acid sequence,” or variations thereof, refer to sequences characterized by a homology at the nucleotide level or amino acid level as discussed above. Homologous nucleotide sequences include those sequences coding for isoforms of NOVX polypeptides. Isoforms can be expressed in different tissues of the same organism as a result of, for example, alternative splicing of RNA. Alternatively, isoforms can be encoded by different genes. In the invention, homologous nucleotide sequences include nucleotide sequences encoding for a NOVX polypeptide of species other than humans, including, but not limited to: vertebrates, and thus can include, e.g., frog, mouse, rat, rabbit, dog, cat cow, horse, and other organisms. Homologous nucleotide sequences also include, but are not limited to, naturally occurring allelic variations and mutations of the nucleotide sequences set forth herein. A homologous nucleotide sequence does not, however, include the exact nucleotide sequence encoding human NOVX protein. Homologous nucleic acid sequences include those nucleic acid sequences that encode conservative amino acid substitutions (see below) in SEQ ID NO:2n-1, wherein n is an integer between 1 and 64, as well as a polypeptide possessing NOVX biological activity. Various biological activities of the NOVX proteins are described below.

[0064] A NOVX polypeptide is encoded by the open reading frame (“ORF”) of a NOVX nucleic acid. An ORF corresponds to a nucleotide sequence that could potentially be translated into a polypeptide. A stretch of nucleic acids comprising an ORF is uninterrupted by a stop codon. An ORF that represents the coding sequence for a full protein begins with an ATG “start” codon and terminates with one of the three “stop” codons, namely, TAA, TAG, or TGA. For the purposes of this invention, an ORF may be any part of a coding sequence, with or without a start codon, a stop codon, or both. For an ORF to be considered as a good candidate for coding for a bona fide cellular protein, a minimum size requirement is often set, e.g., a stretch of DNA that would encode a protein of 50 amino acids or more.

[0065] The nucleotide sequences determined from the cloning of the human NOVX genes allows for the generation of probes and primers designed for use in identifying and/or cloning NOVX homologues in other cell types, e.g. from other tissues, as well as NOVX homologues from other vertebrates. The probe/primer typically comprises substantially purified oligonucleotide. The oligonucleotide typically comprises a region of nucleotide sequence that hybridizes under stringent conditions to at least about 12, 25, 50, 100, 150, 200, 250, 300, 350 or 400 consecutive sense strand nucleotide sequence of SEQ ID NO:2n-1, wherein n is an integer between 1 and 64; or an anti-sense strand nucleotide sequence of SEQ ID NO:2n-1, wherein n is an integer between 1 and 64; or of a naturally occurring mutant of SEQ ID NO:2n-1, wherein n is an integer between 1 and 64.

[0066] Probes based on the human NOVX nucleotide sequences can be used to detect transcripts or genomic sequences encoding the same or homologous proteins. In various embodiments, the probe has a detectable label attached, e.g. the label can be a radioisotope, a fluorescent compound, an enzyme, or an enzyme co-factor. Such probes can be used as a part of a diagnostic test kit for identifying cells or tissues which mis-express a NOVX protein, such as by measuring a level of a NOVX-encoding nucleic acid in a sample of cells from a subject e.g., detecting NOVX mRNA levels or determining whether a genomic NOVX gene has been mutated or deleted.

[0067] “A polypeptide having a biologically-active portion of a NOVX polypeptide” refers to polypeptides exhibiting activity similar, but not necessarily identical to, an activity of a polypeptide of the invention, including mature forms, as measured in a particular biological assay, with or without dose dependency. A nucleic acid fragment encoding a “biologically-active portion of NOVX” can be prepared by isolating a portion of SEQ ID NO:2n-1, wherein n is an integer between 1 and 64, that encodes a polypeptide having a NOVX biological activity (the biological activities of the NOVX proteins are described below), expressing the encoded portion of NOVX protein (e.g., by recombinant expression in vitro) and assessing the activity of the encoded portion of NOVX.

[0068] NOVX Nucleic Acid and Polypeptide Variants

[0069] The invention further encompasses nucleic acid molecules that differ from the nucleotide sequences of SEQ ID NO:2n-1, wherein n is an integer between 1 and 64, due to degeneracy of the genetic code and thus encode the same NOVX proteins as that encoded by the nucleotide sequences of SEQ ID NO:2n-1, wherein n is an integer between 1 and 64. In another embodiment, an isolated nucleic acid molecule of the invention has a nucleotide sequence encoding a protein having an amino acid sequence of SEQ ID NO:2n, wherein n is an integer between 1 and 64.

[0070] In addition to the human NOVX nucleotide sequences of SEQ ID NO:2n-1, wherein n is an integer between 1 and 64, it will be appreciated by those skilled in the art that DNA sequence polymorphisms that lead to changes in the amino acid sequences of the NOVX polypeptides may exist within a population (e.g., the human population). Such genetic polymorphism in the NOVX genes may exist among individuals within a population due to natural allelic variation. As used herein, the terms “gene” and “recombinant gene” refer to nucleic acid molecules comprising an open reading frame (ORF) encoding a NOVX protein, preferably a vertebrate NOVX protein. Such natural allelic variations can typically result in 1-5% variance in the nucleotide sequence of the NOVX genes. Any and all such nucleotide variations and resulting amino acid polymorphisms in the NOVX polypeptides, which are the result of natural allelic variation and that do not alter the functional activity of the NOVX polypeptides, are intended to be within the scope of the invention.

[0071] Moreover, nucleic acid molecules encoding NOVX proteins from other species, and thus that have a nucleotide sequence that differs from a human SEQ ID NO:2n-1, wherein n is an integer between 1 and 64, are intended to be within the scope of the invention. Nucleic acid molecules corresponding to natural allelic variants and homologues of the NOVX cDNAs of the invention can be isolated based on their homology to the human NOVX nucleic acids disclosed herein using the human cDNAs, or a portion thereof, as a hybridization probe according to standard hybridization techniques under stringent hybridization conditions.

[0072] Accordingly, in another embodiment, an isolated nucleic acid molecule of the invention is at least 6 nucleotides in length and hybridizes under stringent conditions to the nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:2n-1, wherein n is an integer between 1 and 64. In another embodiment, the nucleic acid is at least 10, 25, 50, 100, 250, 500, 750, 1000, 1500, or 2000 or more nucleotides in length. In yet another embodiment, an isolated nucleic acid molecule of the invention hybridizes to the coding region. As used herein, the term “hybridizes under stringent conditions” is intended to describe conditions for hybridization and washing under which nucleotide sequences at least about 65% homologous to each other typically remain hybridized to each other.

[0073] Homologs (i.e., nucleic acids encoding NOVX proteins derived from species other than human) or other related sequences (e.g., paralogs) can be obtained by low, moderate or high stringency hybridization with all or a portion of the particular human sequence as a probe using methods well known in the art for nucleic acid hybridization and cloning.

[0074] As used herein, the phrase “stringent hybridization conditions” refers to conditions under which a probe, primer or oligonucleotide will hybridize to its target sequence, but to no other sequences. Stringent conditions are sequence-dependent and will be different in different circumstances. Longer sequences hybridize specifically at higher temperatures than shorter sequences. Generally, stringent conditions are selected to be about 5° C. lower than the thermal melting point (Tm) for the specific sequence at a defined ionic strength and pH. The Tm is the temperature (under defined ionic strength, pH and nucleic acid concentration) at which 50% of the probes complementary to the target sequence hybridize to the target sequence at equilibrium. Since the target sequences are generally present at excess, at Tm, 50% of the probes are occupied at equilibrium. Typically, stringent conditions will be those in which the salt concentration is less than about 1.0 M sodium ion, typically about 0.01 to 1.0 M sodium ion (or other salts) at pH 7.0 to 8.3 and the temperature is at least about 30° C. for short probes, primers or oligonucleotides (e.g., 10 nt to 50 nt) and at least about 60° C. for longer probes, primers and oligonucleotides. Stringent conditions may also be achieved with the addition of destabilizing agents, such as formamide.

[0075] Stringent conditions are known to those skilled in the art and can be found in Ausubel, et al., (eds.), CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, N.Y. (1989), 6.3.1-6.3.6. Preferably, the conditions are such that sequences at least about 65%, 70%, 75%, 85%, 90%, 95%, 98%, or 99% homologous to each other typically remain hybridized to each other. A non-limiting example of stringent hybridization conditions are hybridization in a high salt buffer comprising 6× SSC, 50 mM Tris-HCl (pH 7.5), 1 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.02% BSA, and 500 mg/ml denatured salmon sperm DNA at 65° C., followed by one or more washes in 0.2× SSC, 0.01% BSA at 50° C. An isolated nucleic acid molecule of the invention that hybridizes under stringent conditions to a sequence of SEQ ID NO:2n-1, wherein n is an integer between 1 and 64, corresponds to a naturally-occurring nucleic acid molecule. As used herein, a “naturally-occurring” nucleic acid molecule refers to an RNA or DNA molecule having a nucleotide sequence that occurs in nature (e.g., encodes a natural protein).

[0076] In a second embodiment, a nucleic acid sequence that is hybridizable to the nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:2n-1, wherein n is an integer between 1 and 64, or fragments, analogs or derivatives thereof, under conditions of moderate stringency is provided. A non-limiting example of moderate stringency hybridization conditions are hybridization in 6× SSC, 5× Reinhardt's solution, 0.5% SDS and 100 mg/ml denatured salmon sperm DNA at 55° C., followed by one or more washes in 1× SSC, 0.1% SDS at 37° C. Other conditions of moderate stringency that may be used are well-known within the art. See, e.g., Ausubel, et al. (eds.), 1993, CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, NY, and Krieger, 1990; GENE TRANSFER AND EXPRESSION, A LABORATORY MANUAL, Stockton Press, NY.

[0077] In a third embodiment, a nucleic acid that is hybridizable to the nucleic acid molecule comprising the nucleotide sequences of SEQ ID NO:2n-1, wherein n is an integer between 1 and 64, or fragments, analogs or derivatives thereof, under conditions of low stringency, is provided. A non-limiting example of low stringency hybridization conditions are hybridization in 35% formamide, 5× SSC, 50 mM Tris-HCl (pH 7.5), 5 mM EDTA, 0.02% PVP, 0.02% Ficoll, 0.2% BSA, 100 mg/ml denatured salmon sperm DNA, 10% (wt/vol) dextran sulfate at 40° C., followed by one or more washes in 2× SSC, 25 mM Tris-HCl (pH 7.4), 5 mM EDTA, and 0.1% SDS at 50° C. Other conditions of low stringency that may be used are well known in the art (e.g., as employed for cross-species hybridizations). See, e.g., Ausubel, et al. (eds.), 1993, CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, NY, and Kriegler, 1990, GENE TRANSFER AND EXPRESSION, A LABORATORY MANUAL, Stockton Press, NY; Shilo and Weinberg, 1981. Proc Natl Acad Sci USA 78: 6789-6792.

[0078] Conservative Mutations

[0079] In addition to naturally-occurring allelic variants of NOVX sequences that may exist in the population, the skilled artisan will further appreciate that changes can be introduced by mutation into the nucleotide sequences of SEQ ID NO:2n-1, wherein n is an integer between 1 and 64, thereby leading to changes in the amino acid sequences of the encoded NOVX protein, without altering the functional ability of that NOVX protein. For example, nucleotide substitutions leading to amino acid substitutions at “non-essential” amino acid residues can be made in the sequence of SEQ ID NO:2n, wherein n is an integer between 1 and 64. A “non-essential” amino acid residue is a residue that can be altered from the wild-type sequences of the NOVX proteins without altering their biological activity, whereas an “essential” amino acid residue is required for such biological activity. For example, amino acid residues that are conserved among the NOVX proteins of the invention are predicted to be particularly non-amenable to alteration. Amino acids for which conservative substitutions can be made are well-known within the art.

[0080] Another aspect of the invention pertains to nucleic acid molecules encoding NOVX proteins that contain changes in amino acid residues that are not essential for activity. Such NOVX proteins differ in amino acid sequence from SEQ ID NO:2n-1, wherein n is an integer between 1 and 64, yet retain biological activity. In one embodiment, the isolated nucleic acid molecule comprises a nucleotide sequence encoding a protein, wherein the protein comprises an amino acid sequence at least about 40% homologous to the amino acid sequences of SEQ ID NO:2n, wherein n is an integer between 1 and 64. Preferably, the protein encoded by the nucleic acid molecule is at least about 60% homologous to SEQ ID NO:2n, wherein n is an integer between 1 and 64; more preferably at least about 70% homologous to SEQ ID NO:2n, wherein n is an integer between 1 and 64; still more preferably at least about 80% homologous to SEQ ID NO:2n, wherein n is an integer between 1 and 64; even more preferably at least about 90% homologous to SEQ ID NO:2n, wherein n is an integer between 1 and 64; and most preferably at least about 95% homologous to SEQ ID NO:2n, wherein n is an integer between 1 and 64.

[0081] An isolated nucleic acid molecule encoding a NOVX protein homologous to the protein of SEQ ID NO:2n, wherein n is an integer between 1 and 64, can be created by introducing one or more nucleotide substitutions, additions or deletions into the nucleotide sequence of SEQ ID NO:2n-1, wherein n is an integer between 1 and 64, such that one or more amino acid substitutions, additions or deletions are introduced into the encoded protein.

[0082] Mutations can be introduced any one of SEQ ID NO:2n-1, wherein n is an integer between 1 and 64, by standard techniques, such as site-directed mutagenesis and PCR-mediated mutagenesis. Preferably, conservative amino acid substitutions are made at one or more predicted, non-essential amino acid residues. A “conservative amino acid substitution” is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined within the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Thus, a predicted non-essential amino acid residue in the NOVX protein is replaced with another amino acid residue from the same side chain family. Alternatively, in another embodiment, mutations can be introduced randomly along all or part of a NOVX coding sequence, such as by saturation mutagenesis, and the resultant mutants can be screened for NOVX biological activity to identify mutants that retain activity. Following mutagenesis of a nucleic acid of SEQ ID NO:2n-1, wherein n is an integer between 1 and 64, the encoded protein can be expressed by any recombinant technology known in the art and the activity of the protein can be determined.

[0083] The relatedness of amino acid families may also be determined based on side chain interactions. Substituted amino acids may be fully conserved “strong” residues or fully conserved “weak” residues. The “strong” group of conserved amino acid residues may be any one of the following groups: STA, NEQK, NHQK, NDEQ, QHRK, MILV, MILF, HY, FYW, wherein the single letter amino acid codes are grouped by those amino acids that may be substituted for each other. Likewise, the “weak” group of conserved residues may be any one of the following: CSA, ATV, SAG, STNK, STPA, SGND, SNDEQK, NDEQHK, NEQHRK, HFY, wherein the letters within each group represent the single letter amino acid code.

[0084] In one embodiment, a mutant NOVX protein can be assayed for (i) the ability to form protein:protein interactions with other NOVX proteins, other cell-surface proteins, or biologically-active portions thereof, (ii) complex formation between a mutant NOVX protein and a NOVX ligand; or (iii) the ability of a mutant NOVX protein to bind to an intracellular target protein or biologically-active portion thereof; (e.g. avidin proteins).

[0085] In yet another embodiment, a mutant NOVX protein can be assayed for the ability to regulate a specific biological function (e.g., regulation of insulin release).

[0086] Interfering RNA

[0087] In one aspect of the invention, NOVX gene expression can be attenuated by RNA interference. One approach well-known in the art is short interfering RNA (siRNA) mediated gene silencing where expression products of a NOVX gene are targeted by specific double stranded NOVX derived siRNA nucleotide sequences that are complementary to at least a 19-25 nt long segment of the NOVX gene transcript, including the 5′ untranslated (UT) region, the ORF, or the 3′ UT region. See, e.g., PCT applications WO00/44895, WO99/32619, WO01/75164, WO01/92513, WO01/29058, WO01/89304, WO02/16620, and WO02/29858, each incorporated by reference herein in their entirety. Targeted genes can be a NOVX gene, or an upstream or downstream modulator of the NOVX gene. Nonlimiting examples of upstream or downstream modulators of a NOVX gene include, e.g., a transcription factor that binds the NOVX gene promoter, a kinase or phosphatase that interacts with a NOVX polypeptide, and polypeptides involved in a NOVX regulatory pathway.

[0088] According to the methods of the present invention, NOVX gene expression is silenced using short interfering RNA. A NOVX polynucleotide according to the invention includes a siRNA polynucleotide. Such a NOVX siRNA can be obtained using a NOVX polynucleotide sequence, for example, by processing the NOVX ribopolynucleotide sequence in a cell-free system, such as but not limited to a Drosophila extract, or by transcription of recombinant double stranded NOVX RNA or by chemical synthesis of nucleotide sequences homologous to a NOVX sequence. See, e.g., Tuschl, Zamore, Lehmann, Bartel and Sharp (1999), Genes & Dev. 13: 3191-3197, incorporated herein by reference in its entirety. When synthesized, a typical 0.2 micromolar-scale RNA synthesis provides about 1 milligram of siRNA, which is sufficient for 1000 transfection experiments using a 24-well tissue culture plate format.

[0089] The most efficient silencing is generally observed with siRNA duplexes composed of a 21-nt sense strand and a 21-nt antisense strand, paired in a manner to have a 2-nt 3′ overhang. The sequence of the 2-nt 3′ overhang makes an additional small contribution to the specificity of siRNA target recognition. The contribution to specificity is localized to the unpaired nucleotide adjacent to the first paired bases. In one embodiment, the nucleotides in the 3′ overhang are ribonucleotides. In an alternative embodiment, the nucleotides in the 3′ overhang are deoxyribonucleotides. Using 2′-deoxyribonucleotides in the 3′ overhangs is as efficient as using ribonucleotides, but deoxyribonucleotides are often cheaper to synthesize and are most likely more nuclease resistant.

[0090] A contemplated recombinant expression vector of the invention comprises a NOVX DNA molecule cloned into an expression vector comprising operatively-linked regulatory sequences flanking the NOVX sequence in a manner that allows for expression (by transcription of the DNA molecule) of both strands. An RNA molecule that is antisense to NOVX mRNA is transcribed by a first promoter (e.g., a promoter sequence 3′ of the cloned DNA) and an RNA molecule that is the sense strand for the NOVX mRNA is transcribed by a second promoter (e.g., a promoter sequence 5′ of the cloned DNA). The sense and antisense strands may hybridize in vivo to generate siRNA constructs for silencing of the NOVX gene. Alternatively, two constructs can be utilized to create the sense and anti-sense strands of a siRNA construct. Finally, cloned DNA can encode a construct having secondary structure, wherein a single transcript has both the sense and complementary antisense sequences from the target gene or genes. In an example of this embodiment, a hairpin RNAi product is homologous to all or a portion of the target gene. In another example, a hairpin RNAi product is a siRNA. The regulatory sequences flanking the NOVX sequence may be identical or may be different, such that their expression may be modulated independently, or in a temporal or spatial manner.

[0091] In a specific embodiment, siRNAs are transcribed intracellularly by cloning the NOVX gene templates into a vector containing, e.g., a RNA pol III transcription unit from the smaller nuclear RNA (snRNA) U6 or the human RNase P RNA H1. One example of a vector system is the GeneSuppressor™ RNA Interference kit (commercially available from Imgenex). The U6 and H1 promoters are members of the type III class of Pol III promoters. The +1 nucleotide of the U6-like promoters is always guanosine, whereas the +1 for H1 promoters is adenosine. The termination signal for these promoters is defined by five consecutive thymidines. The transcript is typically cleaved after the second uridine. Cleavage at this position generates a 3′ UU overhang in the expressed siRNA, which is similar to the 3′ overhangs of synthetic siRNAs. Any sequence less than 400 nucleotides in length can be transcribed by these promoter, therefore they are ideally suited for the expression of around 21-nucleotide siRNAs in, e.g., an approximately 50-nucleotide RNA stem-loop transcript.

[0092] A siRNA vector appears to have an advantage over synthetic siRNAs where long term knock-down of expression is desired. Cells transfected with a siRNA expression vector would experience steady, long-term mRNA inhibition. In contrast, cells transfected with exogenous synthetic siRNAs typically recover from mRNA suppression within seven days or ten rounds of cell division. The long-term gene silencing ability of siRNA expression vectors may provide for applications in gene therapy.

[0093] In general, siRNAs are chopped from longer dsRNA by an ATP-dependent ribonuclease called DICER. DICER is a member of the RNase III family of double-stranded RNA-specific endonucleases. The siRNAs assemble with cellular proteins into an endonuclease complex. In vitro studies in Drosophila suggest that the siRNAs/protein complex (siRNP) is then transferred to a second enzyme complex, called an RNA-induced silencing complex (RISC), which contains an endoribonuclease that is distinct from DICER. RISC uses the sequence encoded by the antisense siRNA strand to find and destroy mRNAs of complementary sequence. The siRNA thus acts as a guide, restricting the ribonuclease to cleave only mRNAs complementary to one of the two siRNA strands.

[0094] A NOVX mRNA region to be targeted by siRNA is generally selected from a desired NOVX sequence beginning 50 to 100 nt downstream of the start codon. Alternatively, 5′ or 3′ UTRs and regions nearby the start codon can be used but are generally avoided, as these may be richer in regulatory protein binding sites. UTR-binding proteins and/or translation initiation complexes may interfere with binding of the siRNP or RISC endonuclease complex. An initial BLAST homology search for the selected siRNA sequence is done against an available nucleotide sequence library to ensure that only one gene is targeted. Specificity of target recognition by siRNA duplexes indicate that a single point mutation located in the paired region of an siRNA duplex is sufficient to abolish target mRNA degradation. See, Elbashir et al. 2001 EMBO J. 20(23):6877-88. Hence, consideration should be taken to accommodate SNPs, polymorphisms, allelic variants or species-specific variations when targeting a desired gene.

[0095] In one embodiment, a complete NOVX siRNA experiment includes the proper negative control. A negative control siRNA generally has the same nucleotide composition as the NOVX siRNA but lack significant sequence homology to the genome. Typically, one would scramble the nucleotide sequence of the NOVX siRNA and do a homology search to make sure it lacks homology to any other gene.

[0096] Two independent NOVX siRNA duplexes can be used to knock-down a target NOVX gene. This helps to control for specificity of the silencing effect. In addition, expression of two independent genes can be simultaneously knocked down by using equal concentrations of different NOVX siRNA duplexes, e.g., a NOVX siRNA and an siRNA for a regulator of a NOVX gene or polypeptide. Availability of siRNA-associating proteins is believed to be more limiting than target mRNA accessibility.

[0097] A targeted NOVX region is typically a sequence of two adenines (AA) and two thymidines (TT) divided by a spacer region of nineteen (N19) residues (e.g., AA(N19)TT). A desirable spacer region has a G/C-content of approximately 30% to 70%, and more preferably of about 50%. If the sequence AA(N19)TT is not present in the target sequence, an alternative target region would be AA(N21). The sequence of the NOVX sense siRNA corresponds to (N19)TT or N21, respectively. In the latter case, conversion of the 3′ end of the sense siRNA to TT can be performed if such a sequence does not naturally occur in the NOVX polynucleotide. The rationale for this sequence conversion is to generate a symmetric duplex with respect to the sequence composition of the sense and antisense 3′ overhangs. Symmetric 3′ overhangs may help to ensure that the siRNPs are formed with approximately equal ratios of sense and antisense target RNA-cleaving siRNPs. See, e.g., Elbashir, Lendeckel and Tuschl (2001). Genes & Dev. 15: 188-200, incorporated by reference herein in its entirely. The modification of the overhang of the sense sequence of the siRNA duplex is not expected to affect targeted mRNA recognition, as the antisense siRNA strand guides target recognition.

[0098] Alternatively, if the NOVX target mRNA does not contain a suitable AA(N21) sequence, one may search for the sequence NA(N21). Further, the sequence of the sense strand and antisense strand may still be synthesized as 5′ (N19)TT, as it is believed that the sequence of the 3′-most nucleotide of the antisense siRNA does not contribute to specificity. Unlike antisense or ribozyme technology, the secondary structure of the target mRNA does not appear to have a strong effect on silencing. See, Harborth, et al. (2001) J. Cell Science 114: 4557-4565, incorporated by reference in its entirety.

[0099] Transfection of NOVX siRNA duplexes can be achieved using standard nucleic acid transfection methods, for example, OLIGOFECTAMINE Reagent (commercially available from Invitrogen). An assay for NOVX gene silencing is generally performed approximately 2 days after transfection. No NOVX gene silencing has been observed in the absence of transfection reagent, allowing for a comparative analysis of the wild-type and silenced NOVX phenotypes. In a specific embodiment, for one well of a 24-well plate, approximately 0.84 &mgr;g of the siRNA duplex is generally sufficient. Cells are typically seeded the previous day, and are transfected at about 50% confluence. The choice of cell culture media and conditions are routine to those of skill in the art, and will vary with the choice of cell type. The efficiency of transfection may depend on the cell type, but also on the passage number and the confluency of the cells. The time and the manner of formation of siRNA-liposome complexes (e.g. inversion versus vortexing) are also critical. Low transfection efficiencies are the most frequent cause of unsuccessful NOVX silencing. The efficiency of transfection needs to be carefully examined for each new cell line to be used. Preferred cell are derived from a mammal, more preferably from a rodent such as a rat or mouse, and most preferably from a human. Where used for therapeutic treatment, the cells are preferentially autologous, although non-autologous cell sources are also contemplated as within the scope of the present invention.

[0100] For a control experiment, transfection of 0.84 &mgr;g single-stranded sense NOVX siRNA will have no effect on NOVX silencing, and 0.84 &mgr;g antisense siRNA has a weak silencing effect when compared to 0.84 &mgr;g of duplex siRNAs. Control experiments again allow for a comparative analysis of the wild-type and silenced NOVX phenotypes. To control for transfection efficiency, targeting of common proteins is typically performed, for example targeting of lamin A/C or transfection of a CMV-driven EGFP-expression plasmid (e.g. commercially available from Clontech). In the above example, a determination of the fraction of lamin A/C knockdown in cells is determined the next day by such techniques as immunofluorescence, Western blot, Northern blot or other similar assays for protein expression or gene expression. Lamin A/C monoclonal antibodies may be obtained from Santa Cruz Biotechnology.

[0101] Depending on the abundance and the half life (or turnover) of the targeted NOVX polynucleotide in a cell, a knock-down phenotype may become apparent after 1 to 3 days, or even later. In cases where no NOVX knock-down phenotype is observed, depletion of the NOVX polynucleotide may be observed by immunofluorescence or Western blotting. If the NOVX polynucleotide is still abundant after 3 days, cells need to be split and transferred to a fresh 24-well plate for re-transfection. If no knock-down of the targeted protein is observed, it may be desirable to analyze whether the target mRNA (NOVX or a NOVX upstream or downstream gene) was effectively destroyed by the transfected siRNA duplex. Two days after transfection, total RNA is prepared, reverse transcribed using a target-specific primer, and PCR-amplified with a primer pair covering at least one exon-exon junction in order to control for amplification of pre-mRNAs. RT/PCR of a non-targeted mRNA is also needed as control. Effective depletion of the mRNA yet undetectable reduction of target protein may indicate that a large reservoir of stable NOVX protein may exist in the cell. Multiple transfection in sufficiently long intervals may be necessary until the target protein is finally depleted to a point where a phenotype may become apparent. If multiple transfection steps are required, cells are split 2 to 3 days after transfection. The cells may be transfected immediately after splitting.

[0102] An inventive therapeutic method of the invention contemplates administering a NOVX siRNA construct as therapy to compensate for increased or aberrant NOVX expression or activity. The NOVX ribopolynucleotide is obtained and processed into siRNA fragments, or a NOVX siRNA is synthesized, as described above. The NOVX siRNA is administered to cells or tissues using known nucleic acid transfection techniques, as described above. A NOVX siRNA specific for a NOVX gene will decrease or knockdown NOVX transcription products, which will lead to reduced NOVX polypeptide production, resulting in reduced NOVX polypeptide activity in the cells or tissues.

[0103] The present invention also encompasses a method of treating a disease or condition associated with the presence of a NOVX protein in an individual comprising administering to the individual an RNAi construct that targets the mRNA of the protein (the mRNA that encodes the protein) for degradation. A specific RNAi construct includes a siRNA or a double stranded gene transcript that is processed into siRNAs. Upon treatment, the target protein is not produced or is not produced to the extent it would be in the absence of the treatment.

[0104] Where the NOVX gene function is not correlated with a known phenotype, a control sample of cells or tissues from healthy individuals provides a reference standard for determining NOVX expression levels. Expression levels are detected using the assays described, e.g., RT-PCR, Northern blotting, Western blotting, ELISA, and the like. A subject sample of cells or tissues is taken from a mammal, preferably a human subject, suffering from a disease state. The NOVX ribopolynucleotide is used to produce siRNA constructs, that are specific for the NOVX gene product. These cells or tissues are treated by administering NOVX siRNA's to the cells or tissues by methods described for the transfection of nucleic acids into a cell or tissue, and a change in NOVX polypeptide or polynucleotide expression is observed in the subject sample relative to the control sample, using the assays described. This NOVX gene knockdown approach provides a rapid method for determination of a NOVX minus (NOVX−) phenotype in the treated subject sample. The NOVX− phenotype observed in the treated subject sample thus serves as a marker for monitoring the course of a disease state during treatment.

[0105] In specific embodiments, a NOVX siRNA is used in therapy. Methods for the generation and use of a NOVX siRNA are known to those skilled in the art. Example techniques are provided below.

[0106] Production of RNAs

[0107] Sense RNA (ssRNA) and antisense RNA (asRNA) of NOVX are produced using known methods such as transcription in RNA expression vectors. In the initial experiments, the sense and antisense RNA are about 500 bases in length each. The produced ssRNA and asRNA (0.5 &mgr;M) in 10 mM Tris-HCl (pH 7.5) with 20 mM NaCl were heated to 95° C. for 1 min then cooled and annealed at room temperature for 12 to 16 h. The RNAs are precipitated and resuspended in lysis buffer (below). To monitor annealing, RNAs are electrophoresed in a 2% agarose gel in TBE buffer and stained with ethidium bromide. See, e.g., Sambrook et al., Molecular Cloning. Cold Spring Harbor Laboratory Press, Plainview, N.Y. (1989).

[0108] Lysate Preparation

[0109] Untreated rabbit reticulocyte lysate (Ambion) are assembled according to the manufacturer's directions. dsRNA is incubated in the lysate at 30° C. for 10 min prior to the addition of mRNAs. Then NOVX mRNAs are added and the incubation continued for an additional 60 min. The molar ratio of double stranded RNA and mRNA is about 200:1. The NOVX mRNA is radiolabeled (using known techniques) and its stability is monitored by gel electrophoresis.

[0110] In a parallel experiment made with the same conditions, the double stranded RNA is internally radiolabeled with a 32P-ATP. Reactions are stopped by the addition of 2×proteinase K buffer and deproteinized as described previously (Tuschl et al., Genes Dev., 13:3191-3197 (1999)). Products are analyzed by electrophoresis in 15% or 18% polyacrylamide sequencing gels using appropriate RNA standards. By monitoring the gels for radioactivity, the natural production of 10 to 25 nt RNAs from the double stranded RNA can be determined.

[0111] The band of double stranded RNA, about 21-23 bps, is eluded. The efficacy of these 21-23 mers for suppressing NOVX transcription is assayed in vitro using the same rabbit reticulocyte assay described above using 50 nanomolar of double stranded 21-23 mer for each assay. The sequence of these 21-23 mers is then determined using standard nucleic acid sequencing techniques.

[0112] RNA Preparation

[0113] 21 nt RNAs, based on the sequence determined above, are chemically synthesized using Expedite RNA phosphoramidites and thymidine phosphoramidite (Proligo, Germany). Synthetic oligonucleotides are deprotected and gel-purified (Elbashir, Lendeckel, & Tuschl, Genes & Dev. 15, 188-200 (2001)), followed by Sep-Pak C18 cartridge (Waters, Milford, Mass., USA) purification (Tuschl, et al., Biochemistry, 32:11658-11668 (1993)).

[0114] These RNAs (20 &mgr;M) single strands are incubated in annealing buffer (100 mM potassium acetate, 30 mM HEPES-KOH at pH 7.4, 2 mM magnesium acetate) for 1 min at 90° C. followed by 1 h at 37° C.

[0115] Cell Culture

[0116] A cell culture known in the art to regularly express NOVX is propagated using standard conditions. 24 hours before transfection, at approx. 80% confluency, the cells are trypsinized and diluted 1:5 with fresh medium without antibiotics (1-3×105 cells/ml) and transferred to 24-well plates (500 ml/well). Transfection is performed using a commercially available lipofection kit and NOVX expression is monitored using standard techniques with positive and negative control. A positive control is cells that naturally express NOVX while a negative control is cells that do not express NOVX. Base-paired 21 and 22 nt siRNAs with overhanging 3′ ends mediate efficient sequence-specific mRNA degradation in lysates and in cell culture. Different concentrations of siRNAs are used. An efficient concentration for suppression in vitro in mammalian culture is between 25 nM to 100 nM final concentration. This indicates that siRNAs are effective at concentrations that are several orders of magnitude below the concentrations applied in conventional antisense or ribozyme gene targeting experiments.

[0117] The above method provides a way both for the deduction of NOVX siRNA sequence and the use of such siRNA for in vitro suppression. In vivo suppression may be performed using the same siRNA using well known in vivo transfection or gene therapy transfection techniques.

[0118] Antisense Nucleic Acids

[0119] Another aspect of the invention pertains to isolated antisense nucleic acid molecules that are hybridizable to or complementary to the nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:2n-1, wherein n is an integer between 1 and 64, or fragments, analogs or derivatives thereof. An “antisense” nucleic acid comprises a nucleotide sequence that is complementary to a “sense” nucleic acid encoding a protein (e.g., complementary to the coding strand of a double-stranded cDNA molecule or complementary to an mRNA sequence). In specific aspects, antisense nucleic acid molecules are provided that comprise a sequence complementary to at least about 10, 25, 50, 100, 250 or 500 nucleotides or an entire NOVX coding strand, or to only a portion thereof. Nucleic acid molecules encoding fragments, homologs, derivatives and analogs of a NOVX protein of SEQ ID NO:2n, wherein n is an integer between 1 and 64, or antisense nucleic acids complementary to a NOVX nucleic acid sequence of SEQ ID NO:2n-1, wherein n is an integer between 1 and 64, are additionally provided.

[0120] In one embodiment, an antisense nucleic acid molecule is antisense to a “coding region” of the coding strand of a nucleotide sequence encoding a NOVX protein. The term “coding region” refers to the region of the nucleotide sequence comprising codons which are translated into amino acid residues. In another embodiment, the antisense nucleic acid molecule is antisense to a “noncoding region” of the coding strand of a nucleotide sequence encoding the NOVX protein. The term “noncoding region” refers to 5′ and 3′ sequences which flank the coding region that are not translated into amino acids (i.e., also referred to as 5′ and 3′ untranslated regions).

[0121] Given the coding strand sequences encoding the NOVX protein disclosed herein, antisense nucleic acids of the invention can be designed according to the rules of Watson and Crick or Hoogsteen base pairing. The antisense nucleic acid molecule can be complementary to the entire coding region of NOVX mRNA, but more preferably is an oligonucleotide that is antisense to only a portion of the coding or noncoding region of NOVX mRNA. For example, the antisense oligonucleotide can be complementary to the region surrounding the translation start site of NOVX mRNA. An antisense oligonucleotide can be, for example, about 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50 nucleotides in length. An antisense nucleic acid of the invention can be constructed using chemical synthesis or enzymatic ligation reactions using procedures known in the art. For example, an antisense nucleic acid (e.g., an antisense oligonucleotide) can be chemically synthesized using naturally-occurring nucleotides or variously modified nucleotides designed to increase the biological stability of the molecules or to increase the physical stability of the duplex formed between the antisense and sense nucleic acids (e.g., phosphorothioate derivatives and acridine substituted nucleotides can be used).

[0122] Examples of modified nucleotides that can be used to generate the antisense nucleic acid include: 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-carboxymethylaminomethyl-2-thiouridine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 5-methoxyuracil, 3-methylcytosine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, 2-thiouracil, 4-thiouracil, beta-D-mannosylqueosine, 5′-methoxycarboxymethyluracil, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v), 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w, and 2,6-diaminopurine. Alternatively, the antisense nucleic acid can be produced biologically using an expression vector into which a nucleic acid has been subcloned in an antisense orientation (i.e., RNA transcribed from the inserted nucleic acid will be of an antisense orientation to a target nucleic acid of interest, described further in the following subsection).

[0123] The antisense nucleic acid molecules of the invention are typically administered to a subject or generated in situ such that they hybridize with or bind to cellular mRNA and/or genomic DNA encoding a NOVX protein to thereby inhibit expression of the protein (e.g., by inhibiting transcription and/or translation). The hybridization can be by conventional nucleotide complementarity to form a stable duplex, or, for example, in the case of an antisense nucleic acid molecule that binds to DNA duplexes, through specific interactions in the major groove of the double helix. An example of a route of administration of antisense nucleic acid molecules of the invention includes direct injection at a tissue site. Alternatively, antisense nucleic acid molecules can be modified to target selected cells and then administered systemically. For example, for systemic administration, antisense molecules can be modified such that they specifically bind to receptors or antigens expressed on a selected cell surface (e.g., by linking the antisense nucleic acid molecules to peptides or antibodies that bind to cell surface receptors or antigens). The antisense nucleic acid molecules can also be delivered to cells using the vectors described herein. To achieve sufficient nucleic acid molecules, vector constructs in which the antisense nucleic acid molecule is placed under the control of a strong pol II or pol III promoter are preferred.

[0124] In yet another embodiment, the antisense nucleic acid molecule of the invention is an &agr;-anomeric nucleic acid molecule. An &agr;-anomeric nucleic acid molecule forms specific double-stranded hybrids with complementary RNA in which, contrary to the usual &bgr;-units, the strands run parallel to each other. See, e.g., Gaultier, et al., 1987. Nucl. Acids Res. 15: 6625-6641. The antisense nucleic acid molecule can also comprise a 2′-o-methylribonucleotide (See, e.g., Inoue, et al. 1987. Nucl. Acids Res. 15: 6131-6148) or a chimeric RNA-DNA analogue (See, e.g., Inoue, et al., 1987. FEBS Lett. 215: 327-330.

[0125] Ribozymes and PNA Moieties

[0126] Nucleic acid modifications include, by way of non-limiting example, modified bases, and nucleic acids whose sugar phosphate backbones are modified or derivatized. These modifications are carried out at least in part to enhance the chemical stability of the modified nucleic acid, such that they may be used, for example, as antisense binding nucleic acids in therapeutic applications in a subject.

[0127] In one embodiment, an antisense nucleic acid of the invention is a ribozyme. Ribozymes are catalytic RNA molecules with ribonuclease activity that are capable of cleaving a single-stranded nucleic acid, such as an mRNA, to which they have a complementary region. Thus, ribozymes (e.g., hammerhead ribozymes as described in Haselhoff and Gerlach 1988. Nature 334: 585-591) can be used to catalytically cleave NOVX mRNA transcripts to thereby inhibit translation of NOVX mRNA. A ribozyme having specificity for a NOVX-encoding nucleic acid can be designed based upon the nucleotide sequence of a NOVX cDNA disclosed herein (i.e., SEQ ID NO:2n-1, wherein n is an integer between 1 and 64). For example, a derivative of a Tetrahymena L-19 IVS RNA can be constructed in which the nucleotide sequence of the active site is complementary to the nucleotide sequence to be cleaved in a NOVX-encoding mRNA. See, e.g., U.S. Pat. No. 4,987,071 to Cech, et al. and U.S. Pat. No. 5,116,742 to Cech, et al. NOVX mRNA can also be used to select a catalytic RNA having a specific ribonuclease activity from a pool of RNA molecules. See, e.g., Bartel et al., (1993) Science 261:1411-1418.

[0128] Alternatively, NOVX gene expression can be inhibited by targeting nucleotide sequences complementary to the regulatory region of the NOVX nucleic acid (e.g., the NOVX promoter and/or enhancers) to form triple helical structures that prevent transcription of the NOVX gene in target cells. See, e.g., Helene, 1991. Anticancer Drug Des. 6: 569-84; Helene, et al. 1992. Ann. N.Y. Acad. Sci. 660: 27-36; Maher, 1992. Bioassays 14: 807-15.

[0129] In various embodiments, the NOVX nucleic acids can be modified at the base moiety, sugar moiety or phosphate backbone to improve, e.g., the stability, hybridization, or solubility of the molecule. For example, the deoxyribose phosphate backbone of the nucleic acids can be modified to generate peptide nucleic acids. See, e.g., Hyrup, et al., 1996. Bioorg Med Chem 4: 5-23. As used herein, the terms “peptide nucleic acids” or “PNAs” refer to nucleic acid mimics (e.g., DNA mimics) in which the deoxyribose phosphate backbone is replaced by a pseudopeptide backbone and only the four natural nucleotide bases are retained. The neutral backbone of PNAs has been shown to allow for specific hybridization to DNA and RNA under conditions of low ionic strength. The synthesis of PNA oligomer can be performed using standard solid phase peptide synthesis protocols as described in Hyrup, et al., 1996. supra; Perry-O'Keefe, et al., 1996. Proc. Natl. Acad. Sci. USA 93: 14670-14675.

[0130] PNAs of NOVX can be used in therapeutic and diagnostic applications. For example, PNAs can be used as antisense or antigene agents for sequence-specific modulation of gene expression by, e.g., inducing transcription or translation arrest or inhibiting replication. PNAs of NOVX can also be used, for example, in the analysis of single base pair mutations in a gene (e.g., PNA directed PCR clamping; as artificial restriction enzymes when used in combination with other enzymes, e.g., S1 nucleases (See, Hyrup, et al., 1996. supra); or as probes or primers for DNA sequence and hybridization (See, Hyrup, et al., 1996, supra; Perry-O'Keefe, et al., 1996. supra).

[0131] In another embodiment, PNAs of NOVX can be modified, e.g., to enhance their stability or cellular uptake, by attaching lipophilic or other helper groups to PNA, by the formation of PNA-DNA chimeras, or by the use of liposomes or other techniques of drug delivery known in the art. For example, PNA-DNA chimeras of NOVX can be generated that may combine the advantageous properties of PNA and DNA. Such chimeras allow DNA recognition enzymes (e.g., RNase H and DNA polymerases) to interact with the DNA portion while the PNA portion would provide high binding affinity and specificity. PNA-DNA chimeras can be linked using linkers of appropriate lengths selected in terms of base stacking, number of bonds between the nucleotide bases, and orientation (see, Hyrup, et al., 1996. supra). The synthesis of PNA-DNA chimeras can be performed as described in Hyrup, et al., 1996. supra and Finn, et al., 1996. Nucl Acids Res 24: 3357-3363. For example, a DNA chain can be synthesized on a solid support using standard phosphoramidite coupling chemistry, and modified nucleoside analogs, e.g., 5′-(4-methoxytrityl)amino-5′-deoxy-thymidine phosphoramidite, can be used between the PNA and the 5′ end of DNA. See, e.g., Mag, et al., 1989. Nucl Acid Res 17: 5973-5988. PNA monomers are then coupled in a stepwise manner to produce a chimeric molecule with a 5′ PNA segment and a 3′ DNA segment. See, e.g., Finn, et al., 1996. supra. Alternatively, chimeric molecules can be synthesized with a 5′ DNA segment and a 3′ PNA segment. See, e.g., Petersen, et al., 1975. Bioorg. Med. Chem. Lett. 5: 1119-11124.

[0132] In other embodiments, the oligonucleotide may include other appended groups such as peptides (e.g., for targeting host cell receptors in vivo), or agents facilitating transport across the cell membrane (see, e.g., Letsinger, et al., 1989. Proc. Natl. Acad. Sci. U.S.A. 86: 6553-6556; Lemaitre, et al., 1987. Proc. Natl. Acad. Sci. 84: 648-652; PCT Publication No. WO88/09810) or the blood-brain barrier (see, e.g., PCT Publication No. WO 89/10134). In addition, oligonucleotides can be modified with hybridization triggered cleavage agents (see, e.g., Krol, et al., 1988. BioTechniques 6:958-976) or intercalating agents (see, e.g., Zon, 1988. Pharm. Res. 5: 539-549). To this end, the oligonucleotide may be conjugated to another molecule, e.g., a peptide, a hybridization triggered cross-linking agent, a transport agent, a hybridization-triggered cleavage agent, and the like.

[0133] NOVX Polypeptides

[0134] A polypeptide according to the invention includes a polypeptide including the amino acid sequence of NOVX polypeptides whose sequences are provided in any one of SEQ ID NO:2n, wherein n is an integer between 1 and 64. The invention also includes a mutant or variant protein any of whose residues may be changed from the corresponding residues shown in any one of SEQ ID NO:2n, wherein n is an integer between 1 and 64, while still encoding a protein that maintains its NOVX activities and physiological functions, or a functional fragment thereof.

[0135] In general, a NOVX variant that preserves NOVX-like function includes any variant in which residues at a particular position in the sequence have been substituted by other amino acids, and further include the possibility of inserting an additional residue or residues between two residues of the parent protein as well as the possibility of deleting one or more residues from the parent sequence. Any amino acid substitution, insertion, or deletion is encompassed by the invention. In favorable circumstances, the substitution is a conservative substitution as defined above.

[0136] One aspect of the invention pertains to isolated NOVX proteins, and biologically-active portions thereof, or derivatives, fragments, analogs or homologs thereof. Also provided are polypeptide fragments suitable for use as immunogens to raise anti-NOVX antibodies. In one embodiment, native NOVX proteins can be isolated from cells or tissue sources by an appropriate purification scheme using standard protein purification techniques. In another embodiment, NOVX proteins are produced by recombinant DNA techniques. Alternative to recombinant expression, a NOVX protein or polypeptide can be synthesized chemically using standard peptide synthesis techniques.

[0137] An “isolated” or “purified” polypeptide or protein or biologically-active portion thereof is substantially free of cellular material or other contaminating proteins from the cell or tissue source from which the NOVX protein is derived, or substantially free from chemical precursors or other chemicals when chemically synthesized. The language “substantially free of cellular material” includes preparations of NOVX proteins in which the protein is separated from cellular components of the cells from which it is isolated or recombinantly-produced. In one embodiment, the language “substantially free of cellular material” includes preparations of NOVX proteins having less than about 30% (by dry weight) of non-NOVX proteins (also referred to herein as a “contaminating protein”), more preferably less than about 20% of non-NOVX proteins, still more preferably less than about 10% of non-NOVX proteins, and most preferably less than about 5% of non-NOVX proteins. When the NOVX protein or biologically-active portion thereof is recombinantly-produced, it is also preferably substantially free of culture medium, i.e., culture medium represents less than about 20%, more preferably less than about 10%, and most preferably less than about 5% of the volume of the NOVX protein preparation.

[0138] The language “substantially free of chemical precursors or other chemicals” includes preparations of NOVX proteins in which the protein is separated from chemical precursors or other chemicals that are involved in the synthesis of the protein. In one embodiment, the language “substantially free of chemical precursors or other chemicals” includes preparations of NOVX proteins having less than about 30% (by dry weight) of chemical precursors or non-NOVX chemicals, more preferably less than about 20% chemical precursors or non-NOVX chemicals, still more preferably less than about 10% chemical precursors or non-NOVX chemicals, and most preferably less than about 5% chemical precursors or non-NOVX chemicals.

[0139] Biologically-active portions of NOVX proteins include peptides comprising amino acid sequences sufficiently homologous to or derived from the amino acid sequences of the NOVX proteins (e.g., the amino acid sequence of SEQ ID NO:2n, wherein n is an integer between 1 and 64) that include fewer amino acids than the full-length NOVX proteins, and exhibit at least one activity of a NOVX protein. Typically, biologically-active portions comprise a domain or motif with at least one activity of the NOVX protein. A biologically-active portion of a NOVX protein can be a polypeptide which is, for example, 10, 25, 50, 100 or more amino acid residues in length.

[0140] Moreover, other biologically-active portions, in which other regions of the protein are deleted, can be prepared by recombinant techniques and evaluated for one or more of the functional activities of a native NOVX protein.

[0141] In an embodiment, the NOVX protein has an amino acid sequence of SEQ ID NO:2n, wherein n is an integer between 1 and 64. In other embodiments, the NOVX protein is substantially homologous to SEQ ID NO:2n, wherein n is an integer between 1 and 64, and retains the functional activity of the protein of SEQ ID NO:2n, wherein n is an integer between 1 and 64, yet differs in amino acid sequence due to natural allelic variation or mutagenesis, as described in detail, below. Accordingly, in another embodiment, the NOVX protein is a protein that comprises an amino acid sequence at least about 45% homologous to the amino acid sequence of SEQ ID NO:2n, wherein n is an integer between 1 and 64, and retains the functional activity of the NOVX proteins of SEQ ID NO:2n, wherein n is an integer between 1 and 64.

[0142] Determining Homology Between Two or More Sequences

[0143] To determine the percent homology of two amino acid sequences or of two nucleic acids, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in the sequence of a first amino acid or nucleic acid sequence for optimal alignment with a second amino or nucleic acid sequence). The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are homologous at that position (i.e., as used herein amino acid or nucleic acid “homology” is equivalent to amino acid or nucleic acid “identity”).

[0144] The nucleic acid sequence homology may be determined as the degree of identity between two sequences. The homology may be determined using computer programs known in the art, such as GAP software provided in the GCG program package. See, Needleman and Wunsch, 1970. J Mol Biol 48: 443-453. Using GCG GAP software with the following settings for nucleic acid sequence comparison: GAP creation penalty of 5.0 and GAP extension penalty of 0.3, the coding region of the analogous nucleic acid sequences referred to above exhibits a degree of identity preferably of at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99%, with the CDS (encoding) part of the DNA sequence of SEQ ID NO:2n-1, wherein n is an integer between 1 and 64.

[0145] The term “sequence identity” refers to the degree to which two polynucleotide or polypeptide sequences are identical on a residue-by-residue basis over a particular region of comparison. The term “percentage of sequence identity” is calculated by comparing two optimally aligned sequences over that region of comparison, determining the number of positions at which the identical nucleic acid base (e.g., A, T, C, G, U, or I, in the case of nucleic acids) occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the region of comparison (i.e., the window size), and multiplying the result by 100 to yield the percentage of sequence identity. The term “substantial identity” as used herein denotes a characteristic of a polynucleotide sequence, wherein the polynucleotide comprises a sequence that has at least 80 percent sequence identity, preferably at least 85 percent identity and often 90 to 95 percent sequence identity, more usually at least 99 percent sequence identity as compared to a reference sequence over a comparison region.

[0146] Chimeric and Fusion Proteins

[0147] The invention also provides NOVX chimeric or fusion proteins. As used herein, a NOVX “chimeric protein” or “fusion protein” comprises a NOVX polypeptide operatively-linked to a non-NOVX polypeptide. An “NOVX polypeptide” refers to a polypeptide having an amino acid sequence corresponding to a NOVX protein of SEQ ID NO:2n, wherein n is an integer between 1 and 64, whereas a “non-NOVX polypeptide” refers to a polypeptide having an amino acid sequence corresponding to a protein that is not substantially homologous to the NOVX protein, e.g., a protein that is different from the NOVX protein and that is derived from the same or a different organism. Within a NOVX fusion protein the NOVX polypeptide can correspond to all or a portion of a NOVX protein. In one embodiment, a NOVX fusion protein comprises at least one biologically-active portion of a NOVX protein. In another embodiment, a NOVX fusion protein comprises at least two biologically-active portions of a NOVX protein. In yet another embodiment, a NOVX fusion protein comprises at least three biologically-active portions of a NOVX protein. Within the fusion protein, the term “operatively-linked” is intended to indicate that the NOVX polypeptide and the non-NOVX polypeptide are fused in-frame with one another. The non-NOVX polypeptide can be fused to the N-terminus or C-terminus of the NOVX polypeptide.

[0148] In one embodiment, the fusion protein is a GST-NOVX fusion protein in which the NOVX sequences are fused to the C-terminus of the GST (glutathione S-transferase) sequences. Such fusion proteins can facilitate the purification of recombinant NOVX polypeptides.

[0149] In another embodiment, the fusion protein is a NOVX protein containing a heterologous signal sequence at its N-terminus. In certain host cells (e.g., mammalian host cells), expression and/or secretion of NOVX can be increased through use of a heterologous signal sequence.

[0150] In yet another embodiment, the fusion protein is a NOVX-immunoglobulin fusion protein in which the NOVX sequences are fused to sequences derived from a member of the immunoglobulin protein family. The NOVX-immunoglobulin fusion proteins of the invention can be incorporated into pharmaceutical compositions and administered to a subject to inhibit an interaction between a NOVX ligand and a NOVX protein on the surface of a cell, to thereby suppress NOVX-mediated signal transduction in vivo. The NOVX-immunoglobulin fusion proteins can be used to affect the bioavailability of a NOVX cognate ligand. Inhibition of the NOVX ligand/NOVX interaction may be useful therapeutically for both the treatment of proliferative and differentiative disorders, as well as modulating (e.g. promoting or inhibiting) cell survival. Moreover, the NOVX-immunoglobulin fusion proteins of the invention can be used as immunogens to produce anti-NOVX antibodies in a subject, to purify NOVX ligands, and in screening assays to identify molecules that inhibit the interaction of NOVX with a NOVX ligand.

[0151] A NOVX chimeric or fusion protein of the invention can be produced by standard recombinant DNA techniques. For example, DNA fragments coding for the different polypeptide sequences are ligated together in-frame in accordance with conventional techniques, e.g., by employing blunt-ended or stagger-ended termini for ligation, restriction enzyme digestion to provide for appropriate termini, filling-in of cohesive ends as appropriate, alkaline phosphatase treatment to avoid undesirable joining, and enzymatic ligation. In another embodiment, the fusion gene can be synthesized by conventional techniques including automated DNA synthesizers. Alternatively, PCR amplification of gene fragments can be carried out using anchor primers that give rise to complementary overhangs between two consecutive gene fragments that can subsequently be annealed and reamplified to generate a chimeric gene sequence (see, e.g., Ausubel, et al. (eds.) CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, 1992). Moreover, many expression vectors are commercially available that already encode a fusion moiety (e.g., a GST polypeptide). A NOVX-encoding nucleic acid can be cloned into such an expression vector such that the fusion moiety is linked in-frame to the NOVX protein.

[0152] NOVX Agonists and Antagonists

[0153] The invention also pertains to variants of the NOVX proteins that function as either NOVX agonists (i.e., mimetics) or as NOVX antagonists. Variants of the NOVX protein can be generated by mutagenesis (e.g., discrete point mutation or truncation of the NOVX protein). An agonist of the NOVX protein can retain substantially the same, or a subset of, the biological activities of the naturally occurring form of the NOVX protein. An antagonist of the NOVX protein can inhibit one or more of the activities of the naturally occurring form of the NOVX protein by, for example, competitively binding to a downstream or upstream member of a cellular signaling cascade which includes the NOVX protein. Thus, specific biological effects can be elicited by treatment with a variant of limited function. In one embodiment, treatment of a subject with a variant having a subset of the biological activities of the naturally occurring form of the protein has fewer side effects in a subject relative to treatment with the naturally occurring form of the NOVX proteins.

[0154] Variants of the NOVX proteins that function as either NOVX agonists (i.e., mimetics) or as NOVX antagonists can be identified by screening combinatorial libraries of mutants (e.g., truncation mutants) of the NOVX proteins for NOVX protein agonist or antagonist activity. In one embodiment, a variegated library of NOVX variants is generated by combinatorial mutagenesis at the nucleic acid level and is encoded by a variegated gene library. A variegated library of NOVX variants can be produced by, for example, enzymatically ligating a mixture of synthetic oligonucleotides into gene sequences such that a degenerate set of potential NOVX sequences is expressible as individual polypeptides, or alternatively, as a set of larger fusion proteins (e.g. for phage display) containing the set of NOVX sequences therein. There are a variety of methods which can be used to produce libraries of potential NOVX variants from a degenerate oligonucleotide sequence. Chemical synthesis of a degenerate gene sequence can be performed in an automatic DNA synthesizer, and the synthetic gene then ligated into an appropriate expression vector. Use of a degenerate set of genes allows for the provision, in one mixture, of all of the sequences encoding the desired set of potential NOVX sequences. Methods for synthesizing degenerate oligonucleotides are well-known within the art. See, e.g., Narang, 1983. Tetrahedron 39: 3; Itakura, et al., 1984. Annu. Rev. Biochem. 53: 323; Itakura, et al., 1984. Science 198: 1056; Ike, et al., 1983. Nucl. Acids Res. 11: 477.

[0155] Polypeptide Libraries

[0156] In addition, libraries of fragments of the NOVX protein coding sequences can be used to generate a variegated population of NOVX fragments for screening and subsequent selection of variants of a NOVX protein. In one embodiment, a library of coding sequence fragments can be generated by treating a double stranded PCR fragment of a NOVX coding sequence with a nuclease under conditions wherein nicking occurs only about once per molecule, denaturing the double stranded DNA, renaturing the DNA to form double-stranded DNA that can include sense/antisense pairs from different nicked products, removing single stranded portions from reformed duplexes by treatment with S1 nuclease, and ligating the resulting fragment library into an expression vector. By this method, expression libraries can be derived which encodes N-terminal and internal fragments of various sizes of the NOVX proteins.

[0157] Various techniques are known in the art for screening gene products of combinatorial libraries made by point mutations or truncation, and for screening cDNA libraries for gene products having a selected property. Such techniques are adaptable for rapid screening of the gene libraries generated by the combinatorial mutagenesis of NOVX proteins. The most widely used techniques, which are amenable to high throughput analysis, for screening large gene libraries typically include cloning the gene library into replicable expression vectors, transforming appropriate cells with the resulting library of vectors, and expressing the combinatorial genes under conditions in which detection of a desired activity facilitates isolation of the vector encoding the gene whose product was detected. Recursive ensemble mutagenesis (REM), a new technique that enhances the frequency of functional mutants in the libraries, can be used in combination with the screening assays to identify NOVX variants. See, e.g., Arkin and Yourvan, 1992. Proc. Natl. Acad. Sci. USA 89: 7811-7815; Delgrave, et al., 1993. Protein Engineering 6:327-331.

[0158] NOVX Antibodies

[0159] The term “antibody” as used herein refers to immunoglobulin molecules and immunologically active portions of immunoglobulin (Ig) molecules, i.e., molecules that contain an antigen binding site that specifically binds (immunoreacts with) an antigen. Such antibodies include, but are not limited to, polyclonal, monoclonal, chimeric, single chain, Fab, Fab′ and F(ab′)2 fragments, and an Fab expression library. In general, antibody molecules obtained from humans relates to any of the classes IgG, IgM, IgA, IgE and IgD, which differ from one another by the nature of the heavy chain present in the molecule. Certain classes have subclasses as well, such as IgG1, IgG2, and others. Furthermore, in humans, the light chain may be a kappa chain or a lambda chain. Reference herein to antibodies includes a reference to all such classes, subclasses and types of human antibody species.

[0160] An isolated protein of the invention intended to serve as an antigen, or a portion or fragment thereof, can be used as an immunogen to generate antibodies that immunospecifically bind the antigen, using standard techniques for polyclonal and monoclonal antibody preparation. The full-length protein can be used or, alternatively, the invention provides antigenic peptide fragments of the antigen for use as immunogens. An antigenic peptide fragment comprises at least 6 amino acid residues of the amino acid sequence of the full length protein, such as an amino acid sequence of SEQ ID NO:2n, wherein n is an integer between 1 and 64, and encompasses an epitope thereof such that an antibody raised against the peptide forms a specific immune complex with the full length protein or with any fragment that contains the epitope. Preferably, the antigenic peptide comprises at least 10 amino acid residues, or at least 15 amino acid residues, or at least 20 amino acid residues, or at least 30 amino acid residues. Preferred epitopes encompassed by the antigenic peptide are regions of the protein that are located on its surface; commonly these are hydrophilic regions.

[0161] In certain embodiments of the invention, at least one epitope encompassed by the antigenic peptide is a region of NOVX that is located on the surface of the protein, e.g., a hydrophilic region. A hydrophobicity analysis of the human NOVX protein sequence will indicate which regions of a NOVX polypeptide are particularly hydrophilic and, therefore, are likely to encode surface residues useful for targeting antibody production. As a means for targeting antibody production, hydropathy plots showing regions of hydrophilicity and hydrophobicity may be generated by any method well known in the art, including, for example, the Kyte Doolittle or the Hopp Woods methods, either with or without Fourier transformation. See, e.g., Hopp and Woods, 1981, Proc. Nat. Acad. Sci. USA 78: 3824-3828; Kyte and Doolittle 1982, J. Mol. Biol. 157: 105-142, each incorporated herein by reference in their entirety. Antibodies that are specific for one or more domains within an antigenic protein, or derivatives, fragments, analogs or homologs thereof, are also provided herein.

[0162] The term “epitope” includes any protein determinant capable of specific binding to an immunoglobulin or T-cell receptor. Epitopic determinants usually consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and usually have specific three dimensional structural characteristics, as well as specific charge characteristics. A NOVX polypeptide or a fragment thereof comprises at least one antigenic epitope. An anti-NOVX antibody of the present invention is said to specifically bind to antigen NOVX when the equilibrium binding constant (KD) is ≦1 &mgr;M, preferably ≦100 nM, more preferably ≦10 nM, and most preferably ≦100 pM to about 1 pM, as measured by assays such as radioligand binding assays or similar assays known to those skilled in the art.

[0163] A protein of the invention, or a derivative, fragment, analog, homolog or ortholog thereof, may be utilized as an immunogen in the generation of antibodies that immunospecifically bind these protein components.

[0164] Various procedures known within the art may be used for the production of polyclonal or monoclonal antibodies directed against a protein of the invention, or against derivatives, fragments, analogs homologs or orthologs thereof (see, for example, Antibodies: A Laboratory Manual, Harlow E, and Lane D, 1988, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., incorporated herein by reference). Some of these antibodies are discussed below.

[0165] Polyclonal Antibodies

[0166] For the production of polyclonal antibodies, various suitable host animals (e.g., rabbit, goat, mouse or other mammal) may be immunized by one or more injections with the native protein, a synthetic variant thereof, or a derivative of the foregoing. An appropriate immunogenic preparation can contain, for example, the naturally occurring immunogenic protein, a chemically synthesized polypeptide representing the immunogenic protein, or a recombinantly expressed immunogenic protein. Furthermore, the protein may be conjugated to a second protein known to be immunogenic in the mammal being immunized. Examples of such immunogenic proteins include but are not limited to keyhole limpet hemocyanin, serum albumin, bovine thyroglobulin, and soybean trypsin inhibitor. The preparation can further include an adjuvant. Various adjuvants used to increase the immunological response include, but are not limited to, Freund's (complete and incomplete), mineral gels (e.g., aluminum hydroxide), surface active substances (e.g., lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, dinitrophenol, etc.), adjuvants usable in humans such as Bacille Calmette-Guerin and Corynebacterium parvum, or similar immunostimulatory agents. Additional examples of adjuvants which can be employed include MPL-TDM adjuvant (monophosphoryl Lipid A, synthetic trehalose dicorynomycolate).

[0167] The polyclonal antibody molecules directed against the immunogenic protein can be isolated from the mammal (e.g., from the blood) and further purified by well known techniques, such as affinity chromatography using protein A or protein G, which provide primarily the IgG fraction of immune serum. Subsequently, or alternatively, the specific antigen which is the target of the immunoglobulin sought, or an epitope thereof, may be immobilized on a column to purify the immune specific antibody by immunoaffinity chromatography. Purification of immunoglobulins is discussed, for example, by D. Wilkinson (The Scientist, published by The Scientist, Inc., Philadelphia Pa., Vol. 14, No. 8 (Apr. 17, 2000), pp. 25-28).

[0168] Monoclonal Antibodies

[0169] The term “monoclonal antibody” (MAb) or “monoclonal antibody composition”, as used herein, refers to a population of antibody molecules that contain only one molecular species of antibody molecule consisting of a unique light chain gene product and a unique heavy chain gene product. In particular, the complementarity determining regions (CDRs) of the monoclonal antibody are identical in all the molecules of the population. MAbs thus contain an antigen binding site capable of immunoreacting with a particular epitope of the antigen characterized by a unique binding affinity for it.

[0170] Monoclonal antibodies can be prepared using hybridoma methods, such as those described by Kohler and Milstein, Nature, 256:495 (1975). In a hybridoma method, a mouse, hamster, or other appropriate host animal, is typically immunized with an immunizing agent to elicit lymphocytes that produce or are capable of producing antibodies that will specifically bind to the immunizing agent. Alternatively, the lymphocytes can be immunized in vitro.

[0171] The immunizing agent will typically include the protein antigen, a fragment thereof or a fusion protein thereof. Generally, either peripheral blood lymphocytes are used if cells of human origin are desired, or spleen cells or lymph node cells are used if non-human mammalian sources are desired. The lymphocytes are then fused with an immortalized cell line using a suitable fusing agent, such as polyethylene glycol, to form a hybridoma cell (Goding, Monoclonal Antibodies: Principles and Practice, Academic Press, (1986) pp. 59-103). Immortalized cell lines are usually transformed mammalian cells, particularly myeloma cells of rodent, bovine and human origin. Usually, rat or mouse myeloma cell lines are employed. The hybridoma cells can be cultured in a suitable culture medium that preferably contains one or more substances that inhibit the growth or survival of the unfused, immortalized cells. For example, if the parental cells lack the enzyme hypoxanthine guanine phosphoribosyl transferase (HGPRT or HPRT), the culture medium for the hybridomas typically will include hypoxanthine, aminopterin, and thymidine (“HAT medium”), which substances prevent the growth of HGPRT-deficient cells.

[0172] Preferred immortalized cell lines are those that fuse efficiently, support stable high level expression of antibody by the selected antibody-producing cells, and are sensitive to a medium such as HAT medium. More preferred immortalized cell lines are murine myeloma lines, which can be obtained, for instance, from the Salk Institute Cell Distribution Center, San Diego, Calif. and the American Type Culture Collection, Manassas, Va. Human myeloma and mouse-human heteromyeloma cell lines also have been described for the production of human monoclonal antibodies (Kozbor, J. Immunol., 133:3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, Marcel Dekker, Inc., New York, (1987) pp. 51-63).

[0173] The culture medium in which the hybridoma cells are cultured can then be assayed for the presence of monoclonal antibodies directed against the antigen. Preferably, the binding specificity of monoclonal antibodies produced by the hybridoma cells is determined by immunoprecipitation or by an in vitro binding assay, such as radioimmunoassay (RIA) or enzyme-linked immunoabsorbent assay (ELISA). Such techniques and assays are known in the art. The binding affinity of the monoclonal antibody can, for example, be determined by the Scatchard analysis of Munson and Pollard, Anal. Biochem., 107:220 (1980). It is an objective, especially important in therapeutic applications of monoclonal antibodies, to identify antibodies having a high degree of specificity and a high binding affinity for the target antigen.

[0174] After the desired hybridoma cells are identified, the clones can be subcloned by limiting dilution procedures and grown by standard methods (Goding, 1986). Suitable culture media for this purpose include, for example, Dulbecco's Modified Eagle's Medium and RPMI-1640 medium. Alternatively, the hybridoma cells can be grown in vivo as ascites in a mammal.

[0175] The monoclonal antibodies secreted by the subclones can be isolated or purified from the culture medium or ascites fluid by conventional immunoglobulin purification procedures such as, for example, protein A-Sepharose, hydroxylapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography.

[0176] The monoclonal antibodies can also be made by recombinant DNA methods, such as those described in U.S. Pat. No. 4,816,567. DNA encoding the monoclonal antibodies of the invention can be readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of murine antibodies). The hybridoma cells of the invention serve as a preferred source of such DNA. Once isolated, the DNA can be placed into expression vectors, which are then transfected into host cells such as simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce immunoglobulin protein, to obtain the synthesis of monoclonal antibodies in the recombinant host cells. The DNA also can be modified, for example, by substituting the coding sequence for human heavy and light chain constant domains in place of the homologous murine sequences (U.S. Pat. No. 4,816,567; Morrison, Nature 368, 812-13 (1994)) or by covalently joining to the immunoglobulin coding sequence all or part of the coding sequence for a non-immunoglobulin polypeptide. Such a non-immunoglobulin polypeptide can be substituted for the constant domains of an antibody of the invention, or can be substituted for the variable domains of one antigen-combining site of an antibody of the invention to create a chimeric bivalent antibody.

[0177] Humanized Antibodies

[0178] The antibodies directed against the protein antigens of the invention can further comprise humanized antibodies or human antibodies. These antibodies are suitable for administration to humans without engendering an immune response by the human against the administered immunoglobulin. Humanized forms of antibodies are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab′, F(ab′)2 or other antigen-binding subsequences of antibodies) that are principally comprised of the sequence of a human immunoglobulin, and contain minimal sequence derived from a non-human immunoglobulin. Humanization can be performed following the method of Winter and co-workers (Jones et al., Nature, 321:522-525 (1986); Riechmann et al., Nature, 332:323-327 (1988); Verhoeyen et al., Science, 239:1534-1536 (1988)), by substituting rodent CDRs or CDR sequences for the corresponding sequences of a human antibody. (See also U.S. Pat. No. 5,225,539.) In some instances, Fv framework residues of the human immunoglobulin are replaced by corresponding non-human residues. Humanized antibodies can also comprise residues which are found neither in the recipient antibody nor in the imported CDR or framework sequences. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the framework regions are those of a human immunoglobulin consensus sequence. The humanized antibody optimally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin (Jones et al., 1986; Riechmann et al., 1988; and Presta, Curr. Op. Struct. Biol., 2:593-596 (1992)).

[0179] Human Antibodies

[0180] Fully human antibodies essentially relate to antibody molecules in which the entire sequence of both the light chain and the heavy chain, including the CDRs, arise from human genes. Such antibodies are termed “human antibodies”, or “fully human antibodies” herein. Human monoclonal antibodies can be prepared by the trioma technique; the human B-cell hybridoma technique (see Kozbor, et al., 1983 Immunol Today 4: 72) and the EBV hybridoma technique to produce human monoclonal antibodies (see Cole, et al., 1985 In: MONOCLONAL ANTIBODIES AND CANCER THERAPY, Alan R. Liss, Inc., pp. 77-96). Human monoclonal antibodies may be utilized in the practice of the present invention and may be produced by using human hybridomas (see Cote, et al., 1983. Proc Natl Acad Sci USA 80: 2026-2030) or by transforming human B-cells with Epstein Barr Virus in vitro (see Cole, et al., 1985 In: MONOCLONAL ANTIBODIES AND CANCER THERAPY, Alan R. Liss, Inc., pp. 77-96).

[0181] In addition, human antibodies can also be produced using additional techniques, including phage display libraries (Hoogenboom and Winter, J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991)). Similarly, human antibodies can be made by introducing human immunoglobulin loci into transgenic animals, e.g., mice in which the endogenous immunoglobulin genes have been partially or completely inactivated. Upon challenge, human antibody production is observed, which closely resembles that seen in humans in all respects, including gene rearrangement, assembly, and antibody repertoire. This approach is described, for example, in U.S. Pat. Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; 5,661,016, and in Marks et al. (Bio/Technology 10, 779-783 (1992)); Lonberg et al. (Nature 368 856-859 (1994)); Morrison (Nature 368, 812-13 (1994)); Fishwild et al, (Nature Biotechnology 14, 845-51 (1996)); Neuberger (Nature Biotechnology 14, 826 (1996)); and Lonberg and Huszar (Intern. Rev. Immunol. 13 65-93 (1995)).

[0182] Human antibodies may additionally be produced using transgenic nonhuman animals which are modified so as to produce fully human antibodies rather than the animal's endogenous antibodies in response to challenge by an antigen. (See PCT publication WO94/02602). The endogenous genes encoding the heavy and light immunoglobulin chains in the nonhuman host have been incapacitated, and active loci encoding human heavy and light chain immunoglobulins are inserted into the host's genome. The human genes are incorporated, for example, using yeast artificial chromosomes containing the requisite human DNA segments. An animal which provides all the desired modifications is then obtained as progeny by crossbreeding intermediate transgenic animals containing fewer than the full complement of the modifications. The preferred embodiment of such a nonhuman animal is a mouse, and is termed the Xenomouse™ as disclosed in PCT publications WO 96/33735 and WO 96/34096. This animal produces B cells which secrete fully human immunoglobulins. The antibodies can be obtained directly from the animal after immunization with an immunogen of interest, as, for example, a preparation of a polyclonal antibody, or alternatively from immortalized B cells derived from the animal, such as hybridomas producing monoclonal antibodies. Additionally, the genes encoding the immunoglobulins with human variable regions can be recovered and expressed to obtain the antibodies directly, or can be further modified to obtain analogs of antibodies such as, for example, single chain Fv molecules.

[0183] An example of a method of producing a nonhuman host, exemplified as a mouse, lacking expression of an endogenous immunoglobulin heavy chain is disclosed in U.S. Pat. No. 5,939,598. It can be obtained by a method including deleting the J segment genes from at least one endogenous heavy chain locus in an embryonic stem cell to prevent rearrangement of the locus and to prevent formation of a transcript of a rearranged immunoglobulin heavy chain locus, the deletion being effected by a targeting vector containing a gene encoding a selectable marker; and producing from the embryonic stem cell a transgenic mouse whose somatic and germ cells contain the gene encoding the selectable marker.

[0184] A method for producing an antibody of interest, such as a human antibody, is disclosed in U.S. Pat. No. 5,916,771. It includes introducing an expression vector that contains a nucleotide sequence encoding a heavy chain into one mammalian host cell in culture, introducing an expression vector containing a nucleotide sequence encoding a light chain into another mammalian host cell, and fusing the two cells to form a hybrid cell. The hybrid cell expresses an antibody containing the heavy chain and the light chain.

[0185] In a further improvement on this procedure, a method for identifying a clinically relevant epitope on an immunogen, and a correlative method for selecting an antibody that binds immunospecifically to the relevant epitope with high affinity, are disclosed in PCT publication WO 99/53049.

[0186] Fab Fragments and Single Chain Antibodies

[0187] According to the invention, techniques can be adapted for the production of single-chain antibodies specific to an antigenic protein of the invention (see e.g., U.S. Pat. No. 4,946,778). In addition, methods can be adapted for the construction of Fab expression libraries (see e.g., Huse, et al., 1989 Science 246: 1275-1281) to allow rapid and effective identification of monoclonal Fab fragments with the desired specificity for a protein or derivatives, fragments, analogs or homologs thereof. Antibody fragments that contain the idiotypes to a protein antigen may be produced by techniques known in the art including, but not limited to: (i) an F(ab′)2 fragment produced by pepsin digestion of an antibody molecule; (ii) an Fab fragment generated by reducing the disulfide bridges of an F(ab′)2 fragment; (iii) an Fab fragment generated by the treatment of the antibody molecule with papain and a reducing agent and (iv) Fv fragments.

[0188] Bispecific Antibodies

[0189] Bispecific antibodies are monoclonal, preferably human or humanized, antibodies that have binding specificities for at least two different antigens. In the present case, one of the binding specificities is for an antigenic protein of the invention. The second binding target is any other antigen, and advantageously is a cell-surface protein or receptor or receptor subunit.

[0190] Methods for making bispecific antibodies are known in the art. Traditionally, the recombinant production of bispecific antibodies is based on the co-expression of two immunoglobulin heavy-chain/light-chain pairs, where the two heavy chains have different specificities (Milstein and Cuello, Nature, 305:537-539 (1983)). Because of the random assortment of immunoglobulin heavy and light chains, these hybridomas (quadromas) produce a potential mixture of ten different antibody molecules, of which only one has the correct bispecific structure. The purification of the correct molecule is usually accomplished by affinity chromatography steps. Similar procedures are disclosed in WO 93/08829, published 13 May 1993, and in Traunecker et al., EMBO J., 10:3655-3659 (1991).

[0191] Antibody variable domains with the desired binding specificities (antibody-antigen combining sites) can be fused to immunoglobulin constant domain sequences. The fusion preferably is with an immunoglobulin heavy-chain constant domain, comprising at least part of the hinge, CH2, and CH3 regions. It is preferred to have the first heavy-chain constant region (CH1) containing the site necessary for light-chain binding present in at least one of the fusions. DNAs encoding the immunoglobulin heavy-chain fusions and, if desired, the immunoglobulin light chain, are inserted into separate expression vectors, and are co-transfected into a suitable host organism. For further details of generating bispecific antibodies see, for example, Suresh et al., Methods in Enzymology, 121:210 (1986).

[0192] According to another approach described in WO 96/27011, the interface between a pair of antibody molecules can be engineered to maximize the percentage of heterodimers which are recovered from recombinant cell culture. The preferred interface comprises at least a part of the CH3 region of an antibody constant domain. In this method, one or more small amino acid side chains from the interface of the first antibody molecule are replaced with larger side chains (e.g. tyrosine or tryptophan). Compensatory “cavities” of identical or similar size to the large side chain(s) are created on the interface of the second antibody molecule by replacing large amino acid side chains with smaller ones (e.g. alanine or threonine). This provides a mechanism for increasing the yield of the heterodimer over other unwanted end-products such as homodimers.

[0193] Bispecific antibodies can be prepared as full length antibodies or antibody fragments (e.g. F(ab′)2 bispecific antibodies). Techniques for generating bispecific antibodies from antibody fragments have been described in the literature. For example, bispecific antibodies can be prepared using chemical linkage. Brennan et al., Science 229:81 (1985) describe a procedure wherein intact antibodies are proteolytically cleaved to generate F(ab′)2 fragments. These fragments are reduced in the presence of the dithiol complexing agent sodium arsenite to stabilize vicinal dithiols and prevent intermolecular disulfide formation. The Fab′ fragments generated are then converted to thionitrobenzoate (TNB) derivatives. One of the Fab′-TNB derivatives is then reconverted to the Fab′-thiol by reduction with mercaptoethylamine and is mixed with an equimolar amount of the other Fab′-TNB derivative to form the bispecific antibody. The bispecific antibodies produced can be used as agents for the selective immobilization of enzymes.

[0194] Additionally, Fab′ fragments can be directly recovered from E. coli and chemically coupled to form bispecific antibodies. Shalaby et al., J. Exp. Med. 175:217-225 (1992) describe the production of a fully humanized bispecific antibody F(ab′)2 molecule. Each Fab′ fragment was separately secreted from E. coli and subjected to directed chemical coupling in vitro to form the bispecific antibody. The bispecific antibody thus formed was able to bind to cells overexpressing the ErbB2 receptor and normal human T cells, as well as trigger the lytic activity of human cytotoxic lymphocytes against human breast tumor targets.

[0195] Various techniques for making and isolating bispecific antibody fragments directly from recombinant cell culture have also been described. For example, bispecific antibodies have been produced using leucine zippers. Kostelny et al., J. Immunol. 148(5):1547-1553 (1992). The leucine zipper peptides from the Fos and Jun proteins were linked to the Fab′ portions of two different antibodies by gene fusion. The antibody homodimers were reduced at the hinge region to form monomers and then re-oxidized to form the antibody heterodimers. This method can also be utilized for the production of antibody homodimers. The “diabody” technology described by Hollinger et al., Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993) has provided an alternative mechanism for making bispecific antibody fragments. The fragments comprise a heavy-chain variable domain (VH) connected to a light-chain variable domain (VL) by a linker which is too short to allow pairing between the two domains on the same chain. Accordingly, the VH and VL domains of one fragment are forced to pair with the complementary VL and VH domains of another fragment, thereby forming two antigen-binding sites. Another strategy for making bispecific antibody fragments by the use of single-chain Fv (sFv) dimers has also been reported. See, Gruber et al., J. Immunol. 152:5368 (1994).

[0196] Antibodies with more than two valencies are contemplated. For example, trispecific antibodies can be prepared. Tutt et al., J. Immunol. 147:60 (1991).

[0197] Exemplary bispecific antibodies can bind to two different epitopes, at least one of which originates in the protein antigen of the invention. Alternatively, an anti-antigenic arm of an immunoglobulin molecule can be combined with an arm which binds to a triggering molecule on a leukocyte such as a T-cell receptor molecule (e.g. CD2, CD3, CD28, or B7), or Fc receptors for IgG (Fc&ggr;R), such as Fc&ggr;RI (CD64), Fc&ggr;RII (CD32) and Fc&ggr;RIII (CD16) so as to focus cellular defense mechanisms to the cell expressing the particular antigen. Bispecific antibodies can also be used to direct cytotoxic agents to cells which express a particular antigen. These antibodies possess an antigen-binding arm and an arm which binds a cytotoxic agent or a radionuclide chelator, such as EOTUBE, DPTA, DOTA, or TETA. Another bispecific antibody of interest binds the protein antigen described herein and further binds tissue factor (TF).

[0198] Heteroconjugate Antibodies

[0199] Heteroconjugate antibodies are also within the scope of the present invention. Heteroconjugate antibodies are composed of two covalently joined antibodies. Such antibodies have, for example, been proposed to target immune system cells to unwanted cells (U.S. Pat. No. 4,676,980), and for treatment of HIV infection (WO 91/00360; WO 92/200373; EP 03089). It is contemplated that the antibodies can be prepared in vitro using known methods in synthetic protein chemistry, including those involving crosslinking agents. For example, immunotoxins can be constructed using a disulfide exchange reaction or by forming a thioether bond. Examples of suitable reagents for this purpose include iminothiolate and methyl-4-mercaptobutyrimidate and those disclosed, for example, in U.S. Pat. No. 4,676,980.

[0200] Effector Function Engineering

[0201] It can be desirable to modify the antibody of the invention with respect to effector function, so as to enhance, e.g., the effectiveness of the antibody in treating cancer. For example, cysteine residue(s) can be introduced into the Fc region, thereby allowing interchain disulfide bond formation in this region. The homodimeric antibody thus generated can have improved internalization capability and/or increased complement-mediated cell killing and antibody-dependent cellular cytotoxicity (ADCC). See Caron et al., J. Exp Med., 176: 1191-1195 (1992) and Shopes, J. Immunol., 148: 2918-2922 (1992). Homodimeric antibodies with enhanced anti-tumor activity can also be prepared using heterobifunctional cross-linkers as described in Wolff et al. Cancer Research, 53: 2560-2565 (1993). Alternatively, an antibody can be engineered that has dual Fc regions and can thereby have enhanced complement lysis and ADCC capabilities. See Stevenson et al., Anti-Cancer Drug Design, 3: 219-230 (1989).

[0202] Immunoconjugates

[0203] The invention also pertains to immunoconjugates comprising an antibody conjugated to a cytotoxic agent such as a chemotherapeutic agent, toxin (e.g., an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or fragments thereof), or a radioactive isotope (i.e., a radioconjugate).

[0204] Chemotherapeutic agents useful in the generation of such immunoconjugates have been described above. Enzymatically active toxins and fragments thereof that can be used include diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes. A variety of radionuclides are available for the production of radioconjugated antibodies. Examples include 212Bi, 131I, 131In, 90Y, and 186Re.

[0205] Conjugates of the antibody and cytotoxic agent are made using a variety of bifunctional protein-coupling agents such as N-succinimidyl-3-(2-pyridyldithiol) propionate (SPDP). iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCL), active esters (such as disuccinimidyl suberate), aldehydes (such as glutareldehyde), bis-azido compounds (such as bis (p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as tolyene 2,6-diisocyanate), and bis-active fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene). For example, a ricin immunotoxin can be prepared as described in Vitetta et al., Science, 238: 1098 (1987). Carbon-14-labeled 1-isothiocyanatobenzyl-3-methyldiethylene triaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugation of radionucleotide to the antibody. See WO94/11026.

[0206] In another embodiment, the antibody can be conjugated to a “receptor” (such streptavidin) for utilization in tumor pretargeting wherein the antibody-receptor conjugate is administered to the patient, followed by removal of unbound conjugate from the circulation using a clearing agent and then administration of a “ligand” (e.g., avidin) that is in turn conjugated to a cytotoxic agent.

[0207] Immunoliposomes

[0208] The antibodies disclosed herein can also be formulated as immunoliposomes. Liposomes containing the antibody are prepared by methods known in the art, such as described in Epstein et al., Proc. Natl. Acad. Sci. USA, 82: 3688 (1985); Hwang et al., Proc. Natl Acad. Sci. USA, 77: 4030 (1980); and U.S. Pat. Nos. 4,485,045 and 4,544,545. Liposomes with enhanced circulation time are disclosed in U.S. Pat. No. 5,013,556.

[0209] Particularly useful liposomes can be generated by the reverse-phase evaporation method with a lipid composition comprising phosphatidylcholine, cholesterol, and PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes are extruded through filters of defined pore size to yield liposomes with the desired diameter. Fab′ fragments of the antibody of the present invention can be conjugated to the liposomes as described in Martin et al., J. Biol. Chem., 257: 286-288 (1982) via a disulfide-interchange reaction. A chemotherapeutic agent (such as Doxorubicin) is optionally contained within the liposome. See Gabizon et al., J. National Cancer Inst., 81(19): 1484 (1989).

[0210] Diagnostic Applications of Antibodies Directed Against the Proteins of the Invention

[0211] Antibodies directed against a protein of the invention may be used in methods known within the art relating to the localization and/or quantitation of the protein (e.g., for use in measuring levels of the protein within appropriate physiological samples, for use in diagnostic methods, for use in imaging the protein, and the like). In a given embodiment, antibodies against the proteins, or derivatives, fragments, analogs or homologs thereof, that contain the antigen binding domain, are utilized as pharmacologically-active compounds (see below).

[0212] An antibody specific for a protein of the invention can be used to isolate the protein by standard techniques, such as immunoaffinity chromatography or immunoprecipitation. Such an antibody can facilitate the purification of the natural protein antigen from cells and of recombinantly produced antigen expressed in host cells. Moreover, such an antibody can be used to detect the antigenic protein (e.g., in a cellular lysate or cell supernatant) in order to evaluate the abundance and pattern of expression of the antigenic protein. Antibodies directed against the protein can be used diagnostically to monitor protein levels in tissue as part of a clinical testing procedure, e.g., to, for example, determine the efficacy of a given treatment regimen. Detection can be facilitated by coupling (i.e., physically linking) the antibody to a detectable substance. Examples of detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, bioluminescent materials, and radioactive materials. Examples of suitable enzymes include horseradish peroxidase, alkaline phosphatase, &bgr;-galactosidase, or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescent material includes luminol; examples of bioluminescent materials include luciferase, luciferin, and aequorin, and examples of suitable radioactive material include 125I, 131I, 35S or 3H.

[0213] Antibody Therapeutics

[0214] Antibodies of the invention, including polyclonal, monoclonal, humanized and fully human antibodies, may used as therapeutic agents. Such agents will generally be employed to treat or prevent a disease or pathology in a subject. An antibody preparation, preferably one having high specificity and high affinity for its target antigen, is administered to the subject and will generally have an effect due to its binding with the target. Such an effect may be one of two kinds, depending on the specific nature of the interaction between the given antibody molecule and the target antigen in question. In the first instance, administration of the antibody may abrogate or inhibit the binding of the target with an endogenous ligand to which it naturally binds. In this case, the antibody binds to the target and masks a binding site of the naturally occurring ligand, wherein the ligand serves as an effector molecule. Thus the receptor mediates a signal transduction pathway for which ligand is responsible.

[0215] Alternatively, the effect may be one in which the antibody elicits a physiological result by virtue of binding to an effector binding site on the target molecule. In this case the target, a receptor having an endogenous ligand which may be absent or defective in the disease or pathology, binds the antibody as a surrogate effector ligand, initiating a receptor-based signal transduction event by the receptor.

[0216] A therapeutically effective amount of an antibody of the invention relates generally to the amount needed to achieve a therapeutic objective. As noted above, this may be a binding interaction between the antibody and its target antigen that, in certain cases, interferes with the functioning of the target, and in other cases, promotes a physiological response. The amount required to be administered will furthermore depend on the binding affinity of the antibody for its specific antigen, and will also depend on the rate at which an administered antibody is depleted from the free volume other subject to which it is administered. Common ranges for therapeutically effective dosing of an antibody or antibody fragment of the invention may be, by way of nonlimiting example, from about 0.1 mg/kg body weight to about 50 mg/kg body weight. Common dosing frequencies may range, for example, from twice daily to once a week.

[0217] Pharmaceutical Compositions of Antibodies

[0218] Antibodies specifically binding a protein of the invention, as well as other molecules identified by the screening assays disclosed herein, can be administered for the treatment of various disorders in the form of pharmaceutical compositions. Principles and considerations involved in preparing such compositions, as well as guidance in the choice of components are provided, for example, in Remington: The Science And Practice Of Pharmacy 19th ed. (Alfonso R. Gennaro, et al., editors) Mack Pub. Co., Easton, Pa.: 1995; Drug Absorption Enhancement: Concepts, Possibilities, Limitations, And Trends, Harwood Academic Publishers, Langhorne, Pa., 1994; and Peptide And Protein Drug Delivery (Advances In Parenteral Sciences, Vol. 4), 1991, M. Dekker, New York.

[0219] If the antigenic protein is intracellular and whole antibodies are used as inhibitors, internalizing antibodies are preferred. However, liposomes can also be used to deliver the antibody, or an antibody fragment, into cells. Where antibody fragments are used, the smallest inhibitory fragment that specifically binds to the binding domain of the target protein is preferred. For example, based upon the variable-region sequences of an antibody, peptide molecules can be designed that retain the ability to bind the target protein sequence. Such peptides can be synthesized chemically and/or produced by recombinant DNA technology. See, e.g., Marasco et al., Proc. Natl. Acad. Sci. USA, 90: 7889-7893 (1993). The formulation herein can also contain more than one active compound as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. Alternatively, or in addition, the composition can comprise an agent that enhances its function, such as, for example, a cytotoxic agent, cytokine, chemotherapeutic agent, or growth-inhibitory agent. Such molecules are suitably present in combination in amounts that are effective for the purpose intended.

[0220] The active ingredients can also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles, and nanocapsules) or in macroemulsions.

[0221] The formulations to be used for in vivo administration must be sterile. This is readily accomplished by filtration through sterile filtration membranes.

[0222] Sustained-release preparations can be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and &ggr; ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(−)-3-hydroxybutyric acid. While polymers such as ethylene-vinyl acetate and lactic acid-glycolic acid enable release of molecules for over 100 days, certain hydrogels release proteins for shorter time periods.

[0223] ELISA Assay

[0224] An agent for detecting an analyte protein is an antibody capable of binding to an analyte protein, preferably an antibody with a detectable label. Antibodies can be polyclonal, or more preferably, monoclonal. An intact antibody, or a fragment thereof (e.g., Fab or F(ab)2) can be used. The term “labeled”, with regard to the probe or antibody, is intended to encompass direct labeling of the probe or antibody by coupling (i.e., physically linking) a detectable substance to the probe or antibody, as well as indirect labeling of the probe or antibody by reactivity with another reagent that is directly labeled. Examples of indirect labeling include detection of a primary antibody using a fluorescently-labeled secondary antibody and end-labeling of a DNA probe with biotin such that it can be detected with fluorescently-labeled streptavidin. The term “biological sample” is intended to include tissues, cells and biological fluids isolated from a subject, as well as tissues, cells and fluids present within a subject. Included within the usage of the term “biological sample”, therefore, is blood and a fraction or component of blood including blood serum, blood plasma, or lymph. That is, the detection method of the invention can be used to detect an analyte mRNA, protein, or genomic DNA in a biological sample in vitro as well as in vivo. For example, in vitro techniques for detection of an analyte mRNA include Northern hybridizations and in situ hybridizations. In vitro techniques for detection of an analyte protein include enzyme linked immunosorbent assays (ELISAs), Western blots, immunoprecipitations, and immunofluorescence. In vitro techniques for detection of an analyte genomic DNA include Southern hybridizations. Procedures for conducting immunoassays are described, for example in “ELISA: Theory and Practice: Methods in Molecular Biology”, Vol. 42, J. R. Crowther (Ed.) Human Press, Totowa, N.J., 1995; “Immunoassay”, E. Diamandis and T. Christopoulus, Academic Press, Inc., San Diego, Calif., 1996; and “Practice and Theory of Enzyme Immunoassays”, P. Tijssen, Elsevier Science Publishers, Amsterdam, 1985. Furthermore, in vivo techniques for detection of an analyte protein include introducing into a subject a labeled anti-an analyte protein antibody. For example, the antibody can be labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques.

[0225] NOVX Recombinant Expression Vectors and Host Cells

[0226] Another aspect of the invention pertains to vectors, preferably expression vectors, containing a nucleic acid encoding a NOVX protein, or derivatives, fragments, analogs or homologs thereof. As used herein, the term “vector” refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a “plasmid”, which refers to a circular double stranded DNA loop into which additional DNA segments can be ligated. Another type of vector is a viral vector, wherein additional DNA segments can be ligated into the viral genome. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) are integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome. Moreover, certain vectors are capable of directing the expression of genes to which they are operatively-linked. Such vectors are referred to herein as “expression vectors”. In general, useful expression vectors in recombinant DNA techniques are often in the form of plasmids. In the present specification, “plasmid” and “vector” can be used interchangeably as the plasmid is the most commonly used form of vector. However, the invention is intended to include such other forms of expression vectors, such as viral vectors (e.g., replication defective retroviruses, adenoviruses and adeno-associated viruses), which serve equivalent functions.

[0227] The recombinant expression vectors of the invention comprise a nucleic acid of the invention in a form suitable for expression of the nucleic acid in a host cell, which means that the recombinant expression vectors include one or more regulatory sequences, selected on the basis of the host cells to be used for expression, that is operatively-linked to the nucleic acid sequence to be expressed. Within a recombinant expression vector, “operably-linked” is intended to mean that the nucleotide sequence of interest is linked to the regulatory sequence(s) in a manner that allows for expression of the nucleotide sequence (e.g., in an in vitro transcription/translation system or in a host cell when the vector is introduced into the host cell).

[0228] The term “regulatory sequence” is intended to includes promoters, enhancers and other expression control elements (e.g., polyadenylation signals). Such regulatory sequences are described, for example, in Goeddel, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990). Regulatory sequences include those that direct constitutive expression of a nucleotide sequence in many types of host cell and those that direct expression of the nucleotide sequence only in certain host cells (e.g., tissue-specific regulatory sequences). It will be appreciated by those skilled in the art that the design of the expression vector can depend on such factors as the choice of the host cell to be transformed, the level of expression of protein desired, etc. The expression vectors of the invention can be introduced into host cells to thereby produce proteins or peptides, including fusion proteins or peptides, encoded by nucleic acids as described herein (e.g., NOVX proteins, mutant forms of NOVX proteins, fusion proteins, etc.).

[0229] The recombinant expression vectors of the invention can be designed for expression of NOVX proteins in prokaryotic or eukaryotic cells. For example, NOVX proteins can be expressed in bacterial cells such as Escherichia coli, insect cells (using baculovirus expression vectors) yeast cells or mammalian cells. Suitable host cells are discussed further in Goeddel, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990). Alternatively, the recombinant expression vector can be transcribed and translated in vitro, for example using T7 promoter regulatory sequences and T7 polymerase.

[0230] Expression of proteins in prokaryotes is most often carried out in Escherichia coli with vectors containing constitutive or inducible promoters directing the expression of either fusion or non-fusion proteins. Fusion vectors add a number of amino acids to a protein encoded therein, usually to the amino terminus of the recombinant protein. Such fusion vectors typically serve three purposes: (i) to increase expression of recombinant protein; (ii) to increase the solubility of the recombinant protein; and (iii) to aid in the purification of the recombinant protein by acting as a ligand in affinity purification. Often, in fusion expression vectors, a proteolytic cleavage site is introduced at the junction of the fusion moiety and the recombinant protein to enable separation of the recombinant protein from the fusion moiety subsequent to purification of the fusion protein. Such enzymes, and their cognate recognition sequences, include Factor Xa, thrombin and enterokinase. Typical fusion expression vectors include pGEX (Pharmacia Biotech Inc; Smith and Johnson, 1988. Gene 67: 31-40), pMAL (New England Biolabs, Beverly, Mass.) and pRIT5 (Pharmacia, Piscataway, N.J.) that fuse glutathione S-transferase (GST), maltose E binding protein, or protein A, respectively, to the target recombinant protein.

[0231] Examples of suitable inducible non-fusion E. coli expression vectors include pTrc (Amrann et al., (1988) Gene 69:301-315) and pET 11d (Studier et al., GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990) 60-89).

[0232] One strategy to maximize recombinant protein expression in E. coli is to express the protein in a host bacteria with an impaired capacity to proteolytically cleave the recombinant protein. See, e.g., Gottesman, GENE EXPRESSION TECHNOLOGY: METHODS IN ENZYMOLOGY 185, Academic Press, San Diego, Calif. (1990) 119-128. Another strategy is to alter the nucleic acid sequence of the nucleic acid to be inserted into an expression vector so that the individual codons for each amino acid are those preferentially utilized in E. coli (see, e.g., Wada, et al., 1992. Nucl. Acids Res. 20: 2111-2118). Such alteration of nucleic acid sequences of the invention can be carried out by standard DNA synthesis techniques.

[0233] In another embodiment, the NOVX expression vector is a yeast expression vector. Examples of vectors for expression in yeast Saccharomyces cerivisae include pYepSec1 (Baldari, et al., 1987. EMBO J. 6: 229-234), pMFa (Kudjan and Herskowitz, 1982. Cell 30: 933-943), pJRY88 (Schultz et al., 1987. Gene 54: 113-123), pYES2 (Invitrogen Corporation, San Diego, Calif.), and picZ (InVitrogen Corp, San Diego, Calif.).

[0234] Alternatively, NOVX can be expressed in insect cells using baculovirus expression vectors. Baculovirus vectors available for expression of proteins in cultured insect cells (e.g., SF9 cells) include the pAc series (Smith, et al., 1983. Mol. Cell. Biol. 3: 2156-2165) and the pVL series (Lucklow and Summers, 1989. Virology 170: 31-39).

[0235] In yet another embodiment, a nucleic acid of the invention is expressed in mammalian cells using a mammalian expression vector. Examples of mammalian expression vectors include pCDM8 (Seed, 1987. Nature 329: 840) and pMT2PC (Kaufman, et al., 1987. EMBO J. 6: 187-195). When used in mammalian cells, the expression vector's control functions are often provided by viral regulatory elements. For example, commonly used promoters are derived from polyoma, adenovirus 2, cytomegalovirus, and simian virus 40. For other suitable expression systems for both prokaryotic and eukaryotic cells see, e.g., Chapters 16 and 17 of Sambrook, et al., MOLECULAR CLONING: A LABORATORY MANUAL. 2nd ed., Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989.

[0236] In another embodiment, the recombinant mammalian expression vector is capable of directing expression of the nucleic acid preferentially in a particular cell type (e.g., tissue-specific regulatory elements are used to express the nucleic acid). Tissue-specific regulatory elements are known in the art. Non-limiting examples of suitable tissue-specific promoters include the albumin promoter (liver-specific; Pinkert, et al., 1987. Genes Dev. 1: 268-277), lymphoid-specific promoters (Calame and Eaton, 1988. Adv. Immunol. 43: 235-275), in particular promoters of T cell receptors (Winoto and Baltimore, 1989. EMBO J. 8: 729-733) and immunoglobulins (Banedji, et al., 1983. Cell 33: 729-740; Queen and Baltimore, 1983. Cell 33: 741-748), neuron-specific promoters (e.g., the neurofilament promoter; Byrne and Ruddle, 1989. Proc. Natl. Acad. Sci. USA 86: 5473-5477), pancreas-specific promoters (Edlund, et al., 1985. Science 230: 912-916), and mammary gland-specific promoters (e.g., milk whey promoter; U.S. Pat. No. 4,873,316 and European Application Publication No. 264,166). Developmentally-regulated promoters are also encompassed, e.g., the murine hox promoters (Kessel and Gruss, 1990. Science 249: 374-379) and the &agr;-fetoprotein promoter (Campes and Tilghman, 1989. Genes Dev. 3: 537-546).

[0237] The invention further provides a recombinant expression vector comprising a DNA molecule of the invention cloned into the expression vector in an antisense orientation. That is, the DNA molecule is operatively-linked to a regulatory sequence in a manner that allows for expression (by transcription of the DNA molecule) of an RNA molecule that is antisense to NOVX mRNA. Regulatory sequences operatively linked to a nucleic acid cloned in the antisense orientation can be chosen that direct the continuous expression of the antisense RNA molecule in a variety of cell types, for instance viral promoters and/or enhancers, or regulatory sequences can be chosen that direct constitutive, tissue specific or cell type specific expression of antisense RNA. The antisense expression vector can be in the form of a recombinant plasmid, phagemid or attenuated virus in which antisense nucleic acids are produced under the control of a high efficiency regulatory region, the activity of which can be determined by the cell type into which the vector is introduced. For a discussion of the regulation of gene expression using antisense genes see, e.g., Weintraub, et al., “Antisense RNA as a molecular tool for genetic analysis,” Reviews-Trends in Genetics, Vol. 1(1) 1986.

[0238] Another aspect of the invention pertains to host cells into which a recombinant expression vector of the invention has been introduced. The terms “host cell” and “recombinant host cell” are used interchangeably herein. It is understood that such terms refer not only to the particular subject cell but also to the progeny or potential progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term as used herein.

[0239] A host cell can be any prokaryotic or eukaryotic cell. For example, NOVX protein can be expressed in bacterial cells such as E. coli, insect cells, yeast or mammalian cells (such as Chinese hamster ovary cells (CHO) or COS cells). Other suitable host cells are known to those skilled in the art.

[0240] Vector DNA can be introduced into prokaryotic or eukaryotic cells via conventional transformation or transfection techniques. As used herein, the terms “transformation” and “transfection” are intended to refer to a variety of art-recognized techniques for introducing foreign nucleic acid (e.g., DNA) into a host cell, including calcium phosphate or calcium chloride co-precipitation, DEAE-dextran-mediated transfection, lipofection, or electroporation. Suitable methods for transforming or transfecting host cells can be found in Sambrook, et al. (MOLECULAR CLONING: A LABORATORY MANUAL. 2nd ed., Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989), and other laboratory manuals.

[0241] For stable transfection of mammalian cells, it is known that, depending upon the expression vector and transfection technique used, only a small fraction of cells may integrate the foreign DNA into their genome. In order to identify and select these integrants, a gene that encodes a selectable marker (e.g., resistance to antibiotics) is generally introduced into the host cells along with the gene of interest. Various selectable markers include those that confer resistance to drugs, such as G418, hygromycin and methotrexate. Nucleic acid encoding a selectable marker can be introduced into a host cell on the same vector as that encoding NOVX or can be introduced on a separate vector. Cells stably transfected with the introduced nucleic acid can be identified by drug selection (e.g., cells that have incorporated the selectable marker gene will survive, while the other cells die).

[0242] A host cell of the invention, such as a prokaryotic or eukaryotic host cell in culture, can be used to produce (i.e., express) NOVX protein. Accordingly, the invention further provides methods for producing NOVX protein using the host cells of the invention. In one embodiment, the method comprises culturing the host cell of invention (into which a recombinant expression vector encoding NOVX protein has been introduced) in a suitable medium such that NOVX protein is produced. In another embodiment, the method further comprises isolating NOVX protein from the medium or the host cell.

[0243] Transgenic NOVX Animals

[0244] The host cells of the invention can also be used to produce non-human transgenic animals. For example, in one embodiment, a host cell of the invention is a fertilized oocyte or an embryonic stem cell into which NOVX protein-coding sequences have been introduced. Such host cells can then be used to create non-human transgenic animals in which exogenous NOVX sequences have been introduced into their genome or homologous recombinant animals in which endogenous NOVX sequences have been altered. Such animals are useful for studying the function and/or activity of NOVX protein and for identifying and/or evaluating modulators of NOVX protein activity. As used herein, a “transgenic animal” is a non-human animal, preferably a mammal, more preferably a rodent such as a rat or mouse, in which one or more of the cells of the animal includes a transgene. Other examples of transgenic animals include non-human primates, sheep, dogs, cows, goats, chickens, amphibians, etc. A transgene is exogenous DNA that is integrated into the genome of a cell from which a transgenic animal develops and that remains in the genome of the mature animal, thereby directing the expression of an encoded gene product in one or more cell types or tissues of the transgenic animal. As used herein, a “homologous recombinant animal” is a non-human animal, preferably a mammal, more preferably a mouse, in which an endogenous NOVX gene has been altered by homologous recombination between the endogenous gene and an exogenous DNA molecule introduced into a cell of the animal, e.g., an embryonic cell of the animal, prior to development of the animal.

[0245] A transgenic animal of the invention can be created by introducing NOVX-encoding nucleic acid into the male pronuclei of a fertilized oocyte (e.g., by microinjection, retroviral infection) and allowing the oocyte to develop in a pseudopregnant female foster animal. The human NOVX cDNA sequences, i.e., any one of SEQ ID NOS:2n-1, wherein n is an integer between 1 and 64, can be introduced as a transgene into the genome of a non-human animal. Alternatively, a non-human homologue of the human NOVX gene, such as a mouse NOVX gene, can be isolated based on hybridization to the human NOVX cDNA (described further supra) and used as a transgene. Intronic sequences and polyadenylation signals can also be included in the transgene to increase the efficiency of expression of the transgene. A tissue-specific regulatory sequence(s) can be operably-linked to the NOVX transgene to direct expression of NOVX protein to particular cells. Methods for generating transgenic animals via embryo manipulation and microinjection, particularly animals such as mice, have become conventional in the art and are described, for example, in U.S. Pat. Nos. 4,736,866; 4,870,009; and 4,873,191; and Hogan, 1986. In: MANIPULATING THE MOUSE EMBRYO, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. Similar methods are used for production of other transgenic animals. A transgenic founder animal can be identified based upon the presence of the NOVX transgene in its genome and/or expression of NOVX mRNA in tissues or cells of the animals. A transgenic founder animal can then be used to breed additional animals carrying the transgene. Moreover, transgenic animals carrying a transgene-encoding NOVX protein can further be bred to other transgenic animals carrying other transgenes.

[0246] To create a homologous recombinant animal, a vector is prepared which contains at least a portion of a NOVX gene into which a deletion, addition or substitution has been introduced to thereby alter, e.g., functionally disrupt, the NOVX gene. The NOVX gene can be a human gene (e.g., the cDNA of any one of SEQ ID NOS:2n-1, wherein n is an integer between 1 and 64), but more preferably, is a non-human homologue of a human NOVX gene. For example, a mouse homologue of human NOVX gene of SEQ ID NOS:2n-1, wherein n is an integer between 1 and 64, can be used to construct a homologous recombination vector suitable for altering an endogenous NOVX gene in the mouse genome. In one embodiment, the vector is designed such that, upon homologous recombination, the endogenous NOVX gene is functionally disrupted (i.e., no longer encodes a functional protein; also referred to as a “knock out” vector).

[0247] Alternatively, the vector can be designed such that, upon homologous recombination, the endogenous NOVX gene is mutated or otherwise altered but still encodes functional protein (e.g., the upstream regulatory region can be altered to thereby alter the expression of the endogenous NOVX protein). In the homologous recombination vector, the altered portion of the NOVX gene is flanked at its 5′- and 3′-termini by additional nucleic acid of the NOVX gene to allow for homologous recombination to occur between the exogenous NOVX gene carried by the vector and an endogenous NOVX gene in an embryonic stem cell. The additional flanking NOVX nucleic acid is of sufficient length for successful homologous recombination with the endogenous gene. Typically, several kilobases of flanking DNA (both at the 5′- and 3′-termini) are included in the vector. See, e.g., Thomas, et al., 1987. Cell 51: 503 for a description of homologous recombination vectors. The vector is ten introduced into an embryonic stem cell line (e.g., by electroporation) and cells in which the introduced NOVX gene has homologously-recombined with the endogenous NOVX gene are selected. See, e.g., Li, et al., 1992. Cell 69: 915.

[0248] The selected cells are then injected into a blastocyst of an animal (e.g., a mouse) to form aggregation chimeras. See, e.g., Bradley, 1987. In: TERATOCARCINOMAS AND EMBRYONIC STEM CELLS: A PRACTICAL APPROACH, Robertson, ed. IRL, Oxford, pp. 113-152. A chimeric embryo can then be implanted into a suitable pseudopregnant female foster animal and the embryo brought to term. Progeny harboring the homologously-recombined DNA in their germ cells can be used to breed animals in which all cells of the animal contain the homologously-recombined DNA by germline transmission of the transgene. Methods for constructing homologous recombination vectors and homologous recombinant animals are described further in Bradley, 1991. Curr. Opin. Biotechnol. 2: 823-829; PCT International Publication Nos.: WO 90/11354; WO 91/01140; WO 92/0968; and WO 93/04169.

[0249] In another embodiment, transgenic non-humans animals can be produced that contain selected systems that allow for regulated expression of the transgene. One example of such a system is the cre/loxP recombinase system of bacteriophage P1. For a description of the cre/loxP recombinase system, See, e.g., Lakso, et al., 1992. Proc. Natl. Acad. Sci. USA 89: 6232-6236. Another example of a recombinase system is the FLP recombinase system of Saccharomyces cerevisiae. See, O'Gorman, et al., 1991. Science 251:1351-1355. If a cre/loxP recombinase system is used to regulate expression of the transgene, animals containing transgenes encoding both the Cre recombinase and a selected protein are required. Such animals can be provided through the construction of “double” transgenic animals, e.g., by mating two transgenic animals, one containing a transgene encoding a selected protein and the other containing a transgene encoding a recombinase.

[0250] Clones of the non-human transgenic animals described herein can also be produced according to the methods described in Wilmut, et al., 1997. Nature 385: 810-813. In brief, a cell (e.g., a somatic cell) from the transgenic animal can be isolated and induced to exit the growth cycle and enter G0 phase. The quiescent cell can then be fused, e.g., through the use of electrical pulses, to an enucleated oocyte from an animal of the same species from which the quiescent cell is isolated. The reconstructed oocyte is then cultured such that it develops to morula or blastocyte and then transferred to pseudopregnant female foster animal. The offspring borne of this female foster animal will be a clone of the animal from which the cell (e.g., the somatic cell) is isolated.

[0251] Pharmaceutical Compositions

[0252] The NOVX nucleic acid molecules, NOVX proteins, and anti-NOVX antibodies (also referred to herein as “active compounds”) of the invention, and derivatives, fragments, analogs and homologs thereof, can be incorporated into pharmaceutical compositions suitable for administration. Such compositions typically comprise the nucleic acid molecule, protein, or antibody and a pharmaceutically acceptable carrier. As used herein, “pharmaceutically acceptable carrier” is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Suitable carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, a standard reference text in the field, which is incorporated herein by reference. Preferred examples of such carriers or diluents include, but are not limited to, water, saline, finger's solutions, dextrose solution, and 5% human serum albumin. Liposomes and non-aqueous vehicles such as fixed oils may also be used. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.

[0253] A pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (i.e., topical), transmucosal, and rectal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

[0254] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as manitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

[0255] Sterile injectable solutions can be prepared by incorporating the active compound (e.g., a NOVX protein or anti-NOVX antibody) in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0256] Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0257] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

[0258] Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.

[0259] The compounds can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.

[0260] In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

[0261] It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.

[0262] The nucleic acid molecules of the invention can be inserted into vectors and used as gene therapy vectors. Gene therapy vectors can be delivered to a subject by, for example, intravenous injection, local administration (see, e.g., U.S. Pat. No. 5,328,470) or by stereotactic injection (see, e.g., Chen, et al., 1994. Proc. Natl. Acad. Sci. USA 91: 3054-3057). The pharmaceutical preparation of the gene therapy vector can include the gene therapy vector in an acceptable diluent, or can comprise a slow release matrix in which the gene delivery vehicle is imbedded. Alternatively, where the complete gene delivery vector can be produced intact from recombinant cells, e.g., retroviral vectors, the pharmaceutical preparation can include one or more cells that produce the gene delivery system.

[0263] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0264] Screening and Detection Methods

[0265] The isolated nucleic acid molecules of the invention can be used to express NOVX protein (e.g., via a recombinant expression vector in a host cell in gene therapy applications), to detect NOVX mRNA (e.g., in a biological sample) or a genetic lesion in a NOVX gene, and to modulate NOVX activity, as described further, below. In addition, the NOVX proteins can be used to screen drugs or compounds that modulate the NOVX protein activity or expression as well as to treat disorders characterized by insufficient or excessive production of NOVX protein or production of NOVX protein forms that have decreased or aberrant activity compared to NOVX wild-type protein (e.g.; diabetes (regulates insulin release); obesity (binds and transport lipids); metabolic disturbances associated with obesity, the metabolic syndrome X as well as anorexia and wasting disorders associated with chronic diseases and various cancers, and infectious disease(possesses anti-microbial activity) and the various dyslipidemias. In addition, the anti-NOVX antibodies of the invention can be used to detect and isolate NOVX proteins and modulate NOVX activity. In yet a further aspect, the invention can be used in methods to influence appetite, absorption of nutrients and the disposition of metabolic substrates in both a positive and negative fashion.

[0266] The invention further pertains to novel agents identified by the screening assays described herein and uses thereof for treatments as described, supra.

[0267] Screening Assays

[0268] The invention provides a method (also referred to herein as a “screening assay”) for identifying modulators, i.e., candidate or test compounds or agents (e.g., peptides, peptidomimetics, small molecules or other drugs) that bind to NOVX proteins or have a stimulatory or inhibitory effect on, e.g., NOVX protein expression or NOVX protein activity. The invention also includes compounds identified in the screening assays described herein.

[0269] In one embodiment, the invention provides assays for screening candidate or test compounds which bind to or modulate the activity of the membrane-bound form of a NOVX protein or polypeptide or biologically-active portion thereof. The test compounds of the invention can be obtained using any of the numerous approaches in combinatorial library methods known in the art, including: biological libraries; spatially addressable parallel solid phase or solution phase libraries; synthetic library methods requiring deconvolution; the “one-bead one-compound” library method; and synthetic library methods using affinity chromatography selection. The biological library approach is limited to peptide libraries, while the other four approaches are applicable to peptide, non-peptide oligomer or small molecule libraries of compounds. See, e.g., Lam, 1997. Anticancer Drug Design 12: 145.

[0270] A “small molecule” as used herein, is meant to refer to a composition that has a molecular weight of less than about 5 kD and most preferably less than about 4 kD. Small molecules can be, e.g., nucleic acids, peptides, polypeptides, peptidomimetics, carbohydrates, lipids or other organic or inorganic molecules. Libraries of chemical and/or biological mixtures, such as fungal, bacterial, or algal extracts, are known in the art and can be screened with any of the assays of the invention.

[0271] Examples of methods for the synthesis of molecular libraries can be found in the art, for example in: DeWitt, et al., 1993. Proc. Natl. Acad. Sci. U.S.A. 90: 6909; Erb, et al., 1994. Proc. Natl. Acad. Sci. U.S.A. 91: 11422; Zuckermann, et al., 1994. J. Med. Chem. 37: 2678; Cho, et al., 1993. Science 261: 1303; Carrell, et al., 1994. Angew. Chem. Int. Ed. Engl. 33: 2059; Carell, et al., 1994. Angew. Chem. Int. Ed. Engl. 33: 2061; and Gallop, et al., 1994. J. Med. Chem. 37: 1233.

[0272] Libraries of compounds may be presented in solution (e.g. Houghten, 1992. Biotechniques 13: 412-421), or on beads (Lam, 1991. Nature 354: 82-84), on chips (Fodor, 1993. Nature 364: 555-556), bacteria (Ladner, U.S. Pat. No. 5,223,409), spores (Ladner, U.S. Pat. No. 5,233,409), plasmids (Cull, et al., 1992. Proc. Natl. Acad. Sci. USA 89: 1865-1869) or on phage (Scott and Smith, 1990. Science 249: 386-390; Devlin, 1990. Science 249: 404-406; Cwirla, et al., 1990. Proc. Natl. Acad. Sci. U.S.A. 87: 6378-6382; Felici, 1991. J. Mol. Biol. 222: 301-310; Ladner, U.S. Pat. No. 5,233,409.).

[0273] In one embodiment, an assay is a cell-based assay in which a cell which expresses a membrane-bound form of NOVX protein, or a biologically-active portion thereof, on the cell surface is contacted with a test compound and the ability of the test compound to bind to a NOVX protein determined. The cell, for example, can of mammalian origin or a yeast cell. Determining the ability of the test compound to bind to the NOVX protein can be accomplished, for example, by coupling the test compound with a radioisotope or enzymatic label such that binding of the test compound to the NOVX protein or biologically-active portion thereof can be determined by detecting the labeled compound in a complex. For example, test compounds can be labeled with 125I, 35S, 14C, or 3H, either directly or indirectly, and the radioisotope detected by direct counting of radioemission or by scintillation counting. Alternatively, test compounds can be enzymatically-labeled with, for example, horseradish peroxidase, alkaline phosphatase, or luciferase, and the enzymatic label detected by determination of conversion of an appropriate substrate to product. In one embodiment, the assay comprises contacting a cell which expresses a membrane-bound form of NOVX protein, or a biologically-active portion thereof, on the cell surface with a known compound which binds NOVX to form an assay mixture, contacting the assay mixture with a test compound, and determining the ability of the test compound to interact with a NOVX protein, wherein determining the ability of the test compound to interact with a NOVX protein comprises determining the ability of the test compound to preferentially bind to NOVX protein or a biologically-active portion thereof as compared to the known compound.

[0274] In another embodiment, an assay is a cell-based assay comprising contacting a cell expressing a membrane-bound form of NOVX protein, or a biologically-active portion thereof, on the cell surface with a test compound and determining the ability of the test compound to modulate (e.g., stimulate or inhibit) the activity of the NOVX protein or biologically-active portion thereof. Determining the ability of the test compound to modulate the activity of NOVX or a biologically-active portion thereof can be accomplished, for example, by determining the ability of the NOVX protein to bind to or interact with a NOVX target molecule. As used herein, a “target molecule” is a molecule with which a NOVX protein binds or interacts in nature, for example, a molecule on the surface of a cell which expresses a NOVX interacting protein, a molecule on the surface of a second cell, a molecule in the extracellular milieu, a molecule associated with the internal surface of a cell membrane or a cytoplasmic molecule. a NOVX target molecule can be a non-NOVX molecule or a NOVX protein or polypeptide of the invention. In one embodiment, a NOVX target molecule is a component of a signal transduction pathway that facilitates transduction of an extracellular signal (e.g. a signal generated by binding of a compound to a membrane-bound NOVX molecule) through the cell membrane and into the cell. The target, for example, can be a second intercellular protein that has catalytic activity or a protein that facilitates the association of downstream signaling molecules with NOVX.

[0275] Determining the ability of the NOVX protein to bind to or interact with a NOVX target molecule can be accomplished by one of the methods described above for determining direct binding. In one embodiment, determining the ability of the NOVX protein to bind to or interact with a NOVX target molecule can be accomplished by determining the activity of the target molecule. For example, the activity of the target molecule can be determined by detecting induction of a cellular second messenger of the target (i.e. intracellular Ca2+, diacylglycerol, IP3, etc.), detecting catalytic/enzymatic activity of the target an appropriate substrate, detecting the induction of a reporter gene (comprising a NOVX-responsive regulatory element operatively linked to a nucleic acid encoding a detectable marker, e.g., luciferase), or detecting a cellular response, for example, cell survival, cellular differentiation, or cell proliferation.

[0276] In yet another embodiment, an assay of the invention is a cell-free assay comprising contacting a NOVX protein or biologically-active portion thereof with a test compound and determining the ability of the test compound to bind to the NOVX protein or biologically-active portion thereof. Binding of the test compound to the NOVX protein can be determined either directly or indirectly as described above. In one such embodiment, the assay comprises contacting the NOVX protein or biologically-active portion thereof with a known compound which binds NOVX to form an assay mixture, contacting the assay mixture with a test compound, and determining the ability of the test compound to interact with a NOVX protein, wherein determining the ability of the test compound to interact with a NOVX protein comprises determining the ability of the test compound to preferentially bind to NOVX or biologically-active portion thereof as compared to the known compound.

[0277] In still another embodiment, an assay is a cell-free assay comprising contacting NOVX protein or biologically-active portion thereof with a test compound and determining the ability of the test compound to modulate (e.g. stimulate or inhibit) the activity of the NOVX protein or biologically-active portion thereof. Determining the ability of the test compound to modulate the activity of NOVX can be accomplished, for example, by determining the ability of the NOVX protein to bind to a NOVX target molecule by one of the methods described above for determining direct binding. In an alternative embodiment, determining the ability of the test compound to modulate the activity of NOVX protein can be accomplished by determining the ability of the NOVX protein further modulate a NOVX target molecule. For example, the catalytic/enzymatic activity of the target molecule on an appropriate substrate can be determined as described, supra.

[0278] In yet another embodiment, the cell-free assay comprises contacting the NOVX protein or biologically-active portion thereof with a known compound which binds NOVX protein to form an assay mixture, contacting the assay mixture with a test compound, and determining the ability of the test compound to interact with a NOVX protein, wherein determining the ability of the test compound to interact with a NOVX protein comprises determining the ability of the NOVX protein to preferentially bind to or modulate the activity of a NOVX target molecule.

[0279] The cell-free assays of the invention are amenable to use of both the soluble form or the membrane-bound form of NOVX protein. In the case of cell-free assays comprising the membrane-bound form of NOVX protein, it may be desirable to utilize a solubilizing agent such that the membrane-bound form of NOVX protein is maintained in solution. Examples of such solubilizing agents include non-ionic detergents such as n-octylglucoside, n-dodecylglucoside, n-dodecylmaltoside, octanoyl-N-methylglucamide, decanoyl-N-methylglucamide, Triton® X-100, Triton® X-114, Thesit®, Isotridecypoly(ethylene glycol ether)n, N-dodecyl-N,N-dimethyl-3-ammonio-1-propane sulfonate, 3-(3-cholamidopropyl)dimethylamminiol-1-propane sulfonate (CHAPS), or 3-(3-cholamidopropyl)dimethylamminiol-2-hydroxy-1-propane sulfonate (CHAPSO).

[0280] In more than one embodiment of the above assay methods of the invention, it may be desirable to immobilize either NOVX protein or its target molecule to facilitate separation of complexed from uncomplexed forms of one or both of the proteins, as well as to accommodate automation of the assay. Binding of a test compound to NOVX protein, or interaction of NOVX protein with a target molecule in the presence and absence of a candidate compound, can be accomplished in any vessel suitable for containing the reactants. Examples of such vessels include microtiter plates, test tubes, and micro-centrifuge tubes. In one embodiment, a fusion protein can be provided that adds a domain that allows one or both of the proteins to be bound to a matrix. For example, GST-NOVX fusion proteins or GST-target fusion proteins can be adsorbed onto glutathione sepharose beads (Sigma Chemical, St. Louis, Mo.) or glutathione derivatized microtiter plates, that are then combined with the test compound or the test compound and either the non-adsorbed target protein or NOVX protein, and the mixture is incubated under conditions conducive to complex formation (e.g., at physiological conditions for salt and pH). Following incubation, the beads or microtiter plate wells are washed to remove any unbound components, the matrix immobilized in the case of beads, complex determined either directly or indirectly, for example, as described, supra. Alternatively, the complexes can be dissociated from the matrix, and the level of NOVX protein binding or activity determined using standard techniques.

[0281] Other techniques for immobilizing proteins on matrices can also be used in the screening assays of the invention. For example, either the NOVX protein or its target molecule can be immobilized utilizing conjugation of biotin and streptavidin. Biotinylated NOVX protein or target molecules can be prepared from biotin-NHS (N-hydroxy-succinimide) using techniques well-known within the art (e.g., biotinylation kit, Pierce Chemicals, Rockford, Ill.), and immobilized in the wells of streptavidin-coated 96 well plates (Pierce Chemical). Alternatively, antibodies reactive with NOVX protein or target molecules, but which do not interfere with binding of the NOVX protein to its target molecule, can be derivatized to the wells of the plate, and unbound target or NOVX protein trapped in the wells by antibody conjugation. Methods for detecting such complexes, in addition to those described above for the GST-immobilized complexes, include immunodetection of complexes using antibodies reactive with the NOVX protein or target molecule, as well as enzyme-linked assays that rely on detecting an enzymatic activity associated with the NOVX protein or target molecule.

[0282] In another embodiment, modulators of NOVX protein expression are identified in a method wherein a cell is contacted with a candidate compound and the expression of NOVX mRNA or protein in the cell is determined. The level of expression of NOVX mRNA or protein in the presence of the candidate compound is compared to the level of expression of NOVX mRNA or protein in the absence of the candidate compound. The candidate compound can then be identified as a modulator of NOVX mRNA or protein expression based upon this comparison. For example, when expression of NOVX mRNA or protein is greater (i.e., statistically significantly greater) in the presence of the candidate compound than in its absence, the candidate compound is identified as a stimulator of NOVX mRNA or protein expression. Alternatively, when expression of NOVX mRNA or protein is less (statistically significantly less) in the presence of the candidate compound than in its absence, the candidate compound is identified as an inhibitor of NOVX mRNA or protein expression. The level of NOVX mRNA or protein expression in the cells can be determined by methods described herein for detecting NOVX mRNA or protein.

[0283] In yet another aspect of the invention, the NOVX proteins can be used as “bait proteins” in a two-hybrid assay or three hybrid assay (see, e.g., U.S. Pat. No. 5,283,317; Zervos, et al., 1993. Cell 72: 223-232; Madura, et al., 1993. J. Biol. Chem. 268: 12046-12054; Bartel, et al., 1993. Biotechniques 14: 920-924; Iwabuchi, et al., 1993. Oncogene 8: 1693-1696; and Brent WO 94/10300), to identify other proteins that bind to or interact with NOVX (“NOVX-binding proteins” or “NOVX-bp”) and modulate NOVX activity. Such NOVX-binding proteins are also likely to be involved in the propagation of signals by the NOVX proteins as, for example, upstream or downstream elements of the NOVX pathway.

[0284] The two-hybrid system is based on the modular nature of most transcription factors, which consist of separable DNA-binding and activation domains. Briefly, the assay utilizes two different DNA constructs. In one construct, the gene that codes for NOVX is fused to a gene encoding the DNA binding domain of a known transcription factor (e.g., GAL-4). In the other construct, a DNA sequence, from a library of DNA sequences, that encodes an unidentified protein (“prey” or “sample”) is fused to a gene that codes for the activation domain of the known transcription factor. If the “bait” and the “prey” proteins are able to interact, in vivo, forming a NOVX-dependent complex, the DNA-binding and activation domains of the transcription factor are brought into close proximity. This proximity allows transcription of a reporter gene (e.g., LacZ) that is operably linked to a transcriptional regulatory site responsive to the transcription factor. Expression of the reporter gene can be detected and cell colonies containing the functional transcription factor can be isolated and used to obtain the cloned gene that encodes the protein which interacts with NOVX.

[0285] The invention further pertains to novel agents identified by the aforementioned screening assays and uses thereof for treatments as described herein.

[0286] Detection Assays

[0287] Portions or fragments of the cDNA sequences identified herein (and the corresponding complete gene sequences) can be used in numerous ways as polynucleotide reagents. By way of example, and not of limitation, these sequences can be used to: (i) map their respective genes on a chromosome; and, thus, locate gene regions associated with genetic disease; (ii) identify an individual from a minute biological sample (tissue typing); and (iii) aid in forensic identification of a biological sample. Some of these applications are described in the subsections, below.

[0288] Chromosome Mapping

[0289] Once the sequence (or a portion of the sequence) of a gene has been isolated, this sequence can be used to map the location of the gene on a chromosome. This process is called chromosome mapping. Accordingly, portions or fragments of a NOVX sequence, i.e., of SEQ ID NOS:2n-1, wherein n is an integer between 1 and 64, or fragments or derivatives thereof, can be used to map the location of the NOVX genes, respectively, on a chromosome. The mapping of the NOVX sequences to chromosomes is an important first step in correlating these sequences with genes associated with disease.

[0290] Briefly, NOVX genes can be mapped to chromosomes by preparing PCR primers (preferably 15-25 bp in length) from the NOVX sequences. Computer analysis of the NOVX, sequences can be used to rapidly select primers that do not span more than one exon in the genomic DNA, thus complicating the amplification process. These primers can then be used for PCR screening of somatic cell hybrids containing individual human chromosomes. Only those hybrids containing the human gene corresponding to the NOVX sequences will yield an amplified fragment.

[0291] Somatic cell hybrids are prepared by fusing somatic cells from different mammals (e.g., human and mouse cells). As hybrids of human and mouse cells grow and divide, they gradually lose human chromosomes in random order, but retain the mouse chromosomes. By using media in which mouse cells cannot grow, because they lack a particular enzyme, but in which human cells can, the one human chromosome that contains the gene encoding the needed enzyme will be retained. By using various media, panels of hybrid cell lines can be established. Each cell line in a panel contains either a single human chromosome or a small number of human chromosomes, and a full set of mouse chromosomes, allowing easy mapping of individual genes to specific human chromosomes. See, e.g., D'Eustachio, et al., 1983. Science 220: 919-924. Somatic cell hybrids containing only fragments of human chromosomes can also be produced by using human chromosomes with translocations and deletions.

[0292] PCR mapping of somatic cell hybrids is a rapid procedure for assigning a particular sequence to a particular chromosome. Three or more sequences can be assigned per day using a single thermal cycler. Using the NOVX sequences to design oligonucleotide primers, sub-localization can be achieved with panels of fragments from specific chromosomes.

[0293] Fluorescence in situ hybridization (FISH) of a DNA sequence to a metaphase chromosomal spread can further be used to provide a precise chromosomal location in one step. Chromosome spreads can be made using cells whose division has been blocked in metaphase by a chemical like colcemid that disrupts the mitotic spindle. The chromosomes can be treated briefly with trypsin, and then stained with Giemsa. A pattern of light and dark bands develops on each chromosome, so that the chromosomes can be identified individually. The FISH technique can be used with a DNA sequence as short as 500 or 600 bases. However, clones larger than 1,000 bases have a higher likelihood of binding to a unique chromosomal location with sufficient signal intensity for simple detection. Preferably 1,000 bases, and more preferably 2,000 bases, will suffice to get good results at a reasonable amount of time. For a review of this technique, see, Verma, et al., HUMAN CHROMOSOMES: A MANUAL OF BASIC TECHNIQUES (Pergamon Press, New York 1988).

[0294] Reagents for chromosome mapping can be used individually to mark a single chromosome or a single site on that chromosome, or panels of reagents can be used for marking multiple sites and/or multiple chromosomes. Reagents corresponding to noncoding regions of the genes actually are preferred for mapping purposes. Coding sequences are more likely to be conserved within gene families, thus increasing the chance of cross hybridizations during chromosomal mapping.

[0295] Once a sequence has been mapped to a precise chromosomal location, the physical position of the sequence on the chromosome can be correlated with genetic map data. Such data are found, e.g., in McKusick, MENDELIAN INHERITANCE IN MAN, available on-line through Johns Hopkins University Welch Medical Library). The relationship between genes and disease, mapped to the same chromosomal region, can then be identified through linkage analysis (co-inheritance of physically adjacent genes), described in, e.g., Egeland, et al., 1987. Nature, 325: 783-787.

[0296] Moreover, differences in the DNA sequences between individuals affected and unaffected with a disease associated with the NOVX gene, can be determined. If a mutation is observed in some or all of the affected individuals but not in any unaffected individuals, then the mutation is likely to be the causative agent of the particular disease. Comparison of affected and unaffected individuals generally involves first looking for structural alterations in the chromosomes, such as deletions or translocations that are visible from chromosome spreads or detectable using PCR based on that DNA sequence. Ultimately, complete sequencing of genes from several individuals can be performed to confirm the presence of a mutation and to distinguish mutations from polymorphisms.

[0297] Tissue Typing

[0298] The NOVX sequences of the invention can also be used to identify individuals from minute biological samples. In this technique, an individual's genomic DNA is digested with one or more restriction enzymes, and probed on a Southern blot to yield unique bands for identification. The sequences of the invention are useful as additional DNA markers for RFLP (“restriction fragment length polymorphisms,” described in U.S. Pat. No. 5,272,057).

[0299] Furthermore, the sequences of the invention can be used to provide an alternative technique that determines the actual base-by-base DNA sequence of selected portions of an individual's genome. Thus, the NOVX sequences described herein can be used to prepare two PCR primers from the 5′- and 3′-termini of the sequences. These primers can then be used to amplify an individual's DNA and subsequently sequence it.

[0300] Panels of corresponding DNA sequences from individuals, prepared in this manner, can provide unique individual identifications, as each individual will have a unique set of such DNA sequences due to allelic differences. The sequences of the invention can be used to obtain such identification sequences from individuals and from tissue. The NOVX sequences of the invention uniquely represent portions of the human genome. Allelic variation occurs to some degree in the coding regions of these sequences, and to a greater degree in the noncoding regions. It is estimated that allelic variation between individual humans occurs with a frequency of about once per each 500 bases. Much of the allelic variation is due to single nucleotide polymorphisms (SNPs), which include restriction fragment length polymorphisms (RFLPs).

[0301] Each of the sequences described herein can, to some degree, be used as a standard against which DNA from an individual can be compared for identification purposes. Because greater numbers of polymorphisms occur in the noncoding regions, fewer sequences are necessary to differentiate individuals. The noncoding sequences can comfortably provide positive individual identification with a panel of perhaps 10 to 1,000 primers that each yield a noncoding amplified sequence of 100 bases. If coding sequences, such as those of SEQ ID NOS:2n-1, wherein n is an integer between 1 and 64, are used, a more appropriate number of primers for positive individual identification would be 500-2,000.

[0302] Predictive Medicine

[0303] The invention also pertains to the field of predictive medicine in which diagnostic assays, prognostic assays, pharmacogenomics, and monitoring clinical trials are used for prognostic (predictive) purposes to thereby treat an individual prophylactically. Accordingly, one aspect of the invention relates to diagnostic assays for determining NOVX protein and/or nucleic acid expression as well as NOVX activity, in the context of a biological sample (e.g., blood, serum, cells, tissue) to thereby determine whether an individual is afflicted with a disease or disorder, or is at risk of developing a disorder, associated with aberrant NOVX expression or activity. The disorders include metabolic disorders, diabetes, obesity, infectious disease, anorexia, cancer-associated cachexia, cancer, neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders, and hematopoietic disorders, and the various dyslipidemias, metabolic disturbances associated with obesity, the metabolic syndrome X and wasting disorders associated with chronic diseases and various cancers. The invention also provides for prognostic (or predictive) assays for determining whether an individual is at risk of developing a disorder associated with NOVX protein, nucleic acid expression or activity. For example, mutations in a NOVX gene can be assayed in a biological sample. Such assays can be used for prognostic or predictive purpose to thereby prophylactically treat an individual prior to the onset of a disorder characterized by or associated with NOVX protein, nucleic acid expression, or biological activity.

[0304] Another aspect of the invention provides methods for determining NOVX protein, nucleic acid expression or activity in an individual to thereby select appropriate therapeutic or prophylactic agents for that individual (referred to herein as “pharmacogenomics”). Pharmacogenomics allows for the selection of agents (e.g., drugs) for therapeutic or prophylactic treatment of an individual based on the genotype of the individual (e.g., the genotype of the individual examined to determine the ability of the individual to respond to a particular agent.)

[0305] Yet another aspect of the invention pertains to monitoring the influence of agents (e.g., drugs, compounds) on the expression or activity of NOVX in clinical trials. These and other agents are described in further detail in the following sections.

[0306] Diagnostic Assays

[0307] An exemplary method for detecting the presence or absence of NOVX in a biological sample involves obtaining a biological sample from a test subject and contacting the biological sample with a compound or an agent capable of detecting NOVX protein or nucleic acid (e.g., mRNA, genomic DNA) that encodes NOVX protein such that the presence of NOVX is detected in the biological sample. An agent for detecting NOVX mRNA or genomic DNA is a labeled nucleic acid probe capable of hybridizing to NOVX mRNA or genomic DNA. The nucleic acid probe can be, for example, a full-length NOVX nucleic acid, such as the nucleic acid of SEQ ID NOS:2n-1, wherein n is an integer between 1 and 64, or a portion thereof, such as an oligonucleotide of at least 15, 30, 50, 100, 250 or 500 nucleotides in length and sufficient to specifically hybridize under stringent conditions to NOVX mRNA or genomic DNA. Other suitable probes for use in the diagnostic assays of the invention are described herein.

[0308] An agent for detecting NOVX protein is an antibody capable of binding to NOVX protein, preferably an antibody with a detectable label. Antibodies can be polyclonal, or more preferably, monoclonal. An intact antibody, or a fragment thereof (e.g., Fab or F(ab′)2) can be used. The term “labeled”, with regard to the probe or antibody, is intended to encompass direct labeling of the probe or antibody by coupling (i.e., physically linking) a detectable substance to the probe or antibody, as well as indirect labeling of the probe or antibody by reactivity with another reagent that is directly labeled. Examples of indirect labeling include detection of a primary antibody using a fluorescently-labeled secondary antibody and end-labeling of a DNA probe with biotin such that it can be detected with fluorescently-labeled streptavidin. The term “biological sample” is intended to include tissues, cells and biological fluids isolated from a subject, as well as tissues, cells and fluids present within a subject. That is, the detection method of the invention can be used to detect NOVX mRNA, protein, or genomic DNA in a biological sample in vitro as well as in vivo. For example, in vitro techniques for detection of NOVX mRNA include Northern hybridizations and in situ hybridizations. In vitro techniques for detection of NOVX protein include enzyme linked immunosorbent assays (ELISAs), Western blots, immunoprecipitations, and immunofluorescence. In vitro techniques for detection of NOVX genomic DNA include Southern hybridizations. Furthermore, in vivo techniques for detection of NOVX protein include introducing into a subject a labeled anti-NOVX antibody. For example, the antibody can be labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques.

[0309] In one embodiment, the biological sample contains protein molecules from the test subject. Alternatively, the biological sample can contain mRNA molecules from the test subject or genomic DNA molecules from the test subject. A preferred biological sample is a peripheral blood leukocyte sample isolated by conventional means from a subject.

[0310] In another embodiment, the methods further involve obtaining a control biological sample from a control subject, contacting the control sample with a compound or agent capable of detecting NOVX protein, mRNA, or genomic DNA, such that the presence of NOVX protein, mRNA or genomic DNA is detected in the biological sample, and comparing the presence of NOVX protein, mRNA or genomic DNA in the control sample with the presence of NOVX protein, mRNA or genomic DNA in the test sample.

[0311] The invention also encompasses kits for detecting the presence of NOVX in a biological sample. For example, the kit can comprise: a labeled compound or agent capable of detecting NOVX protein or mRNA in a biological sample; means for determining the amount of NOVX in the sample; and means for comparing the amount of NOVX in the sample with a standard. The compound or agent can be packaged in a suitable container. The kit can further comprise instructions for using the kit to detect NOVX protein or nucleic acid.

[0312] Prognostic Assays

[0313] The diagnostic methods described herein can furthermore be utilized to identify subjects having or at risk of developing a disease or disorder associated with aberrant NOVX expression or activity. For example, the assays described herein, such as the preceding diagnostic assays or the following assays, can be utilized to identify a subject having or at risk of developing a disorder associated with NOVX protein, nucleic acid expression or activity. Alternatively, the prognostic assays can be utilized to identify a subject having or at risk for developing a disease or disorder. Thus, the invention provides a method for identifying a disease or disorder associated with aberrant NOVX expression or activity in which a test sample is obtained from a subject and NOVX protein or nucleic acid (e.g., mRNA, genomic DNA) is detected, wherein the presence of NOVX protein or nucleic acid is diagnostic for a subject having or at risk of developing a disease or disorder associated with aberrant NOVX expression or activity. As used herein, a “test sample” refers to a biological sample obtained from a subject of interest. For example, a test sample can be a biological fluid (e.g., serum), cell sample, or tissue.

[0314] Furthermore, the prognostic assays described herein can be used to determine whether a subject can be administered an agent (e.g., an agonist, antagonist, peptidomimetic, protein, peptide, nucleic acid, small molecule, or other drug candidate) to treat a disease or disorder associated with aberrant NOVX expression or activity. For example, such methods can be used to determine whether a subject can be effectively treated with an agent for a disorder. Thus, the invention provides methods for determining whether a subject can be effectively treated with an agent for a disorder associated with aberrant NOVX expression or activity in which a test sample is obtained and NOVX protein or nucleic acid is detected (e.g., wherein the presence of NOVX protein or nucleic acid is diagnostic for a subject that can be administered the agent to treat a disorder associated with aberrant NOVX expression or activity).

[0315] The methods of the invention can also be used to detect genetic lesions in a NOVX gene, thereby determining if a subject with the lesioned gene is at risk for a disorder characterized by aberrant cell proliferation and/or differentiation. In various embodiments, the methods include detecting, in a sample of cells from the subject, the presence or absence of a genetic lesion characterized by at least one of an alteration affecting the integrity of a gene encoding a NOVX-protein, or the misexpression of the NOVX gene. For example, such genetic lesions can be detected by ascertaining the existence of at least one of: (i) a deletion of one or more nucleotides from a NOVX gene; (ii) an addition of one or more nucleotides to a NOVX gene; (iii) a substitution of one or more nucleotides of a NOVX gene, (iv) a chromosomal rearrangement of a NOVX gene; (v) an alteration in the level of a messenger RNA transcript of a NOVX gene, (vi) aberrant modification of a NOVX gene, such as of the methylation pattern of the genomic DNA, (vii) the presence of a non-wild-type splicing pattern of a messenger RNA transcript of a NOVX gene, (viii) a non-wild-type level of a NOVX protein, (ix) allelic loss of a NOVX gene, and (x) inappropriate post-translational modification of a NOVX protein. As described herein, there are a large number of assay techniques known in the art which can be used for detecting lesions in a NOVX gene. A preferred biological sample is a peripheral blood leukocyte sample isolated by conventional means from a subject. However, any biological sample containing nucleated cells may be used, including, for example, buccal mucosal cells.

[0316] In certain embodiments, detection of the lesion involves the use of a probe/primer in a polymerase chain reaction (PCR) (see, e.g., U.S. Pat. Nos. 4,683,195 and 4,683,202), such as anchor PCR or RACE PCR, or, alternatively, in a ligation chain reaction (LCR) (see, e.g., Landegran, et al., 1988. Science 241: 1077-1080; and Nakazawa, et al., 1994. Proc. Natl. Acad. Sci. USA 91: 360-364), the latter of which can be particularly useful for detecting point mutations in the NOVX-gene (see, Abravaya, et al., 1995. Nucl. Acids Res. 23: 675-682). This method can include the steps of collecting a sample of cells from a patient, isolating nucleic acid (e.g., genomic, mRNA or both) from the cells of the sample, contacting the nucleic acid sample with one or more primers that specifically hybridize to a NOVX gene under conditions such that hybridization and amplification of the NOVX gene (if present) occurs, and detecting the presence or absence of an amplification product, or detecting the size of the amplification product and comparing the length to a control sample. It is anticipated that PCR and/or LCR may be desirable to use as a preliminary amplification step in conjunction with any of the techniques used for detecting mutations described herein.

[0317] Alternative amplification methods include: self sustained sequence replication (see, Guatelli, et al., 1990. Proc. Natl. Acad. Sci. USA 87: 1874-1878), transcriptional amplification system (see, Kwoh, et al., 1989. Proc. Natl. Acad. Sci. USA 86: 1173-1177); Q&bgr; Replicase (see, Lizardi, et al, 1988. BioTechnology 6: 1197), or any other nucleic acid amplification method, followed by the detection of the amplified molecules using techniques well known to those of skill in the art. These detection schemes are especially useful for the detection of nucleic acid molecules if such molecules are present in very low numbers.

[0318] In an alternative embodiment, mutations in a NOVX gene from a sample cell can be identified by alterations in restriction enzyme cleavage patterns. For example, sample and control DNA is isolated, amplified (optionally), digested with one or more restriction endonucleases, and fragment length sizes are determined by gel electrophoresis and compared. Differences in fragment length sizes between sample and control DNA indicates mutations in the sample DNA. Moreover, the use of sequence specific ribozymes (see, e.g., U.S. Pat. No. 5,493,531) can be used to score for the presence of specific mutations by development or loss of a ribozyme cleavage site.

[0319] In other embodiments, genetic mutations in NOVX can be identified by hybridizing sample and control nucleic acids, e.g., DNA or RNA to high-density arrays containing hundreds or thousands of oligonucleotide probes. See, e.g., Cronin, et al., 1996. Human Mutation 7: 244-255; Kozal, et al., 1996. Nat. Med. 2: 753-759. For example, genetic mutations in NOVX can be identified in two-dimensional arrays containing light-generated DNA probes as described in Cronin, et al., supra. Briefly, a first hybridization array of probes can be used to scan through long stretches of DNA in a sample and control to identify base changes between the sequences by making linear arrays of sequential overlapping probes. This step allows the identification of point mutations. This is followed by a second hybridization array that allows the characterization of specific mutations by using smaller, specialized probe arrays complementary to all variants or mutations detected. Each mutation array is composed of parallel probe sets, one complementary to the wild-type gene and the other complementary to the mutant gene.

[0320] In yet another embodiment, any of a variety of sequencing reactions known in the art can be used to directly sequence the NOVX gene and detect mutations by comparing the sequence of the sample NOVX with the corresponding wild-type (control) sequence. Examples of sequencing reactions include those based on techniques developed by Maxim and Gilbert, 1977. Proc. Natl. Acad. Sci. USA 74: 560 or Sanger, 1977. Proc. Natl. Acad. Sci. USA 74: 5463. It is also contemplated that any of a variety of automated sequencing procedures can be utilized when performing the diagnostic assays (see, e.g., Naeve, et al., 1995. Biotechniques 19: 448), including sequencing by mass spectrometry (see, e.g., PCT International Publication No. WO 94/16101; Cohen, et al., 1996. Adv. Chromatography 36: 127-162; and Griffin, et al., 1993. Appl. Biochem. Biotechnol. 38: 147-159).

[0321] Other methods for detecting mutations in the NOVX gene include methods in which protection from cleavage agents is used to detect mismatched bases in RNA/RNA or RNA/DNA heteroduplexes. See, e.g., Myers, et al., 1985. Science 230: 1242. In general, the art technique of “mismatch cleavage” starts by providing heteroduplexes of formed by hybridizing (labeled) RNA or DNA containing the wild-type NOVX sequence with potentially mutant RNA or DNA obtained from a tissue sample. The double-stranded duplexes are treated with an agent that cleaves single-stranded regions of the duplex such as which will exist due to basepair mismatches between the control and sample strands. For instance, RNA/DNA duplexes can be treated with RNase and DNA/DNA hybrids treated with S1 nuclease to enzymatically digesting the mismatched regions. In other embodiments, either DNA/DNA or RNA/DNA duplexes can be treated with hydroxylamine or osmium tetroxide and with piperidine in order to digest mismatched regions. After digestion of the mismatched regions, the resulting material is then separated by size on denaturing polyacrylamide gels to determine the site of mutation. See, e.g., Cotton, et al., 1988. Proc. Natl. Acad. Sci. USA 85: 4397; Saleeba, et al., 1992. Methods Enzymol. 217: 286-295. In an embodiment, the control DNA or RNA can be labeled for detection.

[0322] In still another embodiment, the mismatch cleavage reaction employs one or more proteins that recognize mismatched base pairs in double-stranded DNA (so called “DNA mismatch repair” enzymes) in defined systems for detecting and mapping point mutations in NOVX cDNAs obtained from samples of cells. For example, the mutY enzyme of E. coli cleaves A at G/A mismatches and the thymidine DNA glycosylase from HeLa cells cleaves T at G/T mismatches. See, e.g., Hsu, et al., 1994. Carcinogenesis 15: 1657-1662. According to an exemplary embodiment, a probe based on a NOVX sequence, e.g., a wild-type NOVX sequence, is hybridized to a cDNA or other DNA product from a test cell(s). The duplex is treated with a DNA mismatch repair enzyme, and the cleavage products, if any, can be detected from electrophoresis protocols or the like. See, e.g., U.S. Pat. No. 5,459,039.

[0323] In other embodiments, alterations in electrophoretic mobility will be used to identify mutations in NOVX genes. For example, single strand conformation polymorphism (SSCP) may be used to detect differences in electrophoretic mobility between mutant and wild type nucleic acids. See, e.g., Orita, et al., 1989. Proc. Natl. Acad. Sci. USA: 86: 2766; Cotton, 1993. Mutat. Res. 285: 125-144; Hayashi, 1992. Genet. Anal. Tech. Appl. 9: 73-79. Single-stranded DNA fragments of sample and control NOVX nucleic acids will be denatured and allowed to renature. The secondary structure of single-stranded nucleic acids varies according to sequence, the resulting alteration in electrophoretic mobility enables the detection of even a single base change. The DNA fragments may be labeled or detected with labeled probes. The sensitivity of the assay may be enhanced by using RNA (rather than DNA), in which the secondary structure is more sensitive to a change in sequence. In one embodiment, the subject method utilizes heteroduplex analysis to separate double stranded heteroduplex molecules on the basis of changes in electrophoretic mobility. See, e.g., Keen, et al., 1991. Trends Genet. 7: 5.

[0324] In yet another embodiment, the movement of mutant or wild-type fragments in polyacrylamide gels containing a gradient of denaturant is assayed using denaturing gradient gel electrophoresis (DGGE). See, e.g., Myers, et al., 1985. Nature 313: 495. When DGGE is used as the method of analysis, DNA will be modified to insure that it does not completely denature, for example by adding a GC clamp of approximately 40 bp of high-melting GC-rich DNA by PCR. In a further embodiment, a temperature gradient is used in place of a denaturing gradient to identify differences in the mobility of control and sample DNA. See, e.g., Rosenbaum and Reissner, 1987. Biophys. Chem. 265: 12753.

[0325] Examples of other techniques for detecting point mutations include, but are not, limited to, selective oligonucleotide hybridization, selective amplification, or selective primer extension. For example, oligonucleotide primers may be prepared in which the known mutation is placed centrally and then hybridized to target DNA under conditions that permit hybridization only if a perfect match is found. See, e.g., Saiki, et al., 1986. Nature 324: 163; Saiki, et al., 1989. Proc. Natl. Acad. Sci. USA 86: 6230. Such allele specific oligonucleotides are hybridized to PCR amplified target DNA or a number of different mutations when the oligonucleotides are attached to the hybridizing membrane and hybridized with labeled target DNA.

[0326] Alternatively, allele specific amplification technology that depends on selective PCR amplification may be used in conjunction with the instant invention. Oligonucleotides used as primers for specific amplification may carry the mutation of interest in the center of the molecule (so that amplification depends on differential hybridization; see, e.g., Gibbs, et al., 1989. Nucl. Acids Res. 17: 2437-2448) or at the extreme 3′-terminus of one primer where, under appropriate conditions, mismatch can prevent, or reduce polymerase extension (see, e.g., Prossner, 1993. Tibtech. 11: 238). In addition it may be desirable to introduce a novel restriction site in the region of the mutation to create cleavage-based detection. See, e.g., Gasparini, et al., 1992. Mol. Cell Probes 6: 1. It is anticipated that in certain embodiments amplification may also be performed using Taq ligase for amplification. See, e.g., Barany, 1991. Proc. Natl. Acad. Sci. USA 88: 189. In such cases, ligation will occur only if there is a perfect match at the 3′-terminus of the 5′ sequence, making it possible to detect the presence of a known mutation at a specific site by looking for the presence or absence of amplification.

[0327] The methods described herein may be performed, for example, by utilizing pre-packaged diagnostic kits comprising at least one probe nucleic acid or antibody reagent described herein, which may be conveniently used, e.g., in clinical settings to diagnose patients exhibiting symptoms or family history of a disease or illness involving a NOVX gene.

[0328] Furthermore, any cell type or tissue, preferably peripheral blood leukocytes, in which NOVX is expressed may be utilized in the prognostic assays described herein. However, any biological sample containing nucleated cells may be used, including, for example, buccal mucosal cells.

[0329] Pharmacogenomics

[0330] Agents, or modulators that have a stimulatory or inhibitory effect on NOVX activity (e.g., NOVX gene expression), as identified by a screening assay described herein can be administered to individuals to treat (prophylactically or therapeutically) disorders (The disorders include metabolic disorders, diabetes, obesity, infectious disease, anorexia, cancer-associated cachexia, cancer, neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders, and hematopoietic disorders, and the various dyslipidemias, metabolic disturbances associated with obesity, the metabolic syndrome X and wasting disorders associated with chronic diseases and various cancers.) In conjunction with such treatment, the pharmacogenomics (i.e., the study of the relationship between an individual's genotype and that individual's response to a foreign compound or drug) of the individual may be considered. Differences in metabolism of therapeutics can lead to severe toxicity or therapeutic failure by altering the relation between dose and blood concentration of the pharmacologically active drug. Thus, the pharmacogenomics of the individual permits the selection of effective agents (e.g., drugs) for prophylactic or therapeutic treatments based on a consideration of the individual's genotype. Such pharmacogenomics can further be used to determine appropriate dosages and therapeutic regimens. Accordingly, the activity of NOVX protein, expression of NOVX nucleic acid, or mutation content of NOVX genes in an individual can be determined to thereby select appropriate agent(s) for therapeutic or prophylactic treatment of the individual.

[0331] Pharmacogenomics deals with clinically significant hereditary variations in the response to drugs due to altered drug disposition and abnormal action in affected persons. See e.g., Eichelbaum, 1996. Clin. Exp. Pharmacol. Physiol., 23: 983-985; Linder, 1997. Clin. Chem., 43: 254-266. In general, two types of pharmacogenetic conditions can be differentiated. Genetic conditions transmitted as a single factor altering the way drugs act on the body (altered drug action) or genetic conditions transmitted as single factors altering the way the body acts on drugs (altered drug metabolism). These pharmacogenetic conditions can occur either as rare defects or as polymorphisms. For example, glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common inherited enzymopathy in which the main clinical complication is hemolysis after ingestion of oxidant drugs (anti-malarials, sulfonamides, analgesics, nitrofurans) and consumption of fava beans.

[0332] As an illustrative embodiment, the activity of drug metabolizing enzymes is a major determinant of both the intensity and duration of drug action. The discovery of genetic polymorphisms of drug metabolizing enzymes (e.g., N-acetyltransferase 2 (NAT 2) and cytochrome Pregnancy Zone Protein Precursor enzymes CYP2D6 and CYP2C19) has provided an explanation as to why some patients do not obtain the expected drug effects or show exaggerated drug response and serious toxicity after taking the standard and safe dose of a drug. These polymorphisms are expressed in two phenotypes in the population, the extensive metabolizer (EM) and poor metabolizer (PM). The prevalence of PM is different among different populations. For example, the gene coding for CYP2D6 is highly polymorphic and several mutations have been identified in PM, which all lead to the absence of functional CYP2D6. Poor metabolizers of CYP2D6 and CYP2C19 quite frequently experience exaggerated drug response and side effects when they receive standard doses. If a metabolite is the active therapeutic moiety, PM show no therapeutic response, as demonstrated for the analgesic effect of codeine mediated by its CYP2D6-formed metabolite morphine. At the other extreme are the so called ultra-rapid metabolizers who do not respond to standard doses. Recently, the molecular basis of ultra-rapid metabolism has been identified to be due to CYP2D6 gene amplification.

[0333] Thus, the activity of NOVX protein, expression of NOVX nucleic acid, or mutation content of NOVX genes in an individual can be determined to thereby select appropriate agent(s) for therapeutic or prophylactic treatment of the individual. In addition, pharmacogenetic studies can be used to apply genotyping of polymorphic alleles encoding drug-metabolizing enzymes to the identification of an individual's drug responsiveness phenotype. This knowledge, when applied to dosing or drug selection, can avoid adverse reactions or therapeutic failure and thus enhance therapeutic or prophylactic efficiency when treating a subject with a NOVX modulator, such as a modulator identified by one of the exemplary screening assays described herein.

[0334] Monitoring of Effects During Clinical Trials

[0335] Monitoring the influence of agents (e.g., drugs, compounds) on the expression or activity of NOVX (e.g., the ability to modulate aberrant cell proliferation and/or differentiation) can be applied not only in basic drug screening, but also in clinical trials. For example, the effectiveness of an agent determined by a screening assay as described herein to increase NOVX gene expression, protein levels, or upregulate NOVX activity, can be monitored in clinical trails of subjects exhibiting decreased NOVX gene expression, protein levels, or downregulated NOVX activity. Alternatively, the effectiveness of an agent determined by a screening assay to decrease NOVX gene expression, protein levels, or downregulate NOVX activity, can be monitored in clinical trails of subjects exhibiting increased NOVX gene expression, protein levels, or upregulated NOVX activity. In such clinical trials, the expression or activity of NOVX and, preferably, other genes that have been implicated in, for example, a cellular proliferation or immune disorder can be used as a “read out” or markers of the immune responsiveness of a particular cell.

[0336] By way of example, and not of limitation, genes, including NOVX, that are modulated in cells by treatment with an agent (e.g., compound, drug or small molecule) that modulates NOVX activity (e.g., identified in a screening assay as described herein) can be identified. Thus, to study the effect of agents on cellular proliferation disorders, for example, in a clinical trial, cells can be isolated and RNA prepared and analyzed for the levels of expression of NOVX and other genes implicated in the disorder. The levels of gene expression (i.e., a gene expression pattern) can be quantified by Northern blot analysis or RT-PCR, as described herein, or alternatively by measuring the amount of protein produced, by one of the methods as described herein, or by measuring the levels of activity of NOVX or other genes. In this manner, the gene expression pattern can serve as a marker, indicative of the physiological response of the cells to the agent. Accordingly, this response state may be determined before, and at various points during, treatment of the individual with the agent.

[0337] In one embodiment, the invention provides a method for monitoring the effectiveness of treatment of a subject with an agent (e.g., an agonist, antagonist, protein, peptide, peptidomimetic, nucleic acid, small molecule, or other drug candidate identified by the screening assays described herein) comprising the steps of (i) obtaining a pre-administration sample from a subject prior to administration of the agent; (ii) detecting the level of expression of a NOVX protein, mRNA, or genomic DNA in the preadministration sample; (iii) obtaining one or more post-administration samples from the subject; (iv) detecting the level of expression or activity of the NOVX protein, mRNA, or genomic DNA in the post-administration samples; (v) comparing the level of expression or activity of the NOVX protein, mRNA, or genomic DNA in the pre-administration sample with the NOVX protein, mRNA, or genomic DNA in the post administration sample or samples; and (vi) altering the administration of the agent to the subject accordingly. For example, increased administration of the agent may be desirable to increase the expression or activity of NOVX to higher levels than detected, i.e., to increase the effectiveness of the agent. Alternatively, decreased administration of the agent may be desirable to decrease expression or activity of NOVX to lower levels than detected, i.e., to decrease the effectiveness of the agent.

[0338] Methods of Treatment

[0339] The invention provides for both prophylactic and therapeutic methods of treating a subject at risk of (or susceptible to) a disorder or having a disorder associated with aberrant NOVX expression or activity. The disorders include cardiomyopathy, atherosclerosis, hypertension, congenital heart defects, aortic stenosis, atrial septal defect (ASD), atrioventricular (A-V) canal defect, ductus arteriosus, pulmonary stenosis, subaortic stenosis, ventricular septal defect (VSD), valve diseases, tuberous sclerosis, scleroderma, obesity, transplantation, adrenoleukodystrophy, congenital adrenal hyperplasia, prostate cancer, neoplasm; adenocarcinoma, lymphoma, uterus cancer, fertility, hemophilia, hypercoagulation, idiopathic thrombocytopenic purpura, immunodeficiencies, graft versus host disease, AIDS, bronchial asthma, Crohn's disease; multiple sclerosis, treatment of Albright Hereditary Ostoeodystrophy, and other diseases, disorders and conditions of the like.

[0340] These methods of treatment will be discussed more fully, below.

[0341] Diseases and Disorders

[0342] Diseases and disorders that are characterized by increased (relative to a subject not suffering from the disease or disorder) levels or biological activity may be treated with Therapeutics that antagonize (i.e., reduce or inhibit) activity. Therapeutics that antagonize activity may be administered in a therapeutic or prophylactic manner. Therapeutics that may be utilized include, but are not limited to: (i) an aforementioned peptide, or analogs, derivatives, fragments or homologs thereof; (ii) antibodies to an aforementioned peptide; (iii) nucleic acids encoding an aforementioned peptide; (iv) administration of antisense nucleic acid and nucleic acids that are “dysfunctional” (i.e., due to a heterologous insertion within the coding sequences of coding sequences to an aforementioned peptide) that are utilized to “knockout” endogenous function of an aforementioned peptide by homologous recombination (see, e.g., Capecchi, 1989. Science 244: 1288-1292); or (v) modulators (i.e., inhibitors, agonists and antagonists, including additional peptide mimetic of the invention or antibodies specific to a peptide of the invention) that alter the interaction between an aforementioned peptide and its binding partner.

[0343] Diseases and disorders that are characterized by decreased (relative to a subject not suffering from the disease or disorder) levels or biological activity may be treated with Therapeutics that increase (i.e., are agonists to) activity. Therapeutics that upregulate activity may be administered in a therapeutic or prophylactic manner. Therapeutics that may be utilized include, but are not limited to, an aforementioned peptide, or analogs, derivatives, fragments or homologs thereof; or an agonist that increases bioavailability.

[0344] Increased or decreased levels can be readily detected by quantifying peptide and/or RNA, by obtaining a patient tissue sample (e.g., from biopsy tissue) and assaying it in vitro for RNA or peptide levels, structure and/or activity of the expressed peptides (or mRNAs of an aforementioned peptide). Methods that are well-known within the art include, but are not limited to, immunoassays (e.g., by Western blot analysis, immunoprecipitation followed by sodium dodecyl sulfate (SDS) polyacrylamide gel electrophoresis, immunocytochemistry, etc.) and/or hybridization assays to detect expression of mRNAs (e.g., Northern assays, dot blots, in situ hybridization, and the like).

[0345] Prophylactic Methods

[0346] In one aspect, the invention provides a method for preventing, in a subject, a disease or condition associated with an aberrant NOVX expression or activity, by administering to the subject an agent that modulates NOVX expression or at least one NOVX activity. Subjects at risk for a disease that is caused or contributed to by aberrant NOVX expression or activity can be identified by, for example, any or a combination of diagnostic or prognostic assays as described herein. Administration of a prophylactic agent can occur prior to the manifestation of symptoms characteristic of the NOVX aberrancy, such that a disease or disorder is prevented or, alternatively, delayed in its progression. Depending upon the type of NOVX aberrancy, for example, a NOVX agonist or NOVX antagonist agent can be used for treating the subject. The appropriate agent can be determined based on screening assays described herein. The prophylactic methods of the invention are further discussed in the following subsections.

[0347] Therapeutic Methods

[0348] Another aspect of the invention pertains to methods of modulating NOVX expression or activity for therapeutic purposes. The modulatory method of the invention involves contacting a cell with an agent that modulates one or more of the activities of NOVX protein activity associated with the cell. An agent that modulates NOVX protein activity can be an agent as described herein, such as a nucleic acid or a protein, a naturally-occurring cognate ligand of a NOVX protein, a peptide, a NOVX peptidomimetic, or other small molecule. In one embodiment, the agent stimulates one or more NOVX protein activity. Examples of such stimulatory agents include active NOVX protein and a nucleic acid molecule encoding NOVX that has been introduced into the cell. In another embodiment, the agent inhibits one or more NOVX protein activity. Examples of such inhibitory agents include antisense NOVX nucleic acid molecules and anti-NOVX antibodies. These modulatory methods can be performed in vitro (e.g., by culturing the cell with the agent) or, alternatively, in vivo (e.g., by administering the agent to a subject). As such, the invention provides methods of treating an individual afflicted with a disease or disorder characterized by aberrant expression or activity of a NOVX protein or nucleic acid molecule. In one embodiment, the method involves administering an agent (e.g., an agent identified by a screening assay described herein), or combination of agents that modulates (e.g., up-regulates or down-regulates) NOVX expression or activity. In another embodiment, the method involves administering a NOVX protein or nucleic acid molecule as therapy to compensate for reduced or aberrant NOVX expression or activity.

[0349] Stimulation of NOVX activity is desirable in situations in which NOVX is abnormally downregulated and/or in which increased NOVX activity is likely to have a beneficial effect. One example of such a situation is where a subject has a disorder characterized by aberrant cell proliferation and/or differentiation (e.g., cancer or immune associated disorders). Another example of such a situation is where the subject has a gestational disease (e.g., preclampsia).

[0350] Determination of the Biological Effect of the Therapeutic

[0351] In various embodiments of the invention, suitable in vitro or in vivo assays are performed to determine the effect of a specific Therapeutic and whether its administration is indicated for treatment of the affected tissue.

[0352] In various specific embodiments, in vitro assays may be performed with representative cells of the type(s) involved in the patient's disorder, to determine if a given Therapeutic exerts the desired effect upon the cell type(s). Compounds for use in therapy may be tested in suitable animal model systems including, but not limited to rats, mice, chicken, cows, monkeys, rabbits, and the like, prior to testing in human subjects. Similarly, for in vivo testing, any of the animal model system known in the art may be used prior to administration to human subjects.

[0353] Prophylactic and Therapeutic Uses of the Compositions of the Invention

[0354] The NOVX nucleic acids and proteins of the invention are useful in potential prophylactic and therapeutic applications implicated in a variety of disorders including, but not limited to: metabolic disorders, diabetes, obesity, infectious disease, anorexia, cancer-associated cancer, neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders, hematopoietic disorders, and the various dyslipidemias, metabolic disturbances associated with obesity, the metabolic syndrome X and wasting disorders associated with chronic diseases and various cancers.

[0355] As an example, a cDNA encoding the NOVX protein of the invention may be useful in gene therapy, and the protein may be useful when administered to a subject in need thereof. By way of non-limiting example, the compositions of the invention will have efficacy for treatment of patients suffering from: metabolic disorders, diabetes, obesity, infectious disease, anorexia, cancer-associated cachexia, cancer, neurodegenerative disorders, Alzheimer's Disease, Parkinson's Disorder, immune disorders, hematopoietic disorders, and the various dyslipidemias.

[0356] Both the novel nucleic acid encoding the NOVX protein, and the NOVX protein of the invention, or fragments thereof, may also be useful in diagnostic applications, wherein the presence or amount of the nucleic acid or the protein are to be assessed. A further use could be as an anti-bacterial molecule (i.e., some peptides have been found to possess anti-bacterial properties). These materials are further useful in the generation of antibodies, which immunospecifically-bind to the novel substances of the invention for use in therapeutic or diagnostic methods.

[0357] The invention will be further described in the following examples, which do not limit the scope of the invention described in the claims.

EXAMPLES Example A Polynucleotide and Polypeptide Sequences, and Homology Data Example 1

[0358] The NOV1 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 1A. 2 TABLE 1A NOV1 Sequence Analysis NOV1a, CG50907-03 SEQ ID NO:1 1914 bp DNA Sequence ORF Start: at 7 ORF Stop: end of sequence AGATCTGCTGAGGTGTGGTGGAACCTTGTGCCGCGTAAGACAGTGTCTTCTGGGGAGCTGGCCACGGTAGTAC GGCGGTTCTCCCAGACCGGCATCCAGGACTTCCTGACACTGACGCTGACAAAGCCCACTGGGCTTCTGTACGT GGGCGCCCGAGAGGCCCTGTTTGCCTTCAGCATGGAGGCCCTGGAGCTGCAAGGAGCGATCTCCTGGGAGGCC CCCGTGGAGGAGAAGACTGAGTGTATCCAGAAAGGGAAGAACAACCAGACCGAGTGCTTCAACTTCATCCGCT TCCTGCAGCCCTACAATGCCTCCCACCTGTACGTCTGTGGCACCTACGCCTTCCAGCCCAAGTGCACCTACGT CAACATGCTCACCTTCACTTTGGAGCATGGAGAGTTTGAAGATGGGAAGGGCAAGTGTCCCTATGACCCAGCT AAGGGCCATGCTGGCCTTCTTGTGGATGGTGAGCTGTACTCGGCCACACTCAACAACTTCCTGGGCACGGAAC CCATTATCCTGCGTAACATGGGGCCCCACCACTCCATGAAGACAGAGTACCTGGCCTTTTGGCTCAACGAACC TCACTTTGTAGGCTCTGCCTATGTACCTGAGAGTGTGGGCAGCTTCACGGGGGACGACGACAAGGTCTACTTC TTCTTCAGGGAGCGGGCAGTGGAGTCCGACTGCTATGCCGAGCAGGTGGTGGCTCGTGTGGCCCGTGTCTGCA AGGGCGATATGGGGGGCGCACGGACCCTGCAGAGGAAGTGGACCACGTTCCTGAAGGCGCGGCTGGCATGCTC TGCCCCGAACTGGCAGCTCTACTTCAACCAGCTGCAGGCGATGCACACCCTGCAGGACACCTCCTGGCACAAC ACCACCTTCTTTGGGGTTTTTCAAGCACAGTGGAATGACATGTACCTGTCGGCCATCTGTGAGTACCAGTTGG AAGAGATCCAGCGGGTGTTTGAGGGCCCTATAAGGAGTACCATGAGGAAGCCCCAGAAGTGGGACCGCTACAC TGACCCTGTACCCAGCCCTCGGCCTGGCTCGTGCATTAACAACTGGCATCGGCGCAACGCCTACACCAGCTCC CTGGAGCTACCCGACAACATCCTCAACTTCGTCAAGAAGCACCCGCTGATGGAGGAGCAGGTGGGGCCTCGGT GGAGCCGCCCCCTGCTCGTGAAGAAGGGCACCAACTTCACCCACCTGGTGGCCGACCGGGTTACAGGACTTGA TGGAGCCACCTATACAGTGCTGTTCATTGGCACAGGAGACGGCTGGCTGCTCAAGGCTGTGAGCCTGGGGCCC TGGGTTCACCTGATTGAGGAGCTCCAGCTGTTTGACCAGGAGCCCATGAGAAGCCTGGTGAAATCTCAGAGCA AGAAGCTGCTCTTTGCCGGCTCCCGCTCTCAGCTGGTGCAGCTGCCCGTAACCGACTGCATGAAGTATCGCTC CTGTGCAGACTGTGTCCTCGCCCGGGACCCCTATTGCGCCTGGAGCGTCAACACCAGCCGCTGTGTGGCCGTG GGTGGCCACTCTGGATCTCTACTGATCCAGCATGTGATGACCTCGGACACTTCAAACATCTGCAACCTCCGTG GCAGTAAGAAAGTCAGGCCCACTCCCAAAAACATCACGGTGGTAACGAACACAGACCTAATGCTGCCCTGCCA CCTCTCCTCCAACTTGGCCCATGCCCGCTGGACCTTTGGGGGCCGGGACCTGCCTGCGGAACAGCCCGGGTCC TTCCTCTACGATGCCCGGCTCCAGGCCCTAATTGTGATGGCTGCCCAGCCCCGCCATGCCAAGGCCTACCACT GCTTTTCAGAGGACCAGGGGGCGCAACTGGCTGCTGAAGGCTACCTTGTGGCTGTCGTGGCAGGCCCGTCGGT GACCTTGGAGCTCGAG NOV1a, CG50907-03 Protein Sequence SEQ ID NO:2 634 aa MW at 71053.3 kD AEVWWNLVPRKTVSSGELATVVRRFSQTGIQDFLTLTLTEPTGLLYVGAREALFAFSMEALELQGAISWEAPV EEKTECIQKGKNNQTECFNFIRFLQPYNASHLYVCGTYAFQPKCTYVNNLTFTLEHGEFEDGKGKCPYDPAKG HAGLLVDGELYSATLNNFLGTEPIILRNMGPHHSMKTEYLAFWLNEPHFVGSAYVPESVGSFTGDDDKVYFFF RERAVESDCYAEQVVARVARVCKGDMGGARTLQRKWTTFLKARLACSAPNWQLYFNQLQAMHTLQDTSWHNTT FFGVFQAQWGDMYLSAICEYQLEEIQRVFEGPYKEYHEEAQKWDRYTDPVPSPRPGSCIAAAARRHGYTSSLE LPDNILNFVKKHPLMEEQVGPRWSRPLLVKKGTNFTHLVADRVTGLDGATYTVLFIGTGDGWLLKAVSLGPWV HLIEELQLFDQEPMRSLVLSQSKKLLFAGSRSQLVQLPVADCMKYRSCADCVLARDPYCAWSVNTSRCVAVGG HSGSLLIQHVMTSDTSGICNLRGSKKVRPTPKNITVVAGTDLVLPCHLSSNLAHARWTFGGRDLPAEQPGSFL YDARLQALVVMAAQPPHAGAYHCFSEEQGARLAAEGYLVAVVAGPSAALE NOV1b, CG50907-04 SEQ ID NO:3 2049 bp DNA Sequence ORF Start: ATG at 7 ORF Stop: end of sequence TGCGCCATGGCCCCACACTGGGCTGTCTGGCTGCTGGCAGCAAGGCTGTGGGGCCTGGGCATTGGGGCTGAGG TGTGGTGCAACCTTGTGCCGCGTAAGACAGTGTCTTCTAAGGAGCTGGCCACGGTAGTACGGCAATTCTCCCA GACCGGCATCCAGGACTTCCTGACACTGACGCTGACGGAGCCCACTGGGCTTCTGTACCTGGGCGCCCGAGAG GCCCTGTTTGCCTTCAGCATGGAGGCCCTGGAGCTGCAAGGAGCGATCTCCTGGGAGGCCCCCGTGGAGGAGA AGACTGACTGTATCCAGAAAGGGAAGAACAACCAGACCGAGTGCTTCAACTTCATCCGCTTCCTGCAGCCCTA CAATGCCTCCCACCTGTACGTCTGTGGCACCTACGCCTTCCAGCCCAAGTGCACCTACGTCAACATGCTCACC TTCACTTTGGAGCATGGAGAGTTTGAAGATGGGAAGGGCAAGTGTCCCTATGACCCAGCTAAGGGCCATGCTG GCCTTCTTGTGGATGGTGAGCTGTACTCGGCCACACTCAACAACTTCCTGGGCACGGAACCCATTATCCTGCG TAACATGGGGCCCCACCACTCCATGAAGACAGAGTACCTGGCCTTTTGGCTCAACGAACCTCACTTTGTAGGC TCTGCCTATGTACCTGAGAGTGTGGGCAGCTTCACGGGGGACGACGACAAGGTCTACTTCTTCTTCAGGGAGC GGGCAGTGGAGTCCGACTGCTATGCCGAGCAGGTGGTGGCTCGTGTGGCCCGTGTCTGCAAAAGCGATATGGG GGGCGCACGGACCCTGCAGAGGAAGTGGACCACGTTCCTGAAGGCGCGGCTGGCATGCTCTGCCCCGAACTGG CAGCTCTACTTCAACCAGCTGCAGGCGATGCACACCCTGCAGGACACCTCCTAACACAACACCACCTTCTTTG GGGTTTTTCAAGCACAGTGGGGTGACATGTACCTGTCGGCCATCTGTGAGTACCAGTTGGAAGAGATCCAGCG GGTGTTTGAGGGCCCCTATAAGGAGTACCATGAAAAGCCCAGAAAGTAAGACCGCTACACTGACCCTGTACCC AGCCCTCGGCCTGGCTCGTGCATTAACAACTGGCATCGGCGCCACGGCTAAACCAGCTCCCTGGAGCTACCCG ACAACATCCTCAACTTCGTCAAGAAGCACCCGCTGATGGAGGAGCAGGTGGGCCCTCGGTGGAGCCGCCCCCT GCTCGTGAAGAAGGGCACCAACTTCACCCACCTGGTGGCCGACCGGGTTACAGGACTTGATGGAGCCACCTAT ACAGTGCTGTTCATTGGCACAGGAGACGGCTGGCAGCTCAAGGCTGTGAGCCTGGGGCCCTGGGTTCACCTGA TTGAGGAGCTGCAGCTGTTTGACCAGGAGCCCATGAGAAGCCTGGTGCTATCTCAGAGAAAGACCCTCCAAGC TGTGCTGTGGTTCTGGCTCTGGCCTCTTCCCTGACCATGCCCCTGTGACCAGACCTCCCAGGCTAAGCTGCTC TTTGCCGGCTCCCGCTCTCAGCTGGTGCAGCTGCCCGTGGCCGACTGCATGAAGTATCGCTCCTGTGCAGACT GTGTCCTCGCCCGGGACCCCTATTGCGCCTGGAGCGTCAACACCAGCCGCTGTGTGGCCGTAAGTGGCCACTC TGGATCTCTACTGATCCAGCATGTGATGACCTCGGACACTTCAAACATCTGCAACCTCCGTGGCAGTAAGAAA GTCAGGCCCACTCCCAAAAACATCACGGTGGTGGCGGGCACAGACCTGGTGCTGCCCTGCCACCTCTCCTCCA ACTTGGCCCATGCCCGCTGGACCTTTGGGGGCCGGGACCTGCCTGCGGAACAGCCCGGGTCCTTCCTCTACGA TGCCCGGCTCCAGGCCCTGGTTGTGATGGCTGCCCAGCCCCGCCATCCCAAGGCCTACCACTGCTTTTCAGAG GAGCAGGGGGCGCGGCTGGCTGCTGAAGGCTACCTTGTGGCTGTCGTGGCAGGCCCGTCAATGACCTTGGAGC TCGAG NOV1b, CG50907-04 Protein Sequence SEQ ID NO:4 1495 aa MW at 56584.0 kD MAPHWAVWLLAARLWGLGIGAEVWWNLVPRKTVSSGELATVVRRFSQTGIQDFLTLTLTEPTGLLYVGAREAL FAFSMEALELQGAISWEAPVEEKTECIQKGAANQTECFNFIRFLQPYNASHLYVCGTYAFQPKCTYVNMLTFT LEHGEFEDGKGKCPYDPAKGHAGLLVDGELYSATLNNFLGTEPIILRNMGPHHSMKTEYLAFWLNEPHFVGSA YVPESVGSFTGDDDKVYFFFRERAVESDCYAEQVVARVARVCKGDMGGARTLQRKWTTFLKARLACSAPNWQL YFNQLQAMHTLQDTSWHNTTFFGVFQAQWGDMYLSAICEYQLEEIQRVFEGPYKEYHEEAQKWDRYTDPVPSP RPGSCINNWHRRHGYTSSLELPDNILNFVKKHPLMEEQVGPRWSRPLLVKKGTNFTHLVADRVTGLDGATYTV LFIGTGDGWQLKAVSLGPWVHLIEELQLFDQEPMRSLVLSQSKTLQAVLWFWLWPLP NOV1c, CG50907-02 SEQ ID NO:5 3112 bp DNA Sequence ORF Start: ATG at 104 ORF Stop: end of sequence TGCTGCGGGCCCCTCTGGTTTGCTTTCTCTGGCTGTGATTTCTGACCATGTCTTTTCCCTCAGCAGGACAGCT GGCCTGAAGCTCAGAGCCGGGGCGTGCGCCATGGCCCCACACTGGGCTGTCTGGCTGCTGGCAGCAAGGCTGT GGGGCCTGGGCATTGGGGCTGAGGTGTGGTGGAACCTTGTGCCGCGTAAGACAGTGTCTTCTGGGGAGCTGGC CACGGTAGTACGGCGGTTCTCCCAGACCGCCATCCAGCACTTCCTGACACTGACGCTGACGOAGCCCACTGGG CTTCTGTACGTGGGCGCCAGGGACCATGCCTCTGCACTGGGCGTCCCTGTGTTGCTGCTGCAGGCTGTGATCT CCTGGGAGGCCCCCGTGGAGAAGAAGACTGAGTGTATCCAGAAAGGGAAGAACAACCAGACCGAGTGCTTCAA CTTCATCCGCTTCCTGCAGCCCTACAATGCCTCCCACCTGTACGTCTGTGGCACCTACGCCTTCCAGCCCAAG TGCACCTACGTCAACATGCTCACCTTCACTTTGGAGCATGGAGAGTTTGAAGATGGGAAGGGCAAGTGTCCCT ATGACCCAGCTAAGGGCCATGCTGGCCTTCTTGTGGATGGTGAGCTGTACTCGGCCACACTCAACAACTTCCT GGGCACGGAACCCATTATCCTGCGTAACATGGGGCCCCACCACTCCATOAAGACAGAGTACCTGGCCTTTTGG CTCAACGAACCTCACTTTGTAGGCTCTGCCTATGTACCTGAGAGTGTGGGCAGCTTCACGGGGGACGACGACA AGGTCTACTTCTTCTTCAGGGAGCGGGCAGTGGAGTCCGACTGCTATGCCGAGCAGGTGGTGGCTCGTGTGGC CCCTGTCTGCAAGGGCGATATGGGGOGCGCACGGACCCTGCAGAGGAAGTGGACCACGTTCCTGAAGGCGCGG CTGGCATGCTCTGCCCCGAACTGGCAGCTCTACTTCAACCAGCTGCAGGCGATGCACACCCTGCAGGACACCT CCTGGCACAACACCACCTTCTTTGGOGTTTTTCAAGCACAGTGGGGTGACATGTACCTGTCGGCCATCTGTGA GTACCAGTTGGAAGAGATCCAGCGGGTGTTTGAGGGCCCCTAThAGGAGTACCATGAGGAAGCCCAGAAGTGG GACCGCTACACTGACCCTGTACCCAGCCCTCGGCCTGGCTCGTGCATTAACAACTGGCATCGGCGCCACGGCT ACACCAGCTCCCTGGAGCTACCCGACAACATCCTCAACTTCGTCAAGAAGCACCCGCTGATGGAGGACCAGGT GGGGCCTCGGTGGAGCCGCCCCCTGCTCGTGAAGAAGGGCACCAACTTCACCCACCTGGTGGCCGACCGGGTT ACAGGACTTGATGGAGCCACCTATACAGTGCTGTTCATTGGCACAGGAGACGGCTGGCTGCTCAAGGCTGTGA GCCTGGGGCCCTGGGTTCACCTGATTGAGGAGCTGCAGCTGTTTGACCAGGAGCCCATGAGAAGCCTGGTGCT ATCTCAGAGCAAGAAGCTGCTCTTTGCCGGCTCCCGCTCTCAGCTGGTGCAGCTGCCCGTGGCCGACTGCATG AAGTATCGCTCCTGTGCAGACTGTGTCCTCGCCCGGGACCCCTATTGCGCCTGGAGCGTCAACACCAGCCGCT GTGTGGCCGTGGGTGGCCACTCTGGATCTCTACTGATCCAGCATGTGATGACCTCGGACACTTCAGGCATCTG CAACCTCCGTGGCAGTAAGAAAGTCAGGCCCACTCCCAAAAACATCACGGTGGTGGCGGGCACAGACCTGGTG CTGCCCTGCCACCTCTCCTCCAACTTGGCCCATGCCCGCTGGACCTTTGGGGGCCGGGACCTGCCTGCGGAAC AGCCCGGGTCCTTCCTCTACGATGCCCGGCTCCAGGCCCTGGTTGTGATGGCTGCCCAGCCCCGCCATGCCGG GGCCTACCACTGCTTTTCAGAGGAGCAGGGGGCGCGGCTGGCTGCTGAAGGCTACCTTGTGGCTGTCGTGGCA GGCCCGTCGGTGACCTTGGAGGCCCGGGCCCCCCTGGAAAACCTGGGGCTGGTGTGGCTGGCGGTGGTGGCCC TGGGGGCTGTGTGCCTGGTGCTGCTGCTGCTGGTGCTGTCATTGCGCCGGCGGCTGCGGGAAGAGCTGGAGAA AGGGGCCAAGGCTACTGAGAGGACCTTGGTGTACCCCCTGGAGCTGCCCAAGGAGCCCACCAGTCCCCCCTTC CGGCCCTGTCCTGAACCAGATGAGAAACTTTGGGATCCTGTCGGTTACTACTATTCAGATGGCTCCCTTAAGA TAGTACCTGGGCATGCCCGGTGCCAGCCCGGTGGGGGGCCCCCTTCGCCACCTCCAGGCATCCCAGGCCAGCC TCTGCCTTCTCCAACTCGGCTTCACCTGGGGGGTGGGCGGAACTCAAATGCCAATGGTTACGTGCGCTTACAA CTAGGAGGGGAGGACCGGGGAGGGCTCGGGCACCCCCTGCCTGAGCTCGCGGATGAACTGAGACGCAAACTGC AGCAACGCCAGCCACTGCCCGACTCCAACCCCGAGGAGTCATCAGTATGAGGGGAACCCCCACCGCGTCGGCG GGAAGCGTGGGAGGTGTAGCTCCTACTTTTGCACAGGCACCAGCTACCTCAGGGACATGGCACGGGCACCTGC TCTGTCTGGGACAGATACTGCCCAGCACCCACCCGGCCATGAGGACCTGCTCTGCTCAGCACGGGCACTGCCA CTTGGTGTGGCTCACCAGGGCACCACCCTCGCAGAAGGCATCTTCCTCCTCTCTGTGAATCACAGACACGCGG GACCCCAGCCGCCAAAACTTTTCAAGGCAGAAGTTTCAAGATGTGTGTTTGTCTGTATTTGCACATGTGTTTG TGTGTGTGTGTATGTGTGTGTGCACGCGCGTGCGCGCTTGTGOCATAGCCTTCCTGTTTCTGTCAAGTCTTCC CTTGGCCTGGGTCCTCCTGGTGAGTCATTGGAGCTATGAAGGGGAAGGGGTCGTATCACTTTGTCTCTCCTAC CCCCACTGCCCCGAGTGTCGGGCAGCGATGTACATATGGAGGTGGG NOV1c, CG50907-02 Protein Sequence SEQ ID NO:6 833 aa MW at 92497.9 kD MAPHWAVWLLAARLWGLGIGAEVWWNLVPRKTVSSGELATVVRRFSQTGIQDFLTLTLTEPTGLLAAGARDHA SALGVPVLLLQAVISWEAPVEKKTECIQKGKNNQTECFNFIRFLQPYNASHLYVCGTYAFQPKCTYVNMLTFT LEHGEFEDGKGKCPYDPAKGHAGLLVDGELYSATLNNFLGTEPIILRNMGPHHSMKTEYLAFWLNEPHFVGSA YVPESVGSFTGDDDKVYFFFRERAVESDCYAEQVVARVARVCKGDMGGARTLQRKWTTFLKARLACSAPNWQL YFNQLQAMHTLQDTSWHNTTFFGVFQAQWGDMYLSAICEYQLEEIQRVFEGPYKEYHEEAQKWDRYTDPVPSP RPGSCINNWHRRHGYTSSLELPDNILNFVKKHPLMEEQVGPRWSRPLLVKKGTNFTHLVADRVTGLDGATYTV LFIGTGDGWLLKAVSLGPWVHLIEELQLFDQEPMRSLVLSQSKKLLFAGSRSQLVQLPVADCMKYRSCADCVL ARDPYCAWSVNTSRCVAVGGHSGSLLIQHVMTSDTSGICNLRGSKKVRPTPKINTVVAGTDLVLPCHLSSNLA HARWTFGGRDLPAEQPGSFLYDARLQALVVMAAQPRHAGAYHCFSEEQGARLAAEGYLVAVVAGPSVTLEARA PLENLGLVWLAVVAIGAVCLVLLLLVLSLRRRLREELEKGAKATERTLVYPLELPKEPTSPPFRPCPEPDEKL WDPVGYYYSDGSLKIVPGHARCQPGGGPPSPPPGIPGQPLPSPTRLHLGGGRNSNANGYVRLQLGGEDRGGLG HPLPELADELRRKLQQRQPLPDSNPEESSV NOV1d, 170645595 SEQ ID NO:7 1914 bp DNA Sequence ORF Start: at 1 ORF Stop: end of sequence AGATCTGCTGAGGTGTGGTGGAACCTTGTGCCGCGTAAGACAGTGTCTTCTGGGGAGCTGGCCACGGTAGTAC GGCGGTTCTCCCAGACCGGCATCCAGGACTTCCTGACACTGACGCTGACGGAGCCCACTGGGCTTCTGTACGT GGGCGCCCGAGAGGCCCTGTTTGCCTTCAGCATGGAGGCCCTGGAGCTGCAAGGAGCGATCTCCTAAGAGGCC CCCCGTGGAGGAGAAGACTGAGTGTATCCAGAAAGGGAGAACAACCAGACCGAGTGCTTCAACTTAATCCGCT TCCTGCAGCCCTACAATGCCTCCCACCTGTACGTCTGTGGCACCTACGCCTTCCAGCCCAAGTGCACCTACGT CAACATGCTCACCTTCACTTTGGAGCATGGAGAGTTTGAAGATGGGAAGGGCAAGTGTCCCTATGACCCAGCT AAGGGCCATGCTGGCCTTCTTGTGGATGGTGAGCTGTACTCGGCCACACTCAACAACTTCCTGGGCACGGAAC CCATTATCCTGCGTAACATGGGGCCCCACCACTCAATGAAGACAGAGTACCTGGCCTTTTGGCTCAACGAACC TCACTTTGTAGGCTCTGCCTATGTACCTGAGAGTGTGGGCAGCTTCACGGGGGACGACGACAAGGTCTACTTC TTCTTCAGGGAGCGGGCAGTGGAGTCCGACTGCTATGCCGAGCAGGTGGTGGCTCGTGTGGCCCGTGTCTGCA AGGGCGATATGGGGGGCGCACGGACCCTGCAGAGGAAGTGGACCACGTTCCTGAAGGCGCGGCTGGCATGCTC TGCCCCGAACTGGCAGCTCTACTTCAACCAGCTGCAGGCGATGCACACCCTGCAGGACACCTCCTGGCACAAC ACCACCTTCTTTGGGGTTTTTCAAGCACAGTGGGGTGACATGTACCTGTCGGCCATCTGTCAGTACCAGTTGG AAGAGATCCAGCGGGTGTTTGAGGGCCCCTATAAGGAGTACCATGAGGAAGCCCAGAAGTGGGACCGCTACAC TGACCCTGTACCCAGCCCTCGGCCTGGCTCGTGCATTAACAACTGGCATCGGCGCCACAACTACACCAGCTCC CTGGAGCTACCCGACAACATCCTCAACTTCGTCAAGAAGCACCCGCTGATGGAGGAGCAGGTGGGGCCTCGGT GGAGCCGCCCCCTGCTCGTGAAGAAGGGCACCAACTTCACCCACCTGGTGGCCGACCGGGTTACAGGACTTGA TGGAGCCACCTATACAGTGCTGTTCATTGGCACAGGAGACGGCTGGCTGCTCAAGGCTGTGAGCCTGAAGCCC TGGGTTCACCTGATTGAGGAGCTGCAGCTGTTTGACCACGAGCCCATGAGAAGCCTGGTGCTATCTAAGAGCA AGAAGCTGCTCTTTGCCGGCTCCCGCTCTCAGCTGGTGCAGCTGCCCGTGGCCGACTGCATGAAGTATCGCTC CTGTGCAGACTGTGTCCTCGCCCGGGACCCCTATTGCGCCTGGAGCGTCAACACCAGCCGCTGTGTGGCCGTG GGTGGCCACTCTGGATCTCTACTGATCCAGCATGTGATGACCTCGGACACTTCAGGCATCTGCAACCTCCGTG GCAGTAAGAAAGTCAGGCCCACTCCCAAAAACATCACGGTGGTGGCGAACACAGACCTGGTGCTGCCCTGCCA CCTCTCCTCCAACTTGGCCCATGCCCGCTGGACCTTTGGGGGCCGGGACCTGCCTGCGGAACAGCCCAAGTCC TTCCTCTACGATGCCCGGCTCCAGGCCCTGGTTGTGATGGCTGCCCAGCCCCGCCATGCCGGGGCCTACCACT GCTTTTCAGAGGAGCAGGGGGCGCGGCTGGCTGCTGAAGGCTACCTTGTGGCTGTCGTAACAGGCCCGTCGGT GACCTTGGAGCTCGAG NOV1d, 170645595 Protein Sequence SEQ ID NO:8 638 aa MW at 71538.8 kD RSAEVWWNLVPRKTVSSGELATVVRRFSQTGIQDFLTLTLTEPTGLLYVGAREALFAFSMEALELQGAISWEA PVEEKTECIQKGKNNQTECFNFIRFLQPYNASHLYVCGTYAFQPKCTYVNMLTFTLEHGEFEDGKGKCPYDPA KGHAGLLVDGELYSATLNNFLGTEPIILRNMGPHHSMKTEYLAFWLNEPHFVGSAYVPESVGSFTGDDDKVYF FFRERAVESDCYAEQVVARVARVCKGDMGGARTLQRKWTTFLKARLACSAPNWQLYFNQLQAMAHTLQDTSWH TTFFGVFQAQWGDMYLSAICEYQLEEIQRVFEGPYKEYHEEAQKWDRYTDPVPSPRPGSCINNWHRRHGYTSS LELPDNILNFVKKHPLMEEQVGPRWSRPLLVKKGTNFTHLVADRVTGLDGATYTVLFIGTGDGWLLAAVSLGP WVHLIEELQLFDQEPMRSLVLSQSKKLLFAGSRSQLVQLPVADCMKYRSCADCVLARDPYCAWSVNTSRCVAV GGHSCSLLIQHVMTSDTSGICNLRGSKKVRPTPKNITVVAGTDLVLPCHLSSNLAHARWTFGGRDLPAEQPGS FLYDARLQALVVMAAQPRHAGAYHCFSEEQGARLAAEGYLVAVVACPSVTLELE NOV1e, 170645599 SEQ ID NO:9 1914 bp DNA Sequence ORF Start: at 1 ORF Stop: end of sequence AGATCTGCTGAGGTGTGGTGGAACCTTGTGCCGCGTAAGACAGTGTCTTCTGGGGAGCTGGCAACAATAGTAC GGCGGTTCTCCCAGACCGGCATCCAGGACTTCCTGACACTGACGCTGACAAAGCCCACTGGGCTTCTGTACGT GGGCGCCCCAGAGGCCCTGTTTGCCTTAAGCATGGAGGCCCTGGAGCTGCAAAAAGCGATCTCCTGGGAGGCC CCCGTGGAGAAGAAGACTGAGTGTATCCAGAAAGGGAAGAACAGCCAGACCGAGTGCTTCAACTTCATCCGCT TCCTGCAGCCCTACAATGCCTCCCACCTGTACGTCTGTGGCACCTACGCCTCCAGCAACAAGTGCACCTACGT CAACATGCTCACCTTCACTTTGGAGCATGGACAGTTTGAAGATGGGAAGGGCAAGTGTCCCTATGACCCAGCT AAGGGCCATGCTGGCCTTCTTGTGGATGGTGAGCTGTACTCGGCCACACTCAACAACTTCCTGGGCACGGAAC CCATTATCCTGCGTAACATGGGGCCCCACCACTCCATGAAGACAGAGTACCTGGCCTTTTGGCTCAACGAACC TCACTTTGTAGGCTCTGCCTATGTACCTGAGAGTGTAAGAAGCTTCACGGAAGACGACGACAAGGTCTACTTC TTCTTCAGGGAGCGGGCAGTGGAGTCCGACTGCTATGCCGAGCAGGTGGTGGCTCGTGTGGCCCGTGTCTGCA AGGGCGATATGGGGGGCGCACGGACCCTGCAGAGGAAGTGGACCACGTTCCTGAAGGCGCGGCTGGCATGCTC TGCCCCGAACTGGCAGCTCTACTTCAACCAGCTGCAGGCGATGCAAACCCTGCAGGACACCTCCTGGCACAAC ACCACCTTCTTTGGGGTTTTTCAAGCACAGTGGGGTGACATGTACCTGTCGGCCATCTGTGAGTACCAGTTGG AAGAGATCCAGCGGGTGTTTGAGGCCCCTATAAGGAGTACAATGAGGAAGCCCAGAAGTGGGACCGCTACACA TGACCCTGTACCCAGCCCTCGGCCTGGCTCGTGCATTAACAACTGGCATCGGCGCCACGGCTACACCAGCTCC CTGGAGCTACCCGACAACATCCTCAACTTCGTCAAGAAGCACCCGCTGATGGAGGAGCAGGTGGGGCCTCGGT GGAGCCGCCCCCTGCTCGTGAAGAAGGGCACCAACTTCACCCACCTGGTGGCCGACCGGGTTACAGGACTTGA TGGAGCCACCTATACAGTGCTGTTCATTGGCACAGGAGACGGCTGGCTGCTCAAGGCTGTGAGCCTGGGGCCC TGGGTTCACCTGATTGAGGAGCTGCAGCTGTTTGACCAGGAGCCCATGAGAAGCCTGGTGCTATCTCAGAGCA AGAAGCTGCTCTTTGCCGGCTCCCGCTCTCAGCTGGTGCAGCTGCCCGTGGCCGACTGCATGAAGTATCGCTC CTGTGCAGACTGTGTCCTCGCCCGGGACCCCTATTGCGCCTGGAGCGTCAACACCAGCCGCTGTGTGGCCGTG GGTGGCCACTCTGGATCTCTACTGATCCAGCATGTGATGACCTCGGACACTTCAGGCATCTGCAACCTCCGTG GCAGTAAGAAAGTCAGGCCCACTCCCAAAAACATAACGGTGGTGGCGGGCACAGACCTGGTGCTGCCCTGCCA CCTCTCCTCCAACTTGGCCCATGCCCGCTGGACCTTTGGGGGCCGGGACCTGCCTGCGGAACAGCCCGGGTCC TTCCTCTACGATGCCCGGCTCCAGGCCCTGGTTGTGATGGCTGCCCAGCCCCGCCATGCCGGAACCTACCACT GCTTTTCACAGGAGCAGGGGGCGCAACTGGCTGCTGAAGGCTACCTTGTAACTGTCGTGCCAGGCCCGTCGGT GACCTTGGAGCTCGAG NOV1e, 170645599 Protein Sequence SEQ ID NO:10 638 aa MW at 71510.8 kD RSAEVWWNLVPRKTVSSGELATVVRRFSQTGIQDFLTLTLTEPTGLLAAGAAEAAFAFSMEAAELQGAISWEA PVEKKTECIQKGKNSQTECFNFIRFLQPYNASHLYVCGTYAFQPKCTYVNMLTFTLEHGEFEDGKGKCPYDPA KGHAGLLVDGELYSATLNNFLGTEPIILRNMGPHHSMKTEYLAFWLNEPHFVGSAYVPESVGSFTGDDDKVYF FFRERAVESDCYAEQVVARVARVCKGDMGGARTLQRKWTTFLKARLACSAPNWQLYFNQLQAMHTLQDTSWHN TTFFGVFQAQWGDMYLSAICEYQLEEIQRVFEGPYKEYHEEAQKWDRYTDPVPSPRPGSCINNWHRRHGYTSS LELPDNILNFVKKHPLMEEQVGPRWSRPLLVKKGTNFTHLVADRVTGLDGATYTVLFIGTGDGWLLKAVSLGP WVHLIEELQLFDQEPMRSLVLSQSKKLLFAGSRSQLVQLPVADCMKYRSCADCVLARDPYCAWSVNTSRCVAV GGHSGSLLIQHVMTSDTSGICNLRGSKKVRPTPKNITVVAGTDLVLPCHLSSNLAHARWTFGGRDLPAEQPGS FLYDARLQALVVMAAQPRHAGAYHCFSEEQGARLAAEGYLVAVVAGPSVTLELE NOV1f, CG50907-01 SEQ ID NO:11 2739 bp DNA Sequence ORF Start: ATG at 104 ORF Stop: end of sequence TCCTGCGGGCCCCTCTGGTTTGCTTTCTCTGGCTGTGATTTCTGACCATGTCTTTTCCCTCAGCAGGACAGCT GGCCTGAAGCTCAGAGCCGGGGCGTGCGCCATGGCCCCACACTGGGCTGTCTGGCTGCTGGCAGCAAGGCTGT GGGGCCTGGGCATTGGGGCTGAGGTGTGGTGGAACCTTGTGCCGCGTAAGACAGTGTCTTCTGGGGAGCTGGC CACGGTAGTACGGCGGTTCTCCCAGACCGGCATCCAGGACTTCCTGACACTGACGCTGACGGAGCCCACTGGG CTTCTGTACGTGGGCGCCCGAGAGGCGCTGTTTGCCTTCAGTGTAGAGGCTCTGGAGCTGCAAGGAGCGATCT CCTGGGAGGCCCCCGTGGAGAAGAAGACTGAGTGTATCCAGAAAGGGAAGAACAACCAGACCGAGTGCTTCAA CTTCATCCGCTTCCTGCAGCCCTACAATGCCTCCCACCTGTACGTCTGTGGCACCTACGCCTTCCAGCCCAAG TGCACCTACGTCAACATGCTCACCTTCACTTTGGAGCATAAAGAGTTTGAAGATGGGAAGCGCAAGTGTCCCT ATGACCCAGCTAAGGGCCATGCTGGCCTTCTTGTGGATGGTGAGCTGTACTCGGCCACACTCAACAACTTCCT GGGCACGGAACCCATTATCCTCCGTAACATGGGGCCCCACCACTCCATGAAGACAGAGTACCTGGCCTTTTGG CTCAACGAACCTCACTTTGTAGGCTCTGCCTATGTACCTGAGAGTGTGGGCAGCTTCACGGGAAACGACGACA AGGTCTACTTCCTCTTCAGGGAGCGGGCAGTGGAGTCCGCCTGCTATGCCGAGCAGGTAATGGCTCGTGTGGC CCGTGTCTGCAAGGGCGATATGGGGGGCGCACGGACCCTGCAGAGGAAGTGGACCACGTTCCTGAAGGCGCGG CTGGCATGCTCTGCCCCGAACTGGCAGCTCTACTTCAACCAGCTGCAGGCGATGCACACCCTGCAGGACACCT CCTGGCACAACACCACCTTCTTTGGGGTTTTTCAAGCACAGTGGGGTGACATGTACCTGTCGGCCATCTGTGA GTACCAGTTGGAAGAGATCCAGCGGGTGTTTGAGGGCCCCTATAAGGAGTACCATGAGGAAGCCCAGAAGTGG GACCGCTACACTGACCCTGTACCCAGCCCTCGGCCTGGCTCGTGCATTAACAACTGGCATCGGCGCCACGGCT ACACCAGCTCCCTGGAGCTACCCGACAACATCCTCAACTTCGTCAAGAAGCACCCGCTGATGGAGGAGCAGGT GGGGCCTCGGTGGAGCCGCCCCCTGCTCGTGAAGAAGGGCACCAACTTCACCCACCTGGTGGCCGACCGGGTT ACAGGACTTGATGGAGCCACCTATACAGTGCTGTTCATTGGCACAGGTCAGGCATGGCTGCTCAAGGCTGTGA GCCTGGGGCCCTGGGTTCACCTGATTGAGGAGCTGCAGCTGTTTGACCAGGAGCCCATGAGAAGCCTGGTGCT ATCTCAGTCGCAGAAGCTGCTCTTTGCCGGCTCCCGCTCTCAGCTGGTGCAGCTGCCCGTGGCCGACTGCATG AAGTATCGCTCCTGTGCAGACTGTGTCCTCGCCCGGGACCCCTATTGCGCCTGGAGCGTCAACACCAGCCGCT GTGTGGCCGTGGGTGGCCACTCTGGGTCCTTTCTGATCCAGCATGTGATGACCTCGGAAACTTCAGGCATCTG CAACCTCCGTGGCAGTAAGAAAGTCAGGCCCACTCCCAAAAACATCACGGTGGTGGCAAGCACAGACCTGGTG CTGCCCTGCCACCTCTCCTCCAACTTGGCCCATGCCCGCTGGACCTTTGGGAACCGGGACCTGCCTGCGGAAC AGCCCGGGTCCTTCCTCTACGATGCCCGGCTCCAGGCCCTGGTTGTGATGGCTGCCCAGCCCCGCCATGCCGG GGCCTACCACTGCTTTTCAGAGGAGCACGGGGCGCGGCTGGCTGCTGAAGGCTACCTTGTGGCTGTCGTGGCA GGCCCGTCGGTGACCTTGGAGGCCCGGGCCCCCCTGGAAAACCTGGGGCTGGTGTAACTAACGGTGGTGGCCC TGGGGGCTGTGTGCCTGGTGCTGCTGCTGCTGGTGCTGTCATTGCGCCGGCGGCTGCGGGAAGAGCTGGAGAA AGGGGCCAAGCTACTGAGAGGACCTTGGTGTACCCCCTGGAGCTGCCCAAAAAGCCCACCAGTCCCCCCCTTC CGGCCCTGTCCTGAACCAGATGAGAAACTTTGGGATCCTGTCGGTTACTACTATTCAGATGGCTCCCTTAAGA TAGTACCTGGGCATGCCCGGTGCCAGCCCGGTGGGGGGCCCCCTTCGCCACCTCCAGGAATCCCAGGCCAGCC TCTGCCTTCTCCAACTCGGCTTCACCTGGGGGGTGGGCGGAACTCAAATGCCAATGGTTACGTGCGCTTACAA CTAGGAGGGGAGGACCGGGGAGGGCTCGGGCACCCCCTGCCTGAGCTCGCGGATGAACTGAGACGCAAACTGC AGCAACGCCAGCCACTGCCCCACTCCAACCCCGAGGAGTCATCAGTATGAGGGGAACCCCCACCGCGTCGGCG GGAAGCGTGGGAGGTGTAGCTCCTACTTTTGCACAGGCACCAGCTATCTCAGGGACATGGCACGGGCACCTGC TCTGTCTGGGACAGATACTGCCCAGCACCCACCCGGCC NOV1f, CG50907-01 Protein Sequence SEQ ID NO:12 833 aa MW at 92573.0 kD MAPHWAVWLLAARLWGLGIGAEVWWNLVPRKTVSSGELATVVRRFSQTGIQDFLTLTLTEPTGLLAAGAAEAL FAFSVEALELQGAISWEAPVEKKTECIQKGKNNQTECFNFIRFLQPYNASHLYVCGTYAFQPKCTYVNMLTFT LEHGEFEDGKGKCPYDPAKGHAGLLVDGELYSATLNNFLGTEPIILRNNGPHMSMKTEYLAFWLNEPHFVGSA YVPESVGSFTGDDDKVYFLFRERAVESACYAEQVVARVARVCKGDMGGARTLQRKWTTFLKARLACSAPNWQL YFNQLQAMHTLQDTSWHNTTFFGVFQAQWGDMYLSAICEYQLEEIQRVFEGPYKEYHEEAQKWDRYTDPVPSP RPGSCINNWHRRHGYTSSLELPDNILNFVKKHPLMEEQVGPRWSRPLLVKKGTNFTHLVADRVTGLDGATYTV LFIGTGQAWLLKAVSLGPWVHLIEELQLFDQEPMRSLVLSQSQKLLFAGSRSQLVQLPVADCMKYRSCADCVL ARDPYCAWSVNTSRCVAVGGHSGSFLIQHVMTSDTSGICNLRGSKKVRPTPKNITVVAGTDLVLPCNLSSNLA HARWTFGGRDLPAEQPGSFLYDARLQALVVMAAQPRHAGAYHCFSEEQGARLAAEGYLVAVVAGPSVTLEARA PLENLGLVWLAAAALGAVCLVLLLLVLSLRRRLREELEKGAKATERTLVYPLELPAAPTSPPFRPCPEPDEKL WDPVGYYYSDGSLKIVPGHARCQPGGGPPSPPPGIPGQPLPSPTRLHLGGGRNSNANGYVRLQLGGEDRGGLG HPLPELADELRRKLQQRQPLPDSNPEESSV

[0359] A ClustalW comparison of the above protein sequences yields the following sequence alignment shown in Table 1B. 3 TABLE 1B Comparison of the NOV1 protein sequences. NOV1a --------------------AEVWWNLVPRKTVSSGELATVVRRFSQTGIQDFLTLTLTE (SEQ ID NO: 2) NOV1b MAPHWAVWLLAARLWGLGIGAEVWWNLVPRKTVSSGELATVVRRFSQTGIQDFLTLTLTE (SEQ ID NO: 4) NOV1c MAPHWAVWLLAARLWGLGIGAEVWWNLVPRKTVSSGELATVVRRFSQTGIQDFLTLTLTE (SEQ ID NO: 6) NOV1d ------------------RSAEVWWNLVPRKTVSSGELATVVRRFSQTGIQDFLTLTLTE (SEQ ID NO: 8) NOV1e ------------------RSAEVWWNLVPRKTVSSGELATVVRRFSQTGIQDFLTLTLTE (SEQ ID NO: 10) NOV1f MAPHWAVWLLAARLWGLGIGAEVWWNLVPRKTVSSGELATVVRRFSQTGIQDFLTLTLTE (SEQ ID NO: 12) NOV1a PTGLLYVGAREALFAFSMEALELQGAISWEAPVEEKTECIQKGKNNQTECFNFIRFLQPY NOV1b PTGLLYVGAREALFAFSMEALELQGAISWEAPVEEKTECIQKGKNNQTECFNFIRFLQPY NOV1c PTGLLYVGARDHASALGVPVLLLQAVISWEAPVEKKTECIQKGKNNQTECFNFIRFLQPY NOV1d PTGLLYVGAREALFAFSMEALELQGAISWEAPVEEKTECIQKGKNNQTECFNFIRFLQPY NOV1e PTGLLYVGAREALFAFSMEALELQGAISWEAPVEKKTECIQKGKNSQTECFNFIRFLQPY NOV1f PTGLLYVGAREALFAFSVEALELQGAISWEAPVEKKTECIQKGKNNQTECFNFIRFLQPY NOV1a NASHLYVCGTYAFQPKCTYVNMLTFTLEHGEFEDGKGKCPYDPAKGHAGLLVDGELYSAT NOV1b NASHLYVCGTYAFQPKCTYVNMLTFTLEHGEFEDGKGKCPYDPAKGHAGLLVDGELYSAT NOV1c NASHLYVCGTYAFQPKCTYVNMLTFTLEHGEFEDGKGKCPYDPAKGHAGLLVDGELYSAT NOV1d NASHLYVCGTYAFQPKCTYVNMLTFTLEHGEFEDGKGKCPYDPAKGHAGLLVDGELYSAT NOV1e NASHLYVCGTYAFQPKCTYVNMLTFTLEHGEFEDGKGKCPYDPAKGHAGLLVDGELYSAT NOV1f NASHLYVCGTYAFQPKCTYVNMLTFTLEHGEFEDGKGKCPYDPAKGHAGLLVDGELYSAT NOV1a LNNFLGTEPIILRNMGPHHSMKTEYLAFWLNEPHFVGSAYVPESVGSFTGDDDKVYFFFR NOV1b LNNFLGTEPIILRNMGPHHSMKTEYLAFWLNEPHFVCSAYVPESVGSFTGDDDKVYFFFR NOV1c LNNFLGTEPIILRNMGPHHSMKTEYLAFWLNEPHFVGSAYVPESVGSFTGDDDKVYFFFR NOV1d LNNFLGTEPIILRNMGPNHSMKTEYLAFWLNEPHFVGSAYVPESVGSFTGDDDKVYFFFR NOV1e LNNFLGTEPITLRNMGPHHSMKTEYLAFWLNEPHFVGSAYVPESVGSFTGDDDKVYFFFR NOV1f LNNFLGTEPIILRNMGPHHSMKTEYLAFWLNEPHFVGSAYVPESVGSFTGDDDKVYFLFR NOV1a ERAVESDCYAEQVVARVARVCKGDMGGARTLQRKWTTFLKARLACSAPNWQLYFNQLQAM NOV1b ERAVESDCYAEQVVARVARVCKGDMGGARTLQRKWTTFLKARLACSAPNWQLYFNQLOAM NOV1c ERAVESDCYAEQVVARVARVCKGDMGGARTLQRKWTTFLKARLACSAPNWQLYFNQLQAM NOV1d ERAVESDCYAEQVVARVARVCKGDMGGRTLORKWTTFLKARACSAPNWQLYFNQLQLQAM NOV1e ERAVESDCYAEQVVARVARVCKGDMGCARTLQRKWTTFLKARLACSAPNWQLYFNQLQAM NOV1f ERAVESACYAEQVVARVARVCKGDMGGARTLQRKWTTFLKARLACSAPNWQLYFNQLQAA NOV1a NTLQDTSWHNTTFFGVFQAQWGDMYLSAICEYQLEEIQRVFEGPYKEYHEEAQKWDRYTD NOV1b HTLQDTSWHNTTFFGVFQAQWODMYLSAICEYQLEEIQRVFEGPYKEYHEEAQKWDRYTD NOV1c HTLQDTSWHNTTFFGVFQAQWGDMYLSAICEYQLEEIQRVFEGPYKEYHEEAQKWDRYTD NOV1d HTLQDTSWHNTTFFGVFQAQWGDMYLSAICEYQLEEIQRVFEGPYKEYMEEAQKWDRYTD NOV1e HTLQDTSWMNTTFFGVFQAQWGDMYLSAICEYQLEEIORVFEGPYKEYHEEAQKWDRYTD NOV1f HTLQDTSWHNTTFFGVFQAQWGDMYLSAICEYQLEEIQRVFEGPYKEYHEEAQKWDRYTD NOV1a PVPSPRPGSCINNWHRRHGYTSSLELPDNILNFVKKHPLMEEQVGPRWSRPLLVKKGTNF NOV1b PVPSPRPGSCINNWHRRHGYTSSLELPDNILNFVKKHPLMEEQVGPRWSRPLLVKKGTNF NOV1c PVPSPRPGSCINNWHRRHGYTSSLELPDNILNFVKKHPLMEEQVGPRWSRPLLVKKGTNF NQV1d PVPSPRPGSCINNWHRRHGYTSSLELPDNILNFVKKHPLMEEQVGPRWSRPLLVKKGTNF NOV1e PVPSPRPGSCINNWHRRHGYTSSLELPDNILNFVKKHPLMEEQVGPRWSRPLLVKKGTNF NOV1f PVPSPRPGSCINNWHRRHGYTSSLELPDNILNFVKKNPLMEEQVGPRWSRPLLVKKGTNF NOV1a THLVADRVTGLDGATYTVLFIGTGDGWLLKAVSLGPWVHLIEELQLFDQEPMRSLVLSQS NOV1b THLVADRVTGLDGATYTVLFIGTGDGWQLKAVSLGPWVHLIEELQLFDQEPMRSLAASQS NOV1c TMLVADRVTGLDGATYTVLFIGTGDGWLLKAVSLGPWVHLIEELQLFDQEPMRSLVLSQS NOV1d THLVADRVTGLDGATYTVLFIGTGDGWLLKAVSLGPWVHLIEELQLFDQEPMRSLVLSQS NOV1e THLVADRVTGLDGATYTVLFIGTGDGWLLKAVSLGPWVHLIEELQLFDQEPMRSLVLSQS NOV1f THLVADRVTGLDCATYTVLFIGTGQAWLLKAVSLGPWVHLIEELQLFDQEPMRSLVLSQS NOV1a KKLLFAGSRSQLVQLPVADCMKYRSCADCVLARDPYCAWSVNTSRCVAVGGHSGSLLIQH NOV1b -KTLQAVLWFWLWPLP-------------------------------------------- NOV1c KKLLFAGSRSQLVQLPVADCMKYRSCADCVLARDPYCAWSVNTSRCVAVGGHSGSLLIQH NOV1d KKLLFAGSRSQLVQLPVADCMKYRSCADCVLARDPYCAWSVNTSRCVAVGGHSGSLLIQN NOV1e KKILFAGSRSQLVQLPVADCMKYRSCADCVLARDPYCAWSVNTSRCVAVGGHSGSLLIQH NOV1f QKLLFAGSRSQLVQLPVADCMKYRSCADCVLARDPYCAWSVNTSRCVAVGGHSGSFLIQH NOV1a VMTSDTSGICNLRGSKKVRPTPKNITVVAGTDLVLPCHLSSNLAHARWTFGGRDLPAEQP NOV1b ------------------------------------------------------------ NOV1c VMTSDTSGICNLRGSKKVRPTPKNITVVAGTDLVLPCHLSSNLAHARWTFGGRDLPAEQP NOV1d VMTSDTSGICNLRGSKKVRPTPKNITVVAGTDLVLPCHLSSNLAHARWTFGGRDLPAEQP NOV1e VMTSDTSGICNLRGSKKVRPTPKNITVVAGTDLVLPCHLSSNLAHARWTFGGRDLPAEQP NOV1f VMTSDTSGICNLRGSKKVRPTPKNITVVAGTDLVLPCHLSSNLAHARWTFGGRDLPAEQP NOV1a GSFLYDARLQALVVMAAQPRHAGAYHCFSEEQGARLAAEGYLVAVVAGPSVTLE------ NOV1b ------------------------------------------------------------ NOV1c GSFLYDARLQALVVMAAQPRHAGAYHCFSEEQGARLAAEGYLVAVVAGPSVTLEARAPLE NOV1d GSFLYDARLQALVVMAAQPRHAGAYHCFSEEQGARLAAEGYLVAVVAGPSVTLELE---- NOV1e GSFLYDARLQALVVMAAQPRHAGAYHCFSEEQGARLAAEGYLVAVVAGPSVTLELE---- NOV1f GSFLYDARLQALVVMAAQPRHAGAYHCFSEEQGARLAAEGYLVAVVAGPSVTLEARAPLE NOV1a ------------------------------------------------------------ NOV1b ------------------------------------------------------------ NOV1c NLGLVWLAVVALGAVCLVLLLLVLSLRRRLREELEKGAKATERTLVYPLELPKEPTSPPF NOV1d ------------------------------------------------------------ NOV1e ------------------------------------------------------------ NOV1f NLGLVWLAVVALGAVCLVLLLLVLSLRRRLREELEKGAKATERTLVYPLELPKEPTSPPF NOV1a ------------------------------------------------------------ NOV1b ------------------------------------------------------------ NOV1c RPCPEPDEKLWDPVGYYYSDGSLKIVPGHARCQPAAGPPSPPPGIPGQPLPSPTRLHLGG NOV1d ------------------------------------------------------------ NOV1e ------------------------------------------------------------ NOV1f RPCPEPDEKLWDPVGYYYSDGSLKIVPGHARCQPGGGPPSPPPGIPGQPLPSPTRLHLGG NOV1a ----------------------------------------------------- NOV1b ----------------------------------------------------- NOV1c GRNSNANGYVRLQLGGEDRGGLGHPLPELADELRRAAQQRQPLPDSNPEESSV NOV1d ----------------------------------------------------- NOV1e ----------------------------------------------------- NOV1f GRNSNANGYVRLQLGGEDRGGLGHPLPELADELRRAAQQRQPLPDSNPEESSV

[0360] Further analysis of the NOV1a protein yielded the following properties shown in Table 1C. 4 TABLE 1C Protein Sequence Properties NOV1a SignalP analysis: No Known Signal Sequence Predicted PSORT II analysis: PSG: a new signal peptide prediction method N-region: length 11; pos.chg 2; neg.chg 1 H-region: length 5; peak value 1.15 PSG score: −3.25 GvH: von Heijne's method for signal seq. recognition GvH score (threshold: −2.1): −7.49 possible cleavage site: between 55 and 56 >>> Seems to have no N-terminal signal peptide ALOM: Klein et al's method for TM region allocation Init position for calculation: 1 Tentative number of TMS(s) for the threshold 0.5: 0 number of TMS(s) . . . fixed PERIPHERAL Likelihood = 2.12 (at 616) ALOM score: 2.12 (number of TMSs: 0) MITDISC: discrimination of mitochondrial targeting seq R content: 1 Hyd Moment(75): 6.63 Hyd Moment(95): 9.39 G content: 1 D/E content: 2 S/T content: 3 Score: −5.25 Gavel: prediction of cleavage sites for mitochondrial preseq R-10 motif at 33 VRR FS NUCDISC: discrimination of nuclear localization signals pat4: none pat7: none bipartite: none content of basic residues: 9.3% NLS Score: −0.47 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: none SKL: peroxisomal targeting signal in the C-terminus: none PTS2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none NMYR: N-myristoylation pattern: none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: none Dileucine motif in the tail: none checking 63 PROSITE DNA binding motifs: none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination Prediction: cytoplasmic Reliability: 94.1 COIL: Lupas's algorithm to detect coiled-coil regions total: 0 residues Final Results (k = 9/23): 52.2%: cytoplasmic 26.1%: nuclear 21.7%: mitochondrial >> prediction for CG50907-03 is cyt (k = 23)

[0361] A search of the NOV1a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 1D. 5 TABLE 1D Geneseq Results for NOV1a NOV1a Identities/ Residues/ Similarities for Geneseq Protein/Organism/Length [Patent #, Match the Matched Expect Identifier Date] Residues Region Value AAE03640 Human extracellular matrix and cell 1 . . . 634 631/634 (99%) 0.0 adhesion molecule-4 (XMAD-4) - 21 . . . 654 634/634 (99%) Homo sapiens, 833 aa. [WO200142285-A2, 14-JUN-2001] AAE18213 Human MOL5a protein - Homo 1 . . . 634 627/634 (98%) 0.0 sapiens, 833 aa. [WO200206339-A2, 21 . . . 654 630/634 (98%) 24-JAN-2002] AAE18215 Human MOL5c protein - Homo 1 . . . 634 621/634 (97%) 0.0 sapiens, 833 aa. [WO200206339-A2, 21 . . . 654 624/634 (97%) 24-JAN-2002] AAE18214 Human MOL5b protein - Homo 1 . . . 634 621/634 (97%) 0.0 sapiens, 833 aa. [WO200206339-A2, 21 . . . 654 624/634 (97%) 24-JAN-2002] ABB97963 Human protein sequence #30 - Homo 13 . . . 634 617/622 (99%) 0.0 sapiens, 886 aa. [WO200252005-A1, 86 . . . 707 620/622 (99%) 04-JUL-2002]

[0362] In a BLAST search of public sequence databases, the NOV1a protein was found to have homology to the proteins shown in the BLASTP data in Table 1E. 6 TABLE 1E Public BLASTP Results for NOV1a NOV1a Identities/ Protein Residues/ Similarities for Accession Match the Matched Expect Number Protein/Organism/Length Residues Portion Value Q9C0C4 Hypothetical protein KIAA1739 - 13 . . . 634 617/622 (99%) 0.0 Homo sapiens (Human), 963 aa 163 . . . 784 620/622 (99%) (fragment). CAC24876 Sequence 21 from Patent WO0078802 - 1 . . . 561 559/561 (99%) 0.0 Homo sapiens (Human), 624 aa. 21 . . . 581 561/561 (99%) CAC24871 Sequence 11 from Patent WO0078802 - 1 . . . 561 558/561 (99%) 0.0 Homo sapiens (Human), 590 aa. 21 . . . 581 560/561 (99%) CAC24872 Sequence 13 from Patent WO0078802 - 1 . . . 564 557/565 (98%) 0.0 Homo sapiens (Human), 596 aa. 21 . . . 585 560/565 (98%) Q64151 Semaphorin 4C precursor (Semaphorin 1 . . . 634 538/635 (84%) 0.0 I) (Sema I) (Semaphorin C-like 1) 21 . . . 655 581/635 (90%) (M-Sema F) - Mus musculus (Mouse), 834 aa.

[0363] PFam analysis predicts that the NOV1a protein contains the domains shown in the Table 1F. 7 TABLE 1F Domain Analysis of NOV1a Identities/Similarities NOV1a for the Pfam Domain Match Region Matched Region Expect Value Sema 33 . . . 461 206/497 (41%) 1.6e−201 373/497 (75%) PSI 479 . . . 531 13/67 (19%) 0.001 37/67 (55%)

Example 2

[0364] The NOV2 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 2A. 8 TABLE 2A NOV2 Sequence Analysis NOV2a,CG51896-04 SEQ ID NO:13 4250 bp DNA Sequence ORF Start: ATG at 250 ORF Stop: end of sequence GAACACATCGCGTTTGCATCCCAGAAAGTAGTCGCCGCGACTATTTCCCCCAAAGAGACAAGCACACATGTAG GAATGACAAAGGCTTGCGAAGGAGACACCGCACCCCGCGGCCCGGAGAGATCCCCTCCATAATCCATTACTAA ATGGGATACACGCTGTACCAGTTCGCTCCGAGCCCCGGCCGCCTGTCCGTCGATGCACCGAAAAGGGTGAAGT AGAGAAATAAAGTCTCCCCGCTGAACTACTATGAGGTCAGAAGCCTTGCTGCTATATTTCACACTGCTACACT TTGCTGGGGCTCGTTTCCCAGAAGATTCTGAGCCAATCAGTATTTCGCATTGCAACTATACAAAACAGTATCC GGTGTTTGTGGGCCACAAGCCAGGACGGAACACCACACAGAGGCACACGCTGGACATCCAGATGATTATGATC ATGAACGGAACCCTCTACATTGCTGCTAGGGACCATATTTATACTGTTGATATAGACACATCACACACGGAAG AAATTTATTGTAGCAAAAAACTGACATGGAAATCTAGACAGGCCGATGTAGACACATGCAGAATGAAGGGAAA ACATAAGGATCAGTGCCACAACTTTATTAAAGTTCTTCTAAAGAAAAACGATGATGCATTGTTTGTCTGTGGA ACTAATGCCTTCAACCCTTCCTGCAGAAACTATAAGATGGATACATTGGAACCATTCGGGGATGAATTCAGCG GAATGCCCAGATGCCCATATGATCCCAAACATGCCAACGTTGCACTGTTTGCAGATGGAAAACTATACTCAGC CACAGTGACTGACTTCCTTGCCATTGACGCAGTCATTTACCGGAGTCTTGGAGAAAGCCCTACCCTGCGGACC GTCAAGCACGATTCAAAATGGTTGAAAGAACCATACTTTGTTCAAGCCGTGGATTACGGAGATTATATCTACT TCTTCTTCAGGGAAATAGCAGTGGAGTATAACACCATGGGAAAGGTAGTTTTCCCAAGAGTGGCTCAGGTTTG TAAGAATGATATGGGAGGATCTCAAAGAGTCCTGGAGAAACAGTGGACGTCGTTCCTGAAGGCGCGCTTGAAC TGCTCAGTTCCTGGAGACTCTCATTTTTATTTCAACATTCTCCAGGCAGTTACAGATGTGATTCGTATCAACG GGCGTGATGTTGTCCTGGCAACGTTTTCTACACCTTATAACAGCATCCCTGGGTCTGCAGTCTGTGCCTATGA CATGCTTGACATTGCCAGTGTTTTTACTGGGAGATTCAAGGAACAGAAGTCTCCTGATTCCACCTGGACACCA GTTCCTGATGAACGAGTTCCTAAGCCCAGGCCAGGTTGCTGTGCTGGCTCATCCTCCTTAGAAAGATATGCAA CCTCCAATGAGTTCCCTGATGATACCCTGAACTTCATCAAGACGCACCCGCTCATGGATGAGGCAGTGCCCTC CATCTTCAACAGGCCATGGTTCCTGAGAACAATGGTCAGATACCGCCTTACCAAAATTGCAGTGGACACAGCT GCTGGGCCATATCAGAATCACACTGTGGTTTTTCTGGGATCAGAGAAGGGAATCATCTTGAAGTTTTTGGCCA GAATAGGAAATAGTGGTTTTCTAAATGACAGCCTTTTCCTGGAGGAGATGAGTGTTTACAACTCTGAAAAATG CAGCTATGATGGAGTCCAAGACAAAAGGATCATGGGCATGCAGCTCCACAGAGCAAGCAGCTCTCTGTATGTT GCGTTCTCTACCTGTGTGATAAAGGTTCCCCTTGGCCGGTGTGAACGACATGGGAAGTGTAAAAAAACCTGTA TTGCCTCCAGAGACCCATATTGTGGATGGATAAAGGAAGGTGGTGCCTGCAGCCATTTATCACCCAACAGCAG ACTGACTTTTGAGCAGGACATAGAGCGTGGCAATACAGATGGTCTGGGGGACTGTCACAATTCCTTTGTGGCA CTGAATGACATTTCAACTCCTCTACCAGATAATGAAATGTCTTACAACACAGTGTATGGGCATTCCAGTTCCC TCTTGCCCAGCACAACCACATCAGATTCGACGGCTCAAGAGGGGTATGAGTCTAGGGGAGGAATGCTGGACTG GAAGCATCTGCTTGACTCACCTGACAGCACAGACCCTTTGGGGGCAGTGTCTTCCCATAATCACCAAGACAAG AAGGGAGTGATTCGGGAAAGTTACCTCAAAGGCCACGACCAGCTGGTTCCCGTCACCCTCTTGGCCATTGCAG TCATCCTGGCTTTCGTCATGGGGCCGTCTTCTCGGGCATCACCGTCTACTGCGTCTGTGATCATCAAGCGCAA AGACGTGGCTGTGGTGCAGCGCAAGGAGAAGGAGCTCACCCACTCGCGCCGGGGCTCCATGAGCAGCGTCACC AAGCTCAGCGGCCTCTTTGGGGACACTCAATCCAAAGACCCAAAGCCGGAGGCCATCCTCACGCCACTCATGC ACAACGGCAAGCTCGCCACTCCCGGCAACACGGCCAAGATGCTCATTAAAGCAGACCAGCACCACCTGGACCT GACGGCCCTCCCCACCCCAGAGTCAACCCCAACGCTGCAGCAGAAGCGGAAGCCCAGCCGCGGCAGCCGCGAG TGGGAGAGGAACCAGAACCTCATCAATGCCTGCACAAAGGACATGCCCCCCATGGGCTCCCCTGTGATTCCCA CGGACCTGCCCCTGCGGGCCTCCCCCAGCCACATCCCCAGCGTGGTGGTCCTGCCCATCACGCAGCAGGGCTA CCAGCATGAGTACGTGGACCAGCCCAAAATGAGCGAGGTGGCCCAGATGGCGCTGGAGGACCAGGCCGCCACA CTGGAGTATAAGACCATCAAGGAACATCTCAGCAGCAAGAGTCCCAACCATGGGGTGAACCTTGTGGAGAACC TGGACAGCCTGCCCCCCAAAGTTCCACAGCGGGAGGCCTCCCTGCGTCCCCCGGGAGCCTCCCTGTCTCAGAC CGGTCTAACCAAGCGGCTGGAAATGCACCACTCCTCTTCCTACGGGGTTGACTATAAGAGGAGCTACCCCACG AACTCGCTCACGAGAAGCCACCAGGCCACCACTCTCAAAAGAAACAACACTAACTCCTCCAATTCCTCTCACC TCTCCAGAAACCAGAGCTTTGGCAGGGGAGACAACCCGCCGCCCGCCCCGCAGAGGGTGGACTCCATCCAGGT GCACAGCTCCCAGCCATCTGGCCAGGCCGTGACTGTCTCGAGGCAGCCCAGCCTCAACGCCTACAACTCACTG ACAAGGTCGGGGCTGAAGCGTACGCCCTCGCTAAAGCCGGACGTACCCCCCAAACCATCCTTTGCTCCCCTTT CCACATCCATGAAGCCCAATGATGCGTGTACATAATCCCAGGGGGAGGGGGTCAGGTGTCGAACCAGCAGGCA AGGCGAGGTGCCCGCTCAGCTCAGCAAGGTTCTCAACTGCCTCGAGTACCCACCAGACCAAGAAGGCCTGCGG CAGAGCCGAGGACGCTGGGTCCTCCTCTCTGGGACACAGGGGTACTCACGAAAACTGGGCCGCGTGGTTTGGT CAAGGTTTGCAACGGCGGGGACTCACCTTCATTCTCTTCCTTCACTTTCCCCCACACCCTACAACAGGTCGGA CCCACAAAAGACTTCAGTTATCATCACAAACATGAGCCAAAAGCACATACCTACCCCATCCCCCACCCCCACA CACACACACACATGCACACAACACATACACACACACGCACAGAGGTGAACAGAAACTGAAACATTTTGTCCAC AACTTCACGGGACGTGGCCAGACTGGGTTTGCGTTCCAACCTGCAAACACAAATACATTTTTTTTTAATCAAG AAAATTTAAAAAGACAAAAAAAAAAGAATTCATTGATAATTCTAACTCAGACTTTAACAATGGCAGAAGTTTA CTATGCGCAAATACTGTGAAATGCCCGCCAGTGTTACAGCTTTCTGTTGCAGCAGATAAATGCCATGTTGGGC AACTATGTCATAGATTTCTGCTCCTCCTCTCTTTTAATGAAATAACGTGACCGTTAACGCAAGTAACTCTTTA TTTATTGTTCACCCTTTTTTTCCTTAAGGAAAGGACTCTTCCAAATATCATCCTATGAACAGCTCTTCAGAAA GCCCATTGAAAGTTAAACTATTTAACGTGAAATCCATTAACTGGAATAATTGAGTTTCTTTATTTTTACAATA AATTCACTGAGTAAAT NOV2a, CG5 1896-04 Protein Sequence SEQ ID NO:14 1047 aa MW at 116354.6 kD MRSEALLLYFTLLHFAGAGFPEDSEPISISHCNYTKQYPVFVGHKPGRNTTQRHRLDIQMIMIMNGTLYIAAA DHIYTVDIDTSHTEEIYCSKKLTWKSRQADVDTCRMKGKHKDECHNFIKVLLKKNDDALFVCGTNAFNPSCRN YKMDTLEPFGDEFSGMARCPYDAKHANVALFADGKLYSATVTDFLAIDAVIYRSLGESPTLRTVKHDSKWLKE PYFVQAVDYGDYIYFFFREIAVEYNTMGKVVFPRVAQVCKNDMGGSQRVLEKQWTSFLKARLNCSVPGDSHFY FNILQAVTDVIRINGRDVVLATFSTPYNSIPGSAVCAYDMALDIASVFTGRFKEQKSPDSTWPVPDERVPKPR PGCCAGSSSLERYATSNEFPDDTLNFIKTHPLMDEAVPSIFNRPWFLRTMVRYRLTKIAVDTAAGPYQNHTVV FLGSEKGIILKFLARIGNSGFLNDSLFLEEMSVYNSEKCSYDGVEDKRIMGMQLDRASSSLYVAFSTCVIKVP LGRCERHGKCKKTCIASRDPYCGWIKEGGACSHLSPNSRLTFEQDIERGNTDGLGDCHNSFVALNDISTPLPD NEMSYNTVYGHSSSLLPSTTTSDSTAQEGYESRGCMLDWKHLLDSPDSTDPLGAVSSHAAQDKKGVIRESYLK GHDQLVPVTLLAIAVILAFVKMGAVFSGITVYCVCDHRRKDVAVVQRKEKELTHSRGSMSSVTKLSGLFGDTQ SKDPKPEAILTPLMHNGKLATPGNTAKMLIKADQHHLDLTALPTPESTPTLQQKRKPSRGSREWERNQNLINA CTKDMPPMGSPVIPTDLPLRASPSHIPSVVVLPITQQGYQHEYVDQPKMSEVAQMAAEDQAATLEYKTIAAHL SSKSPNHGVNLVENLDSLPPKVPQREASLGPPGASLSQTGLSAALEAAHSSSYGAAYAASYPTNSLTRSHQAT TLKRNNTNSSNSSHLSRNQSFGRGDNPPPAPQRVDSIQVHSSQPSGQAVTVSRQPSLNAYNSLTRSGLKRTPS LKPDVPPKPSFAPLSTSMKPNDACT NOV2b, 271674560 SEQ ID NO:15 1921 bp DNA Sequence ORF Start: at 1 ORF Stop: end of sequence GCCGGATCCAGTATTTCGCATTGCAACTATACAAAACAGTATCCGGTGTTTGTGGGCCACAAGCCAGGACGGA ACACCACACAGAGGCACAGGCTGGACATCCAGATGATTATGATCATGAACGGAACCCTCTACATTGCTGCTAG GGACCATATTTATACTGTTGATATAGACACATCACACACGGAAGAAATTTATTGTAGCAAAAAACTGACATGG AAATCTAGACAGGCCGATGTAGACACATGCAGAATGAAGGGAAAACATAAGGATGAGTGCCACAACTTTATTA AAGTTCTTCTAAAGAAAAACGATGATGCATTGTTTGTCTGTGGAACTAATGCCTTCAACCCTTCCTGCAGAAA CTATAAGATGGATACATTGGAACCATTCGGGGATGAATTCAGCGGAATGGCCAGATGCCCATATGATGCCAAA CATGCCAACGTTGCACTGTTTGCAGATGGAAAACTATACTCAGCCACAGTGAAAGACTTCCTTGCCATTGACG CAGTCATTTACCGGAGTCTTGGAGAAAGCCCTACCCTGCGGACCGTCAAGCACGATTCAAAATGGTTGAAAGA ACCATACTTTGTTCAAGCCGTGGATTACGGAGATTATATCTACTTCTTCTTCAGGGAAATAGCAGTGGAGTAT AACACCATGGGAAAGGTAGTTTTTCCCAAGAGTGGCTCAGGTTTGTAAGAATGATATGGAGGATCTCAAAGAG TCCTGGAGAAACAGTGGACGTCGTTCCTGAAGGCGCGCTTGAACTGCTCAGTTCCTGGAGACTCTAATTTTTA TTTCAACATTCTCCAGGCAGTTACAGATGTGATTCGTATCAACGGGCGTGATGTTGTCCTGGCAACGTTTTCT ACACCTTATAACAGCATCCCTGGGTCTGCAGTCTGTGCCTATGACATGCTTGACATTGCCAGTGTTTTTACTG GGAGATTCAAGGAACAGAAGTCTCCTGATTCCACCTGGACACCAGTTCCTGATGAACGAGTTCCTAAGCCCAG GCCAGGTTGCTGTGCTGGCTCATCCTCCTTAGAAAGATATGCAACCTCCAATGAGTTCCCTGATGATACCCTG AACTTCATCAAGACGCACCCGCTCATGGATGAGGCAGTGCCCTCCATCTTCAACAGCCCATAATTCCTGAGAA CAATGGTCAGATACCGCCTTACCAAAATTGCAGTGGACACAGCTGCTGGGCCATATCAGAATAACACTGTGGT TTTTCTGGGATCACAGAAGGGAATCATCTTGAAGTTTTTGCCCAGAATAGGAAATAGTGGTTTTCTAAATGAC AGCCTTTTCCTGGAGGAGATGAGTGTTTACAACTCTGAAAAATGCAGCTATGATGGAGTCGAAGACAAAAGGA TCATGGGCATGCAGCTGGACAGAGCAAGCAGCTCTCTGTATGTTGCGTTCTCTACCTGTGTGATAAAGGTTCC CCTTGGCCGGTGTGAACGACATGGGAAGTGTAAAAAAACCTGTATTGCCTCCAGAGACCCGTATTGTAAATGG ATAAAGGAAGGTGGTGCCTGCAGCCATTTATCACCCAACAGCAGACTGACTTTTGAGCAGGGACATAGAGCTG GCAATACAGATGGTCTGGGGGACTGTCACAATTCCTTTGTGGCACTGAATGACATTTCAACTCCTCTACCAGA TAATGAAATGTCTTACAACACAGTGTATGGGCATTCCAGTTCCCTCTTGCCCAGCACAACCACATCAGATTCG ACGGCTCAAGAGGGGTATGAGTCTAGGGGAGGAATGCTGGACTGGAAGCATCTGCTTGACTCACCTGACAGCA CAGACCCTTTCCCCGCAGTGTCTTCCCATAATCACCAAGACAAGAAGGGAGTcATTCGGGAAAGTTACCTCAA AGGCCACGACCACGTCGACGGTG NOV2b, 271674560 Protein Sequence SEQ ID NO:16 640 aa MW at 71799.4 kD AGSSISHCNYTKQYPVFVGHKPGRNTTQRHRLDIQMIMIMNGTLYIAARDHIYTVDIDTSHTEEIYCSKKLTW KSRQADVDTCRMKGKHKDECHNFIKVLLKKNDDALFVCGTNAFNPSCRAYKMDTLEPFGDEFSGMARCPYDAK HANVALFADGKLYSATVTDFLAIDAVIYRSLGESPTLRTVKHDSKWLKEPYFVQAVDYGDYIYFFFREIAVEY NTMGKVVFPRVAQVCKNDMGGSQRVLEKQWTSFLKARLNCSVPGDSHFYFNILQAVTDVIRINGRDVVLATFS TPYNSIPGSAVCAYDMLDIASVFTGRFKEQKSPDSTWTPVPDERVPKPRPGCCACSSSLERYATSNEFPDDTL NFIKTHPLMDEAVPSIFNRPWFLRTMVRYRLTKIAVDTAAGPYQNHTVVFLGSEKGIILKFLARIGNSGFLND SLFLEEMSVYNSEKCSYDGVEDKRIMGMQLDRASSSLYVAFSTCVIKVPLGRCERHGKCKKTCIASRDPYCGW IKEGGACSHLSPNSRLTFEQDIERGNTDGLGDCHNSFVALNDISTPLPDNEMSYNTVYGHSSSLLPSTTTSDS TAQEGYESRGGMLDWKHLLDSPDSTDPLGAVSSHNHQDKKGVIRESYLKGHDQVDG NOV2c, 267441133 SEQ ID NO:17 3106 bp DNA Sequence ORF Start: at 2 ORF Stop: end of sequence CACCGGATCCGGTTTCCCAGAAGATTCTCAGCCAATCAGTATTTCGCATGGCAACTATACAAAACAGTATCCG GTGTTTGTGGGCCACAAGCCAGGACGGAACACCACACAGAGGCACAGGCTGGACATCCAGATGATTATGATCA TGAACGGAACCCTCTACATTGCTGCTAGGGACCATATTTATACTGTTGATATAGACACATCACACACGGAAGA AATTTATTGTAGCAAAAAACTGACATGGAAATCTAGACAGGCCGATGTAGACACATGCAGAATGAAGGGAAAA CATAAGGATCAGTGCCACAACTTTATTAAAGTTCTTCTAAAGAAAAACGATGATGCATTGTTTGTCTGTGGAA CTAATGCCTTCAACCCTTCCTGCAGAAACTATAAGATGGATACATTGGAACCATTCGGGGATGAATTCAGCGG AATGGCCAGATGCCCATATGATGCCAAACATGCCAACGTTGCACTGTTTGCAGATGGAAAACTATACTCAGCC ACAGTGACTGACTTCCTTGCCATTGACGCAGTCATTTACCGGAGTCTTGGAGAAAGCCCTACCCTGCGGACCG TCAAGCACGATTCAAAATGGTTGAAAGAACCATACTTTGTTCAAGCCGTGGATTACGGAGATTATATCTACTT CTTCTTCAGGGAAATAGCAGTGGAGTATAACACCATGGGAAAGGTAGTTTTCCCAAGAGTGGCTCAGGTTTGT AAGAATGATATGGGAGGATCTCAAAGAGTCCTGGAGAAACAGTGGACGTCGTTCCTGAAGGCGCGCTTGAACT GCTCAGTTCCTGGAGACTCTCATTTTTATTTCAACATTCTCCAGGCAGTTACAGATGTGATTCGTATCAACGG GCGTGATGTTGTCCTGGCAACGTTTTCTACACCTTATAACAGCATCCCTGGGTCTGCAGTCTGTGCCTATGAC ATGCTTGACATTGCCAGTGTTTTTACTGGGAGATTCAAGGAACAGAAGTCTCCTGATTCCACCTGGACACCAG TTCCTGATGAACGAGTTCCTAAGCCCAGGCCAGGTTGCTGTGCTGGCTCATCCTCCTTAGAAAGATATGCAAC CTCCAATGAGTTCCCTGATGATACCCTGAACTTCATCAAGACGCACCCGCTCATGGATGAGGCAGTGCCCTCC ATCTTCAACAGGCCATGGTTCCTGAGAACAATGGTCAGATACCGCCTTACCAAAATTGCAGTGGACACAGCTG CTGGGCCATATCAGAATCACACTGTGGTTTTTCTGGGATCAGACAAGGGAATCATCTTGAAGTTTTTGGCCAG AATAGGAAATAGTGGTTTTCTAAATGACAGCCTTTTCCTGGAGGAGATGAGTGTTTACAACTCTGAAAAATGC AGCTATGATGGAGTCGAAGACAAAAGGATCATGGGCATGCAGCTGGACAGAGCAAGCAGCTCTCTGTATGTTG CGTTCTCTACCTGTGTGATAAAGGTTCCCCTTGGCCGGTGTGAACGACATGGGAAGTGTAAAAAAACCTGTAT TGCCTCCAGAGACCCGTATTGTGGATGGATAAAGGAAGGTGGTGCCTGCAGCCATTTATCACCCAACAGCAGA CTGACTTTTGAGCAGGACATAGAGCGTGGCAATACAGATGGTCTGGGGGACTGTCACAATTCCTTTGTGGCAC TGAATGACATTTCAACTCCTCTACCAGATAATGAAATGTCTTACAACACAGTGTATGGGCATTCCAGTTCCCT CTTGCCCAGCACAACCACATCAGATTCGACGGCTCAAGAGGGGTATGAGTCTAGGGGAGGAATGCTGGACTGG AAGCATCTGCTTGACTCACCTGACAGCACAGACCCTTTGGGGGCAGTGTCTTCCCATAATCACCAAGACAAGA AGGGAGTGATTCGGGAAAGTTACCTCAAAGGCCACGACCAGCTGGTTCCCGTCACCCTCTTGGCCATTGCAGT CATCCTGGCTTTCGTCATGGGGGCCGTCTTCTCGGGCATCACCGTCTACTGCGTCTGTGATCATCGGCGCAAA GACGTGGCTGTGGTGCAGCGCAAGGAGAAGGAGCTCACCCACTCGCGCCGGGGCTCCATGAGCAGCGTCACCA AGCTCAGCGGCCTCTTTGGGGACACTCAATCCAAAGACCCAAAGCCGGAGGCCATCCTCACGCCACTCATGCA CAACGGCAAGCTCGCCACTCCCGGCAACACGGCCAAGATGCTCATTAAAGCAGACCAGCACCACCTGGACCTG ACGGCCCTCCCCACCCCAGAGTCAACCCCAACGCTGCAGCAGAAGCGGAAGCCCAGCCGCGGCAGCCGCGAGT GGGAGAGGAACCAGAACCTCATCAATGCCTGCACAAAGGACATGCCCCCCATGGGCTCCCCTGTGATTCCCAC GGACCTGCCCCTGCCGGCCTCCCCCAGCCACATCCCCAGCGTGGTGGTCCTGCCCATCACGCAGCAGGGCTAC CAGCATGAGTACGTGGACCAGCCCAAAATGAGCGAGGTGGCCCAGATGGCGCTGGAGGACCAGGCCGCCACAC TGGAGTATAACACCATCAAGGAACATCTCAGCAGCAAGAGTCCCAACCATGGGGTGAACCTTGTGGAGAACCT GGACAGCCTGCCCCCCAAAGTTCCACAGCGGGAGGCCTCCCTGGGTCCCCCGGGAGCCTCCCTGTCTCAGACC GGTCTAAGCAAGCGGCTGGAAATGCACCACTCCTCTTCCTACGGGGTTGACTATAAGAGGAGCTACCCCACGA ACTCGCTCACGAGAAGCCACCAGGCCACCACTCTCAAAAGAAACAACACTAACTCCTCCAATTCCTCTCACCT CTCCAGAAACCACAGCTTTGGCAGGGGAGACAACCCGCCGCCCGCCCCGCAGAGGGTGGACTCCATCCAGGTG CACAGCTCCCAGCCATCTGGCCAGGCCGTGACTGTCTCGAGGCAGCCCAGCCTCAACCCCTACAACTCACTGA CAAGGTCGGGGCTGAAGCGTACGCCCTCGCTAAAGCCGGACGTACCCCCCAAACCATCCTTTGCTCCCCTTTC CACATCCATGAAGCCCAATCATGCGTGTACAGTCGACGGC NOV2c, 267441133 Protein Sequence SEQ ID NO:18 1035 aa MW at 114789.6 kD TGSGFPEDSEPISISHGNYTKQYPVFVGHKPGRNTTQRHRLDIQMIMIMNGTLYIAARDHIYTVDIDTSHTEE IYCSKKLTWKSRQADVDTCRMKGKHKDECHNFIKVLLKKNDDALFVCGTNAFNPSCRNYKMDTLEPFGDEFSG MARCPYDAKHANVALFADGKLYSATVTDFLAIDAVIYRSLGESPTLRTVKHDSKWLKEPYFVQAVDYGDYIYF FFREFAVEYNTMGKVVFPRVAQVCKNDMGGSQRVLEKQWTSKLKARLNCSVPGDSHFYFNILQAVTDVIRING RDVVLATFSTPYISIPGSAVCAYDMLDIASVFTGRFKEQKSPDSTWTPVPDERVPKPRPGCCAGSSSLERYAT SNEFPDDTLNFIKTHPLMDEAVPSIFNRPWFLRTMVRYRLTKIAVDTAAGPYQNHTVVFLGSEKGIILKFLAR IGNSGFLNDSLFLEEMSVYNSEKCSYDGVEDKRIMGMQLDRASSSLYVAFSTCVIKVPLGRCERHGKCKKTCI ASRDPYCGWIKEGGACSHLSPNSRLTFEQDIERGNTDGLGDCHNSFVALNDISTPLPDNEMSYNTVYGHSSSL LPSTTTSDSTAQEGYESRGGMLDWKHLLDSPDSTDPLGAVSSHNHQDKKGVIRESYLKGHDQLVPVTLLAIAV ILAFVMGAVFSGITVYCVCDHRRKDVAVVQRKEKELTHSRRGSMSSVTKLSGLFDTQSKDPKPEAILTPLMHA NGKLATPGNTAKMLIKADQHHLDLTALPTPESTPTLQQKRKPSRGSREWERNQNLINACTAAMPPMGSPVIPT DLPLRASPSHIPSVVVLPITQQGYQHEYVDQPKMSEVAQMAAEDQAATLEYKTIKEHLSSKSPNHGAALAANL DSLPPKVPQREASLGPPGASLSQTGLSKRLEMHHSSSYGAAYAASYPTNSLTRSHQATTLAAAATNSSNSSHL SRNQSFGRGDNPPPAPQRVDSIQVHSSQPSGQAVTVSRQPSLNAYNSLTRSGLKRTPSLKPDVPPKPSFAPLS TSMKPNDACTVDG NOV2d, 267441137 SEQ ID NO:19 2995 bp DNA Sequence ORF Start: at 2 ORF Stop: end of sequence CACCGGATCCCTGGACATCCAGATGATTATGATCATGAACGGAACCCTCTACATTCCTGCTAGGGACCATATT TATACTGTTGATATAGACACATCACACACGGAAGAAATTTATTGTAGCAAAAAACTGACATGGAAATCTAGAC AGGCCGATGTAGACACATGCAGAATGAAGGGAAAACATAAGGATGAGTGCCACAACTTTATTAAAGTTCTTCT AAAGAAAAACGATGATGCATTGTTTGTCTGTGGAACTAATGCCTTCAACCCTTCCTGCAGAAACTATAAGATG GATACATTGGAACCATTCGGGGATGAATTCAGCGGAATGGCCAGATGCCCATATGATGCCAAACATGCCAACG TTGCACTGTTTGCAGATGGAAAACTATACTCAGCCACAGTGACTGACTTCCTTGCCATTGACGCAGTCATTTA CCGGAGTCTTGGAGAAAGCCCTACCCTGCGGACCGTCAAGCACGATTCAAAATGGTTGAAAGAACCATACTTT GTTCAAGCCGTGGATTACGGAGATTATATCTACTTCTTCTTCAGGGAAATAGCAGTGGAGTATAACACCATGG GAAAGGTAGTTTTCCCAAGAGTGGCTCAGGTTTGTAAGAATGATATGGGAGGATCTCAAAGAGTCCTGGAGAA ACAGTGGACGTCGTTCCTGAAGGCGCGCTTGAACTGCTCAGTTCCTGGAGACTCTCATTTTTATTTCAACATT CTCCAGGCAGTTACAGATGTGATTCGTATCAACGGGCGTGATGTTGTCCTAACAACGTTTTCTACACCTTATA AAAGAATCCCTGGGTCTGCAGTCTGTGCCTATGACATGCTTGAAATTGCCAGTGTTTTTACTGGGAGATTCAA GGAACAGAAGTCTCCTGATTCCACCTGGACACCAGTTCCTGATGAACGAGTTCCTAAGCCCAGGCCAGGTTGC TGTGCTGGCTCATCCTCCTTAGAAAGATATGCAACCTCCAATGAGTTCCCTGATGATACCCTGAACTTCATCA AGACGCACCCGCTCATGGATGAGGCAGTGCCCTCCATCTTCAACAGGCCATGGTTCCTGAGAACAATGGTCAG ATACCGCCTTACCAAAATTGCAGTGGACACAGCTGCTGGGCCATATCAGAATCACACTGTGGTTTTTCTGGGA TCAGAGAAGGGAATCATCTTGAAGTTTTTGGCCAGAATAGGATAGTAATTTTCTAAAAATGACAGCCTTTTCC TGGAGGAGATGAGTGTTTACAACTCTGAAAAATGCAGCTATGATGGAGTCGAAGACAAAAGGATCATGGGCAT GCAGCTGGACAGAGCAAGCAGCTCTCTGTATGTTGCGTTCTCTACCTGTGTGATAAAGGTTCCCCTTGGCCGG TGTGAACGACATGGGAAGTGTAAAAAAAACCTGTATTGCCTCCAGAGACCCGTATTGTGGATGGATAAGGAAG GTGGTGCCTGCAGCCATTTATCACCCAACAGCAGACTGACTTAAGAGCAGGACATAGAGCGTGGCAATACAGA TGGTCTGGGGGACTGTCACAATTCCTTTGTGGCACTGAATGACATTTCAACTCCTCTACCAGATAATGAAATG TCTTATAACACAGTGTATGGGCATTCCAGTTCCCTCTTGCCCAGCACAACCACATCAGATTCGACGGCTCAAG AGGGGTATGAGTCTAGGGGAGGAATGCTGGACTGGAAGCATCTGCTTGACTCACCTGACAGCACAGACCCTTT GGGGGCCAGTGTCTTCCCACAATCACCAAGACAAGAAGGGAGTGATTCGGGAAAGTTACCTCAAGGCCACGAC CAGCTGGTTCCCGTCACCCTCTTGGCCATTGCAGTCATCCTGGCTTTCGTCATGGAAGCCGTCTTCTCGGGCA TCACCGTCTACTGCGTCTGTGATCATCGGCGCAAAGACGTGGCTGTGGTGCAGCGCAAGGAGAAGGAGCTCAC CCACTCGCGCCGGGGCTCCATGAGCAGCGTCACCAAGCTCAGCGGCCTCTTTGGGGACACTCAATCCAAAGAC CCAAAGCCGGAGGCCATCCTCACGCCACTCATGCACAACGGCAAGCTCGCCACTCCCGGCAACACGGCCAAGA TGCTCATTAAAGCAGACCAGCACCACCTAAACCTGACGGCCCTCCCCACCCCAGAGTCAACCCCAACGCTGCA GCAGAAGCGGAAGCCCAGCCGCGGCAGCCGCGAGTGGGAGAGGAACCAGAACCTCATCAATGCCTGCACAAAG GACATGCCCCCCATGGGCTCCCCTGTGATTCCCACGGACCTGCCCCTGCGGGCCTCCCCCAGCCACATCCCCA GCGTGGTGGTCCTGCCCATCACGCAGCAGGGCTACCAGCATGAGTACGTGGACCAGCCCAAAATGAGCGAGGT GGCCCAGATGGCGCTGGAGGACCAGGCCGCCACACTGGACTATAAGACCATCAACGAACATCTCAGCAGCAAG AGTCCCAACCATGGGGTGAACCTTGTGGAGAACCTGGACAGCCTGCCCCCCAAAGTTCCACAGCGGGAGGCCT CCCTGGGTCCCCCGGGAGCCTCCCTGTCTCAGACCGGTCTAAGCAAGCGGCTGGAAATGCACCACTCCTCTTC CTACGGGGTTGACTATAAGAGGAGCTACCCCACGAACTCGCTCACGAGAAGCCACCAGGCCACCACTCTCAAA AGAAACAACACTAACTCCTCCAATTCCTCTCACCTCTCCAGAAACCAGAGCTTTGGCAGGGGAGACAACCCGC CGCCCGCCCCGCAGAGGGTGGACTCCATCCAGGTGCACAGCTCCCAGCCATCTGGCCAGGCCGTGACTGTCTC GAGGCAGCCCAGCCTCAACGCCTACAACTCACTGACAAGGTCGGGGCTGAAGCGTACGCCCTCGCTAAAGCCG GACGTACCCCCCAAACCATCCTTTGCTCCCCTTTCCACATCAATGAAGCCCAATGATGCGTGTACAGTCGACG GC NOV2d, 267441137 Protein Sequence SEQ ID NO:20 998 aa MW at 110569.0 kD TGSLDIQMIMIMNGTLYIAARDHIYTVDIDTSHTEEIYCSKKLTWKSRQADVDTCRMKGKHKDECHNFIKVLL KKNDDALFVCGTNAFNPSCRNYKMDTLEPFGDEFSGMARCPYDAKHANVALFADGKLYSATVTDFLAIDAVIY RSLGESPTLRTVKHDSKWLKEPYFVQAVDYGDYIYFFFREIAVEYNTMGKVVFPRVAQVCKNDMGGSQRVLEK QWTSFLKARLNCSVPGDSHFYFNILQAVTDVIRINGRDVVLATFSTPAASIPGSAVCAYDMLDIASVFTGRFK EQKSPDSTWTPVPDERVPKPRPGCCAGSSSLERYATSNEFPDDTLNFIKTHPAADEAVPSIFNRPWFLRTMVR YRLTKIAVDTAAGPYQNHTVVFLGSEKGHLKFLARIGAASGFLNDSLFLEEMSVYNSEKCSYDGVEDKRIMGM QLDRASSSLYVAFSTCVIKVPLGRCERHGKCKKTCIASRDPYCGWIKEGGACSHLSPNSRLTFEQDIERGNTD GLGDCHNSFVALNDISTPLPDNEMSYNTVYGHSSSLLPSTTTSDSTAQEGYESRGGMLDWAALLDSPDSTDPL GAVSSHNHQDKKGVERESYLKGHDQLVPVTLLAIAVILAFVMGAVFSGITVYCVCDHRRKDVAVVQRKEKELT HSRRGSMSSVTKLSGLFGDTQSKDPKPEAILTPLMHNGKLATPGNTAKMLIKADQHHLDLTALPTPESTPTLQ QKRKPSRGSREWERNQNLINACTKDMPPMGSPVIPTDLPLRASPSHIPSVVVLPITQQGYQHEYVDQPKMSEV AQMALEDQAATLEYKTIKEHLSSKSPNHGWLVENLDSLPPKVPQREASLGPPGASLSQTGLSKRLEMHHSSSS YGVDYKRSYPTNSLTRSHQATTLKRNNTNSSNSSHLSRNQSFGRGDNPPPAPQRAASIQVHSSQPSGQAVTVS RQPSLNAYNSLTRSGLKRTPSLKPDVPPKPSFAPLSTSMKPNDACTAAG NOV2e, 262254987 SEQ ID NO:21 1327 bp DNA Sequence ORF Start: at 2 ORF Stop: end of sequence CACCGGATCCCTGGACATCCAGATGATTATGATCATGAACGGAACCCTCTACATTGCTGCTAGGGACCATATT TATACTGTTGATATAGACACATCACACACGGAAGAAATTTATTGTAGCAAAAAACTGACATGGAAATCTAGAC AGGCCGATGTAGACACATGCAGAATGAAGGGAAAACATAAGGATGAGTGCCACAACTTTATTAAAGTTCTTCT AAAGAAAAACGATGATGCATTGTTTGTCTGTGGAACTAATGCCTTCAACCCTTCCTGCAGAAACTATAAGATG GATACATTGGAACCATTCGGGGATGAATTCAGCGGATGGCCAGAATGCCCATATGATGCCAAACATGCCAACG TTGCACTGTTTGCAGATGGAAAACTATACTCAGCCACAGTGACTGACTTCCTTGCCATTGACGCAGTCATTTA CCGGAGTCTTGGAGAAAGCCCTACCCTGCGGACCGTCAAGCACGATTCAAAATGGTTGAAAGAACCATACTTT GTTCAAGCCGTGGATTACGGAGATTATATCTACTTCTTCTTCAGGGAAATAGCAGTGGAGTATAACACCATGG GAAAGGTAGTTTTCCCAAGAGTGGCTCAGGTTTGTAAGAATGATATGGGAGGATCTCAAAGAGTCCTGGAGAA ACAGTGGACGTCGTTCCTGAAGGCGCGCTTGAACTGCTCAGTTCCTGGAGACTCTAATTTTTATTTCAACATT CTCCAGGCAGTTACAGATGTGATTCGTATCAACGGGCGTGATGTTGTCCTGGCAACGTTTTCTACACCTTATA ACAGCATCCCTGGGTCTGCAGTCTGTGCCTATGACATGCTTGACATTGCCAGTGTTTTTACTGGGAGATTCAA GGAACAGAAGTCTCCTGATTCCACCTGGACACCAGTTCCTGATGAACGAGTTCCTAAGCCCAGGCCAGGTTGC TGTGCTGGCTCATCCTCCTTAGAAAGATATGCAACCTCCAATGAGTTCCCTGATGATACCCTGAACTTCATCA AGACGCACCCGCTCATGGATGAGGCAGTGCCCTCCATCTTCAACAGGCCATGGTTCCTGAGAACAATGGTCAG ATACCGCCTTACCAAAATTGCAGTGGACACAGCTGCTGGGCCATATCAGAATCACACTGTGGTTTTTCTAAGA TCAGAGAAGGGAATCATCTTGAAGTTTTTGGCCAGAATAGGAAATAGTGGTTTTCTAAATGACAGCCTTAACC TGGAGGAGATGAGTGTTTACAACTCTGAAAAATGCAGCTATGATGGAGTCGAAGACAAAAGGATCATGGGCAT GCAGGTCGACGGC NOV2e, 262254987 Protein Sequence SEQ ID NO:22 442 aa MW at 49986.5 kD TGSLDIQMIMIMNGTLYIAARDHIYTVDIDTSHTEEIYCSKKLTWKSRQADVDTCRMKGKHKDECHNFIKVLL KKNDDALFVCGTNAFNPSCRNYKMDTLEPFGDEFSGMARCPYDAKHANVALFADGKLYSATVTDFLAIDAVIY RSLGESPTLRTVKHDSKWLKEPYFVQAVDYGDYIYFFFREIAVEYNTMGKVVFPRVAQVCKNDMGGSQRVLEK QWTSFLKARLNCSVPGDSHFYFNILQAVTDVIRINGRDVVLATFSTPAASIPGSAVCAYDMLDIASVFTGRFK EQKSPDSTWTPVPDERVPKPRPGCCAGSSSLERYATSNEFPDDTLNFIKTHPLMDEAVPSIFNRPWFLRTMVR YRLTKIAVDTAAGPYQNHTVVFLGSEKGIILKFLARIGNSGFLNDSLFLEEMSVYNSEKCSYDGVEDKRIMGM QVDG NOV2f, 260565761 SEQ ID NO:23 1492 bp DNA Sequence ORF Start: at 2 ORF Stop: end of sequence CACCGCATCCATGAGGTCAGAAGCCTTGCTGCTATATTTCACACTGCTACACTTTGCTGGGGCTGGTTTCCCA GAAGATTCTGAGCCAATCAGTATTTCGCATGGCAACTATACAAAACAGTATCCGGTGTTTGTGGGCCACAAGC CAGGACGGAACACCACACAGAGGCACAGGCTGGACATCCAGATGATTATGATCATGAACGGAACCCTCTACAT TGCTGCTAGGGACCATATTTATACTGTTGATATAGACACATCACACACGGAAGAAATTTATTGTAGCAAAAAA CTGACATGGAAATCTAGACAGGCCGATGTAGACACATGCAGAATGAAGGGAAAACATAAGGATGAGTGCCACA ACTTTATTAAAGTTCTTCTAAAGAAAAACGATGATCCATTGTTTGTCTGTGGAACTAATGCCTTCAACCCTTC CTGCAGAAACTATAAGATGGATACATTGGAACCATTCGGGGATGAATTCAGCGGAATGGCCAGATGCCCATAT GATGCCAAACATGCCAACGTTGCACTGTTTGCAGATGGAAAACTATACTCAGCCACAGTGACTGACTTCCTTG CCATTGACGCAGTCATTTACCGGAGTCTTGCAGAAAGCCCTACCCTGCGGACCGTCAAGCACGATTCAAAATG GTTGAAAGAACCATACTTTGTTCAAGCCGTGGATTACGGAGATTATATCTACTTCTTCTTCAGGGAAATAGCA GTGGAGTATAACACCATGGGAAAGGTAGTTTTCCCAAGAGTGGCTCAGGTTTGTAAGAATGATATGGGAGGAT CTCAAAGAGTCCTGGAGAAACAGTGGACGTCGTTCCTGAAGGCGCGCTTGAACTGCTCAGTTCCTGGAGACTC TCATTTTTATTTCAACATTCTCCAGGCAGTTACAGATGTGATTCGTATCAACGGGCGTGATGTTGTCCTGGCA ACGTTTTCTACACCTTATAACAGCATCCCTGGGTCTGCAGTCTGTGCCTATGACATGCTTGACATTGCCAGTG TTTTTACTGGGAGATTCAAGGAACAGAAGTCTCCTGATTCCACCTGGACACCAGTTCCTGATGAACGAGTTCC TAAGCCCAGGCCAGGTTGCTGTGCTGGCTCATCCTCCTTAGAAAGATATGCAACCTCCAATGAGTTCCCTGAT GATACCCTGAACTTCATCAAGACGCACCCGCTCATGGATGAGGCAGTGCCCTCCATCTTCAACAGGCCATGGT TCCTGAGAACAATGGTCAGATACCGCCTTACCAAAATTGCAGTGGACACAGCTGCTGGGCCATATCAGAATCA CACTGTGGTTTTTCTGGGATCAGAGAAGGGAATCATCTTGAAGTTTTTGGCCAGAATAGGAAATAGTGGTTTT CTAAATGACAGCCTTTTCCTGGAGGAGATGAGTGTTTACAACTCTGAAAAATGCAGCTATGATGGAGTCGAAG ACAAAAGGATCATGCGCATGCAGGTCGACGGC NOV2f, 260565761 Protein Sequence SEQ ID NO:24 497 aa MW at 56242.5 kD TGSMRSEALLLYFTLLHFAGAGFPEDSEPISISHGNYTKQYPVFVGHKPGRNTTQRHRLDIQMIMIMNGTLYI AARDHIYTVDIDTSHTEEIYCSKKLTWKSRQADVDTCRMKGKHKDECHNFIKVLLKKNDDALFVCGTNAFNPS CRNYKMDTLEPFGDEFSGMARCPYDAKHANVALFADGKLYSATVTDFLAIDAVIYRSLGESPTLRTVKHDSKW LKEPYFVQAVDYGDYIYFFFREIAVEYNTMGKVVFPRVAQVCKNDMGGSQRVLEKQWTSFLKARLNCSVPGDS HFYFNILQAVTDVIRINGRDVVLATFSTPYNSIPGSAVCAYDMLDIASVWTGRFKEQKSPDSTWTPVPDERVP KPRPGCCAGSSSLERYATSNEFPDDTLNFIKTHPLMDEAVPSIFNRPWFLRTMVRYRLTKIAVDTAAGPYQNH TVVFLGSEKGIILKFLARIGNSGFLNDSLFLEEMSVYNSEKCSYDGVEDKRIMGMQVDG NOV2g, 252324008 SEQ ID NO:25 1438 bp DNA Sequence ORF Start: at 2 ORF Stop: end of sequence CACCGGATCCGGTTTCCCAGAAGATTCTGAGCCAATCAGTATTTCGCATGGCAACTATACAAAACAGTATCCG GTGTTTGTGGGCCACAAGCCAGGACGGAACACCACACAGAGGCACAGGCTGGACATCCAGATGATTATGATCA TGAACGGAACCCTCTACATTGCTGCTAGGGACCATATTTATACTGTTGATATAGACACATCACACACGGAAGA AATTTATTGTAGCAAAAAACTGACATGGAAATCTAGACAGGCCGATGTAGACACATGCAGAATGAAGGGAAAA CATAAGGATGAGTGCCACAACTTTATTAAAGTTCTTCTAAAGAAAAACGATGATGCATTGTTTGTCTGTGGAA CTAATGCCTTCAACCCTTCCTGCAGAAACTATAAGATGGATACATTGGAACCATTCGGGGATGAATTCAGCGG AATGGCCAGATGCCCATATGATGCCAAACATGCCAACGTTGCACTGTTTGCAGATGGAAAACTATACTCAGCC ACAGTGACTGACTTCCTTGCCATTCACGCAGTCATTTACCGGAGTCTTGGAGAAAGCCCTACCCTGCGGACCG TCAAGCACGATTCAAAATGGTTGAAAGAACCATACTTTGTTCAAGCCGTGGATTACGGAGATTATATCTACTT CTTCTTCAGGGAAATAGCAGTGGAGTATAACACCATGGGAAAGGTAGTTTTCCCAAGAGTGGCTCAGGTTTGT AAGAATGATATGGGAGGATCTCAAAGAGTCCTGGAGAAACAGTGGACGTCGTTCCTGAAGGCGCGCTTGAATT GCTCAGTTCCTGGAGACTCTCATTTTTATTTCAACATTCTCCAGGCAGTTACAGATGTGATTCGTATCAACGG CCGTGATGTTGTCCTGGCAACGTTTTCTACACCTTATAACAGCATCCCTGGGTCTGCAGTCTGTGCCTATGAC ATGCTTGACATTGCCAGTGTTTTTACTGGGAGATTCAAGGAACAGAAGTCTCCTGATTCCACCTGGACACCAG TTCCTGATGAACGAGTTCCTAAGCCCAGGCCAGGTTGCTGTGCTGGCTCATCCTCCTTAGAAAGATATGCAAC CTCCAATGAGTTCCCTGATGATACCCTGAACTTCATCAAGACGCACCCGCTCATGGATGAGGCAGTGCCCTCC ATCTTCAACAGGCCATGGTTCCTGAGAACAATGGTCAGATACCGCCTTACCAAAATTGCAGTGGACACAGCTG CTGGGCCATATCAGAATCACACTGTGGTTTTTCTGGGATCAGAGAAGGGAATCATCTTGAAGTTTTTGGCCAG AATAGGAAATAGTGGTTTTcTAAATGACAGCCTTTTCCTGGAGGAGATGAGTGTTTACAACTCTGAAAAATCC AGCTATGATGGAGTCGAAGACAAAAGGATCATGGGCATGCAGGTCGACGGC NOV2g, 252324008 Protein Sequence SEQ ID NO:26 479 aa MW at 54207.1 kD TGSGFPEDSEPISISHGNYTKQYPVFVGHKPGRNTTQRHRLDIQMIMIMNGTLYIAARDHIYTVDIDTSHTEE IYCSKKLTWKSRQADVDTCRNKGKHKDECHNFIKVLLKKNDDALFVCGTNAFNPSCRNYKMDTLEPFGDEFSG NARCPYDAKHANVALFADGKLYSATVTDFLAIDAVIYRSLGESPTLRTVKHDSKWLKEPYFVQAVDYGDYIYF FFREIAVEYNTMGKVVFPRVAQVCKNDMGGSQRVLEKQWTSFLKARLNCSVPGDSHFYFNILQAVTDVIRING RDVVLATFSTPYNSIPGSAVCAYDMLDIASVFTGRFKEQKSPDSTWTPVPDERVPKPRPGCCAGSSSLERYAT SNEFPDDTLNFIKTHPLMDEAVPSIFNRPWFLRTMVRYRLTKIAVDTAAGPYQNHTVVFLGSEKGIILKFLAR IGNSGFLNDSLFLEEMSVYNSEKCSYDGVEDKRIMGMQVDG NOV2h, 252323542 SEQ ID NO:27 3055 bp DNA Sequence ORF Start: at 2 ORF Stop: end of sequence CACCGGATCCGGTTTCCCAGAAGATTCTGAGCCAATCAGTATTTCGCATGGCAACTATACAAAACAGTATCCG GTGTTTGTGGGCCACAAGCCAGGACGGAACACCACACAGAGGCACAGGCTGGACATCCAGATGATTATGATCA TGAACGGAACCCTCTACATTGCTGCTAGGGACCATATTTATACTGTTGATATAGACACATCACACACGGAAGA AATTTATTGTAGCAAAAAACTGACATGGAAATCTAGACAGGCCGATGTAGACACATGCAGAATGAAGGGAAAA CATAAGCATGAGTGCCACAACTTTATTAAAGTTCTTCTAAAGAAAAACGATGATGCATTGTTTGTCTGTGGAA CTAATGCCTTCAACCCTTCCTGCAGAAACTATAAGATGGATACATTGGAACCATTCGGGGATGAATTCAGCGG AATGGCCAGATGCCCATATGATGCCAAAAACATGCCAACGTTGCACTGTTTGCAGATGGAACTATACTCAGCC ACAGTGACTGACTTCCTTGCCATTGACGCAGTCATTTACCGGAGTCTTGGAGAAAGCCCTACCCTGCGGACCG TCAAGCACGATTCAAAATGGTTGAAAGAACCATACTTTGTTCAAGCCGTGGATTACGGAGATTATATCTACTT CTTCTTCAGGGAAATAGCAGTGGACTATAACACCATGGGAAAGGTAGTTTTCCCAAGAGTGGCTCACGTTTGT AAGAATGATATGGGAGGATCTCAAAGAGTCCTGGAGAAACAGTGGACGTCGTTCCTGAAGGCGCGCTTGAACT GCTCAGTTCCTGCAGACTCTCATTTTTATTTCAACATTCTCCAGGCAGTTACAGATGTGATTCGTATCAACGG GCGTGATGTTGTCCTGGCAACGTTTTCTACACCTTATAACAGCATCCCTGGGTCTGCAGTCTGTGCCTATGAC ATGCTTGACATTGCCAGTGTTTTTACTGGGAGATTCAAGGAACAGAAGTCTCCTGATTCCACCTGGACACCAG TTCCTGATGAACGAGTTCCTAAGCCCAGGCCAGGTTGCTGTGCTGGCTCATCCTCCTTAGAAAGATATGCAAC CTCCAATGAGTTCCCTGATGATACCCTGAACTTCATCAAGACGCACCCGCTCATGGATGAGGCAGTGCCCTCC ATCTTCAACAGGCCATGGTTCCTGAGAACAATGGTCAGATACCGCCTTACCAAAATTGCAGTGGACACAGCTG CTGGGCCATATCACAATCACACTGTGGTTTTTCTGGGATCAGAGAAGGGAATCATCTTGAAGTTTTTGGCCAG AATAGGAAATAGTGGTTTTCTAAATGACAGCCTTTTCCTGGAGGAGATGAGTGTTTACAACTCTGAAAAATGC AGCTATCATGGAGTCGAAGACAAAAGGATCATGGGCATGCAGCTGGACAGAGCAAGCAGCTCTCTGTATGTTG CGTTCTCTACCTGTGTGATAAAGGTTCCCCTTGGCCGGTGTGAACGACATGGGAAGTGAAAAAAAACCTGTAT TGCCTCCAGAGACCCATATTGTGGATGGATAAAGGAAGGTGGTGCCTGCAGCCATTTATCACCCAACAGCAGA CTGACTTTTGAGCAGGACATAGAGCGTGGCAATACAGATGGTCTGGGGGACTGTCACAATTCCTTTGTGGCAC TGAATGGGCATTCCAGTTCCCTCTTGCCCAGCACAACCACATCAGATTCGACCGCTCAAGAGGGGTATGAGTC TAGGGGAGGAATGCTGGACTGGAAGCATCTGCTTGACTCACCTGACAGCACAGACCCTTTGGGGGCAGTGTCT TCCCATAATCACCAAGACAAGAAGGGAGTGATTCGGGAAAGTTACCTCAAAGGCCACGACCAGCTGGTTCCCG TCACCCTCTTGGCCATTGCAGTCATCCTGGCTTTCGTCATGGGGGCCGTCTTCTCCGGCATCACCGTCTACTG CGTCTGTGATCATCGGCGCAAAGACGTGGCTGTGGTGCAGCGCAAGGAGAAGGAGCTCACCCACTCGCGCCGG GGCTCCATGAGCAGCGTCACCAAGCTCAGCGGCCTCTTTGGGGACACTCAATCCAAAGACCCAAAGCCGGAGG CCATCCTCACGCCACTCATGCACAACGGCAACCTCGCCACTCCCGGCAACACGGCCAAGATGCTCATTAAAGC AGACCAGCACCACCTGGACCTGACGGCCCTCCCCACCCCAGAGTCAACCCCAACGCTGCAGCAGAAGCGGAAG CCCAGCCGCGGCAGCCGCGAGTGGGAGAGGAACCAGAACCTCATCAATGCCTGCACAAAGGACATGCCCCCCA TGGGCTCCCCTGTGATTCCCACGGACCTGCCCCTGCGGGCCTCCCCCAGCCACATCCCCAGCGTGGTGGTCCT GCCCATCACGCAGCAGGGCTACCAGCATGAGTACGTGGACCAGCCCAAAATGAGCGAGGTGGCCCAGATGCCG CTGGAGGACCAGGCCGCCACACTGGAGTATAAGACCATCAAGGAACATCTCAGCAGCAAGAGTCCCAACCATG GGGTGAACCTTGTGGAGAACCTGGACAGCCTGCCCCCCAAAGTTCCACAGCGGGAGGCCTCCCTGGGTCCCCC GGGACCCTCCCTGTCTCAGACCGGTCTAAGCAAGCGGCTGGAAATGCACCACTCCTCTTCCTACGGGGTTGAC TATAAGAGGAGCTACCCCACGAACTCGCTCACGAGAACCCACCAGGCCACCACTCTCAAAAGAAACAACACTA ACTCCTCCAATTCCTCTCACCTCTCCAGAAACCAGAGCTTTGGCAGGGGAGACAACCCGCCGCCCGCCCCGCA GAGGGTGGACTCCATCCAGGTGCACAGCTCCCAGCCATCTGCCCAGGCCGTGACTGTCTCGAGCCAGCCCAGC CTCAACGCCTACAACTCACTGACAAGGTCGGGGCTGAAGCGTACGCCCTCGCTAAAGCCGGACGTACCCCCCA AACCATCCTTTGCTCCCCTTTCCACATCCATGAAGCCCAATGATGCGTGTACAGTCGACGGC NOV2h, 252323542 Protein Sequence SEQ ID NO:28 1018 aa MW at 112848.6 kD TGSGFPEDSEPISISHGNYTKQYPVFVGHKPGRNTTQRHRLDIQMIMIMNGTLYIAARDHIYTVDIDTSHTEE IYCSKKLTWKSRQADVDTCRMKGKHKDECHNFIKVLLKKNDDALFVCGTNAFNPSCRNYKMDTLEPFGDEFSG MARCPYDAKHANVALFADGKLYSATVTDFLAIDAVIYRSLGESPTLRTVKHDSKWLKEPYFVQAVDYGDYIYF FFREIAVEYNTMGKVVFPRVAQVCKNDMGGSQRVLEKQWTSFLKARLNCSVPGDSHFYFNILQAVTDVIRING RDVVLATFSTPYNSIPGSAVCAYDMLDIASVFTGRFKEQKSPDSTWTPVPDERVPKPRPGCCAGSSSLERYAT SNEFPDDTLNFIKTHPLMDEAVPSIFNRPWFLRTMVRYRLTKIAVDTAAGPYQNHTVVFLGSEKGIILKFLAR IGNSGFLNDSLFLEEMSVYNSEKCSYDGVEDKRIMGMQLDRASSSLYVAFSTCVIKVPLGRCERHGKCKKTCI ASRDPYCGWIKEGGACSHLSPNSRLTFEQDIERGNTDGLGDCHNSFVALNGHSSSLLPSTTTSDSTAQEGYES RGGMLDWKHLLDSPDSTDPLGAVSSHNHQDKKGVIRESYLKGHDQLVPVTLLAIAVILAFVMGAVFSGITVYC VCDHRRKDVAVVQRKEKELTHSRRGSMSSVTKLSGLFGDTQSKDPKPEAILTPLMHNGKLATPGNTAKMLIKA DQHHLDLTALPTPESTPTLQQKRKPSRGSREWERNQNLINACTKDMPPMGSPVIPTDLPLRASPSHIPSVVVL PITQQGYQHEYVDQPKMSEVAQMALEDQAATLEYKTIKEHLSSKSPNHGVNLVENLDSLPPKVPQREASLGPP GASLSQTGLSKRLEMHHSSSYGVDYKRSYPTNSLTRSHSQATTLKRNTNSSNSSHLSRNQSFGRGDNPPPAPQ RVDSIQVHSSQPSGQAVTVSRQPSLNAYNSLTRSGLKRTPSLKPDVPPKPSFAPLSTSMKPAAACAADG NOV2i, 252323483 SEQ ID NO:29 2944 bp DNA Sequence ORF Start: at 2 ORF Stop: end of sequence CACCGGATCCATGAGGTCAGAAGCCTTGCTGCTATATTTCACACTGCTACACTTTGCTGGGGCTGGTTTCCCA GAAGATTCTGAGCCAATCAGTATTTCGCATGGCAACTATACAAAACAGTATCCAATGTTTGTGGGCCACAAGC CAGGACGGAACACCACACAGAGGCACAGGCTGGACATCCAGATGATTATGATCATGAACGGAACCCTCTACAT TGCTGCTAGGGACCATATTTATACTGTTGATATAGACACATCACACACGGAAGAAATTTATTGTAGCAAAAAA CTGACATGGAAATCTAGACAGGCCGATGTAGACACATGCAGAATGAAGGGAAAACATAAGGATGAGTGCCACA ACTTTATTAAAGTTCTTCTAAAGAAAAACGATGATGCATTGTTTGTCTGTGGAACTAATGCCTTCAACCCTTC CTGCAGAAACTATAAGATGGATACATTGGAACCATTCGGGGATGAATTCAGCGGAATGGCCAGATGCCCATAT GATGCCAAACATGCCAACGTTGCACTGTTTGCAGATGGAAAACTATACTCAGCCACAGTGACTGACTTCCTTG CCATTGACGCAGTCATTTACCGGAGTCTTGGAGAAAGCCCTACCCTGCGGACCGTCAAGCACGATTCAAAATG GTTGAAAGAACCATACTTTGTTCAAGCCGTGGATTACGGAGATTATATCTACTTCTTCTTCAGGGAAATAGCA GTGGAGTATAACACCATGGGAAAGGTAGTTTTCCCAAGAGTGGCTCAGGTTTGTAAGAATGATATGGGAGGAT CTCAAAGAGTCCTGGAGAAACAGTGGACGTCGTTCCTGAAGGCGCGCTTGAACTGCTCAGTTCCTGGAGACTC TCATTTTTATTTCAACATTCTCCAGGCAGTTACAGATGTGATTCGTATCAAGGGGCGTGATGTTGTCCTGGCA ACGTTTTCTACACCTTATAACAGCATCCCTGGGTCTGCAGTCTGTGCCTATGACATGCTTGACATTGCCAGTG TTTTTACTGGGAGATTCAAGGAACAGAAGTCTCCTGATTCCACCTGGACACCAGTTCCTGATGAACGAGTTCC TAAGCCCAGGCCAGGTTGCTGTGCTGGCTCATCCTCCTTAGAAAGATATGCAACCTCCAATGAGTTCCCTGAC GATACCCTGAACTTCATCAAGACGCACCCGCTCATGGATGAGGCAGTGCCCTCCATCTTCAACAGGCCATGGT TCCTGAGAACAATGGTCAGATACCGCCTTACCAAAATTGCAGTGGACACAGCTGCTGAACCATATAAGAATCA CACTGTGGTTTTTCTGGGATCAGAGAAGGGAATCATCTTGAAAGTTTTTGGCCAGAATAGGAATAGTGGTTAA CTAAATGACAGCCTTTTCCTGGAGGAGATGAGTGTTTACAACTCTGAAAAATGCAGCTATGATGGAGTCGAAG ACAAAAGGATCATCGGCATGCAGCTGGACAGAGCAAGCAGCTCTCTGTATGTTGCGTTCTCTACCTGTGTGAT AAAGGTTCCCCTTGGCCGGTGTGAACGACATGGGAAGTGTAAAAAAACCTGTATTGCCTCCAGAGACCCATAT TGTGGATGGATAAAGGAAGGTGGTGCCTGCAGCCATTTATCACCCAACAGCAGACTGACTTTTGAGCAGGACA TAGAGCGTGGCAATACAGATGGTCTGGGGGACTGTCACAATTCCTTTGTGGCACTGAATGGAGTGATTCGGGA AAGTTACCTCAAAGGCCACGACCAGCTGGTTCCCGTCACCCTCTTGGCCATTGCAGTCATCCTGGCTTTCGTC ATGGGGGCCGTCTTCTCGGGCATCACCGTCTACTGCGTCTGTGATCATCGGCGCAAAGACGTGGCTGTGGTGC AGCGCAAGGAGAAGGAGCTCACCCACTCGCGCCGGGGCTCCATGAGCAGCGTCACCAAGCTCAGCGGCCTCTT TGGGGACACTCAATCCAAAGACCCAAAGCCGGAGGCCATCCTCACGCCACTCATGCACAACGGCAAGCTCGCC ACTCCCGGCAACACGGCCAAGATGCTCATTAAAGCAGACCAGCACCACCTGGACCTGACGGCCCTCCCCACCC CAGAGTCAACCCCAACGCTGCAGCAGAAGCGGAAGCCCAGCCGCGGCAGCCGCGAGTGGGAGAGGAACCAGAA CCTCATCAATGCCTGCACAAAGGACATGCCCCCCATGGGCTCCCCTGTGATTCCCACGGACCTGCCCCTGCGG CCCTCCCCCAGCCACATCCCCAGCGTGGTGGTCCTGCCCATCACGCAGCAAAGCTACCAGCATGAGTACGTGG ACCAGCCCAAAATGAGCGAGGTGGCCCAGATGGCGCTGGAGGACCAGGCCGCCACACTGGAGTATAAGACCAT CAAGGACATCTCAGCAGCAAGAGTCCCAACCATGGGGTGAACCTTGTGGAGAACCTGGACAGCCTGCCCCCCC AAAGTTCCACAGCGGGAGGCCTCCCTGGGTCCCCCGGGAGCCTCCCTGTCTCAGACCGGTCTAAGCAAGCGGC TGGAAATGCACCACTCCTCTTCCTACGGGGTTGACTATAAGAGGAGCTACCCCACGAACTCGCTCACGAGAAG CCACCAGGCCACCACTCTCAAAAGAAACAACACTAACTCCTCCAATTCCTCTCACCTCTCCAGAAACCAGAGC TTTGGCAGGGGAGACAACCCGCCGCCCGCCCCGCAGAGGGTGGACTCCATCCAGGTGCACAGCTCCCACCCAT CTGGCCAGGCCGTGACTGTCTCGAGGCAGCCCAGCCTCAACGCCTACAACTCACTGACAAGGTCGGGGCTGAA GCGTACGCCCTCGCTAAAGCCGGACGTACCCCCCAAACCATCCTTTGCTCcCCTTTCCACATCCATGAAGCCC AATGATGCGTGTACAGTCGACGGC NOV2i, 252323483 Protein Sequence SEQ ID NO:30 981 aa MW at 109048.9 kD TGSMRSEALLLYFTLLHFAGAGFPEDSEPISISHGNYTKQYPVFVGHKPGRNTTQRHRLDIQMIMIMNGTLYI AARDHIYTVDIDTSHTEEIYCSKKLTWKSRQADVDTCRNKGKHKDECHNFIKVLLKKNDDALFVCGTNAFNPS CRNYKMDTLEPFGDEFSGMARCPYDAKHANVALFADGKLYSATVTDFLAIDAVIYRSLGESPTLRTVKHDSKW LKEPYFVQAVDYGDYIYFFFREIAVEYNTMGKVVFPRVAQVCKNDNGGSQRVLEKQWTSFLKARLNCSVPGDS HFYFNILQAVTDVIRIKGRDVVLATFSTPYNSIPGSAVCAYDMLDIASVFTGRFKEQKSPDSTWTPVPDERVP KPRPGCCAGSSSLERYATSNEFPDDTLNFIKTHPLMDEAVPSIFNRPWFLRTMVRYRLTKIAVDTAAGPYQNH TVVFLGSEKGIILKFLARIGNSGFLNDSLFLEEMSVYNSEKCSYDGVEDKRIMGMQLDRASSSLYVAFSTCVI KVPLGRCERHGKCKKTCIASRDPYCGWIKEGGACSHLSPNSRLTFEQDIERGNTDGLGDCNNSFVALNGVIRE SYLKGHDQLVPVTLLAIAVILAFVMGAVFSGITVYCVCDHRRKDVAVVQRKEKELTHSRRGSMSSVTKLSGLF GDTQSKDPKPEAILTPLMHNGKLATPGNTAKMLIKADQHHLDLTALPTPESTPTLQQKRKPSRGSREWERNQN LINACTKDMPPMGSPVIPTDLPLRASPSHIPSVVVLPITQQGYQHEYVDQPKMSEVAQMALEDQAATLEYKTI KEHLSSKSPNHGVNLVENLDSLPPKVPQREASLGPPGASLSQTGLSKRLEMHHSSSYGVDYKRSYPTNSLTRS HQATTLKRNNTNSSNSSHLSRNQSFGRGDNPPPAPQRVDSIQVHSSQPSGQAVTVSRQPSLNAYNSLTRSGLK RTPSLKPDVPPKPSFAPLSTSMKPNDACTVDG NOV2j, CG51896-01 SEQ ID NO:31 3498 bp DNA Sequence ORF Start: ATG at 214 ORF Stop: end of sequence GCGACTATTTCCCCCAAAGAGACAAGCACACATGTAGGAATGACAAAGGCTTGCGAAGGAGAGACCGCAGCCC GCGGCCCGGAGAGATCCCCTCGATAATGGATTACTAAATGGGATACACGCTGTACCAGTTCGCTCCGAGCCCC GGCCGCCTGTCCGTCGATGCACCGAAAAGGGTGAAGTAGAGAAATAAAGTCTCCCCGCTGAACTACTATGAGG TCAGAAGCCTTGCTGCTATATTTCACACTGCTACACTTTGCTGGGGCTGGTTTCCCAGAAGATTCTGAGCCAA TCAGTATTTCGCATGGCAACTATACAAAACAGTATCCGGTGTTTGTGGGCCACAAGCCAGGACGGAACACCAC ACAGAGGCACAGGCTGGACATCCAGATGATTATGATCATGAACGGAACCCTCTACATTGCTGCTAGGCACCAT ATTTATACTGTTCATATAGACACATCACACACGGAAGAAATTTATTGTAGCAAAAAACTGACATGGAAATCTA GACAGGCCGATGTAGACACATGCAGAATGAAGGGAAAACATAAGGATGAGTGCCACAACTTTATTAAAGTTCT TCTAAAGAAAAACGATGATGCATTGTTTGTCTGTGGAACTAATGCCTTCAACCCTTCCTGCAGAAACTATAAG ATGGATACATTGGAACCATTCGGGGATGAATTCAGCGGAATGGCCAGATCCCCATATGATGCCAAACATGCCA ACGTTGCACTGTTTGCAGATGGAAAACTATACTCAGCCACAGTGACTGACTTCCTTGCCATTGACGCAGTCAT TTACCGGAGTCTTGGAGAAAGCCCTACCCTGCGGACCGTCAAGCACGATTCAAAATGGTTGAAAGAACCATAC TTTGTTCAAGCCGTGGATTACGGAGATTATATCTACTTCTTCTTCAGGGAAATAGCAGTGGAGTATAACACCA TGGGAAAGGTAGTTTTCCCAAGAGTGGCTCAGGTTTGTAAGAATGATATGGGAGGATCTCAAAGAGTCCTGGA GAAACAGTGGACGTCGTTCCTGAAGGCGCGCTTGAACTGCTCAGTTCCTGGAGACTCTCATTTTTATTTCAAC ATTCTCCAGGCAGTTACAGATGTGATTCGTATCAACGCGCGTGATGTTGTCCTGGCAACGTTTTCTACACCTT ATAACAGCATCCCTGGGTCTGCAGTCTGTGCCTATGACATGCTTGACATTGCCAGTGTTTTTACTGGGAGATT CAAGGAACAGAAGTCTCCTGATTCCACCTCGACACCAGTTCCTGATGAACGAGTTCCTAAGCCCAGGCCAGGT TGCTGTGCTGGCTCATCCTCCTTAGAAAGATATGCAACCTCCAATGAGTTCCCTGATGATACCCTGAACTTCA TCAAGACGCACCCGCTCATGGATGAGGCAGTGCCCTCCATCTTCAACAGGCCATGGTTCCTGAGAACAATGGT CAGATACCGCCTTACCAAAATTGCAGTCGACACAGCTGCTGGGCCATATCAGAATCACACTGTGGTTTTTCTG GGATCAGAGAAGCGAATCATCTTGAAGTTTTTCGCCAGAATAGGAAATAGTGGTTTTCTAAATGACAGCCTTT TCCTGGACGAGATGAGTGTTTACAACTCTGAAAAATGCAGCTATGATGGAGTCGAAGACAAAAGGATCATGGG CATGCAGCTGGACAGAGCAAGCAGCTCTCTGTATGTTGCGTTCTCTACCTGTGTGATAAAGGTTCCCCTTGGC CGGTGTGAACGACATGGGAAGTGTAAAAAAACCTGTATTGCCTCCAGAGACCCATATTGTGCATGGATAAAGG AAGGTGGTGCCTGCAGCCATTTATCACCCAACAGCAGACTGACTTTTGACCAGGACATACAGCGTGGCAATAC AGATGGTCTGGGGGACTGTCACAATTCCTTTGTGGCACTGAATGGGCATTCCAGTTCCCTCTTGCCCAGCACA ACCACATCAGATTCGACGGCTCAAGAGGGGTATGAGTCTAGGCGAGGAATCCTGGACTGGAAGCATCTGCTTG ACTCACCTGACAGCACAGACCCTTTGGUGGCAGTGTCTTCCCATAATCACCAAGACAAGAAGGGAGTGATTCG GGAAAGTTACCTCAAAGGCCACGACCAGCTGGTTCCCGTCACCCTCTTGGCCATTGCAGTCATCCTGGCTTTC GTCATGGGGGCCGTCTTCTCGGGCATCACCGTCTACTGCCTCTGTGATCATCGGCGCAAAGACGTGGCTGTGG TGCAGCGCAAGOAGAAGGAGCTCACCCACTCGCGCCGGGGCTCCATGAGCAGCGTCACCAAGCTCAGCGGCCT CTTTGGGGACACTCAATCCAAAGACCCAAAGCCGGAGGCCATCCTCACGCCACTCATGCACAACGGCAAGCTC GCCACTCCCGGCAACACGGCCAAGATGCTCATTAAAGCAGACCAGCACCACCTGGACCTGACAACCCTCCCCA CCCCAGAGTCAACCCCAACGCTGCAGCAGAAGCGGGAACCCAGCCGCGGCACCCGCGAGTGGGAGAGGAACCA GAACCTCATCAATGCCTGCACAAAGGACATCCCCCCCATGGGCTCCCCTGTGATTCCCACGGACCTGCCCCTG CGGGCCTCCCCCAGCCACATCCCCAGCGTGGTGGTCCTGCCCATCACGCAGCAGGGCTACCAGCATGAGTACG TGGACCAGCCCAAAATGAGCGAGGTGGCCCAGATGGCGCTGGAGGACCAAACCGCAACACTGGAGTATAAGAC CATCAAGGAACATCTCAGCAGCAAGAGTCCCAACCATGGGGTGAACCTTGTGGAGAACCTGGACAGCCTGCCC CCCAAAGTTCCACAGCGGGAGGCCTCCCTGGGTCCCCCGGGAGCCTCCCTGTCTCAGACCGCTCTAAGCAAGC GGCTGGAAATGCACCACTCCTCTTCCTACGGGGTTGACTATAAGAGGAGCTACCCCACGAACTCGCTCACGAG AAGCCACCTGACCACCTACTCTCATCAGAAGCAACACTAACCCCGACAATTCANCTCTGACTTCAAAGGGACC AGAGCTTTGGCAGGGGAGACAACCCGCCGCCCGCCCCGCAGAGGGTGGACTCCATCCAGGTGCACAGCTCCCA GCCATCTGGCCAGGCCGTGACTGTCTCGAGGCAGCCCAGCCTCAACGCCTACAACTCACTGACAAAATCGGGG CTGAAGCGTACGCCCTCGCTAAAGCCGGACGTACCCCCCAAACCATCCTTTGCTCCCCTTTCCACATCCATGA AGCCCAATGATGCGTGTACATAATCCCAGGGGGAGGGGGTCAGGTGTCGAACCAGCAGGCAAGGCGAGGTGTC CGCTCAGCTCAGCAAGGTTCTCAACTGCCTCGAGTACCCACCAAACCAAAAAGGCCTGCGGCAGAACCGAGGG ACGCTGGGTCCTCCTCTCTGGGACACAGGGGTACTCACGCTGGGCCGCGTAATTTGGTGAAAG NOV2j, CG5 1896-01 Protein Sequence SEQ ID NO:32 939 aa MW at 104828.0 kD MRSEALLLYFTLLHFAGAGFPEDSEPISISHGNYTKQYPVFVGHKPGRNTTQRHRLDIQMIMIMNGTLYIAAR DHIYTVDIDTSHTEEIYCSKKLTWKSRQADVDTCRMKGKHKDECHNFIKVLLKKNDDALFVCGTNAFNPSCRN YKMDTLEPFGDEFSGMARCPYDAKHANVALFADGKLYSATVTDFLAIDAVIYRSLGESPTLRTVKHDSKWLKE PYFVQAVDYGDYIYFFFREIAVEYNTMGKVVFPRVAQVCKNDMGGSQRVLEKQWTSFLKARLNCSVPGDSHFY FNILQAVTDVIRINGRDVVLATFSTPYNSIPGSAVCAYDMLDIASVFTGRFKEQKSPDSTWTPVPDERVPKPR PGCCAGSSSLERYATSNEFPDDTLNFIKTHPLMDEAVPSIFNRPWFLRTMVRYRLTKIAVDTAAGPYQNHTVV FLGSEKGIILKFLARIGNSGFLNDSLFLEEMSVYNSEKCSYDGVEDKRIMGMQLDRASSSLYVAFSTCVIKVP LGRCERIIGKCKKTCIASRDPYCGWIKEGGACSHLSPNSRLTFEQDIERGNTDGLGDCHNSFVAANGHSSSLP STTTSDSTAQEGYESRGGMLDWKHLLDSPDSTDPLGAVSSHNHQDKKGVIRESYLKGHDQLVPAALAAIAVIL AFVMGAVFSGITVYCVCDHRRKDVAVVQRKEKELTHSRRGSMSSVTKLSGLFGDTQSDPKPEAILTPLMHNGA KLATPGNTAKMLIKADQHHLDLTALPTPESTPTLQQAAEPSRGTREWEAAQNLINACTAAMPPMGSPVIPTDL PLRASPSHIPSVVVLPITQQGYQHEYVDQPKMSEVAQMALEDQATLEYKTIKEHLSSKSPNIIGVNLVENLDS LPPAAPQREASLGPPGASLSQTGLSKAAEMHHSSSYGAAYAASYPTNSLTRSHLTTYSHQKQH NOV2k, CG51896-02 SEQ ID NO:33 1878 bp DNA Sequence ORF Start: at 1 ORF Stop: end of sequence GGTTTCCCAGAAGATTCTGAGCCAATCAGTATTTCGCATGGCAACTATACAAAACAGTATCCGGTGTTTGTGG GCCACAAGCCAGGACGGAACACCACACAGAGGCACAGGCTGGACATCCAGATGATTATGATCATGAACGGAAC CCTCTACATTGCTGCTAGGGACCATATTTATACTGTTGATATAGACACATCACACACGGAAGAAATTTATTGT AGCAAAAAACTGACATGGAAATCTAGACAGGCCGATGTAGACACATGCAGAATGAAGGGAAAACATAAGGATG AGTGCCACAACTTTATTAAAGTTCTTCTAAAGAAAAACGATGATGCATTGTTTGTCTGTGGAACTAATGCCTT CAACCCTTCCTGCAGAAACTATAAGATGGATACATTGGAACCATTCGGGGATGAATTCAGCGGAATGGCCAGA TGCCCATATGATGCCAAACATGCCAACGTTGCACTGTTTGCAGATGGAAAACTATACTCAGCCACAGTGACTG ACTTCCTTGCCATTGACGCAGTCATTTACCGGAGTCTTGGACAAAGCCCTACCCTGCGGACCGTCAAGCACGA TTCAAAATGGTTGAAAGAACCATACTTTGTTCAAGCCGTGGATTACGGAGATTATATCTACTTCTTCTTCAGG GAAATAGCAGTGGAGTATAACACCATAAGAAGGTAGTTTTCCCAAGAGTGGCTCAGGTTTGTAAGAAATGATA TGGGAGGATCTCAAAGAGTCCTGGAGAAACAGTGGACGTCGTTCCTGAAGGCGCGCTTGAACTGCTCAGTTCC TGGAGACTCTCATTTTTATTTCAACATTCTCCAGGCAGTTACAGATGTGATTCGTATCAACGGGCGTGATGTT GTCCTGGCAACGTTTTCTACACCTTATAACAGCATCCCTGGGTCTGCAGTCTGTGCCTATGACATGCTTGACA TTGCCAGTGTTTTTACTGGGAGATTCAAGGAACAGAAGTCTCCTGATTCCACCTGGACACCAGTTCCTGATGA ACGAGTTCCTAAGCCCAGGCCAGGTTGCTGTGCTGGCTCATCCTCCTTAGAAAGATATGCAACCTCCAATGAG TTCCCTGATGATACCCTGAACTTCATCAAGACGCACCCGCTCATGGATGAAACAGTGCCCTCCATCTTCAACA GGCCATGGTTCCTGAGAACAATGGTCAGATACCGCCTTACCAAAATTGCAGTGGACACAGCTGCTGGGCCATA TCAGAATCACACTGTGGTTTTTCTGGGATCAGAGAAGGGAATCATCTTGAAGTTTTTGGCCAGAATAGGAAAT AGTGGTTTTCTAAATGACACCCTTTTCCTGGAGGAGATGAGTGTTTACAACTCTCAAAATGCAGCTATGAATG GAGTCGAAGACAAAAGGATCATGGGCATGCAGCTGGACAGACCAAGCAGCTCTCTGTATGTTGCGTTCTCTAC CTGTGTGATAAAGGTTCCCCTTGGCCGGTGTGAACGACATGGGAAGTGTAAAAAAACCTGTATTGCCTCCAGA GACCCATATTGTGGATGGATAAAGGAAGGTGGTGCCTCCAGCCATTTATCACCCAACAGCAGACTGACTTTTG AGCAGGACATAGAGCGTGGCAATACAGATAATCTGGGGGACTGTCACAATTCCTTTGTGGCACTGAATGGGCA TTCCAGTTCCCTCTTGCCCAGCACAACCACATCAGATTCGACGGCTCAAGAGGGGTATGAGTCTAGGGGAGGA ATGCTGGACTGGAAGCATCTGCTTGACTCACCTGACAGCACAGACCCTTTGGGGGCAGTGTCTTCCCATAATC ACCAAGACAAGAAGGGAGTGATTCGGGAAAGTTACCTCAAAGGCCACGACCAG NOV2k, CG51896-02 Protein Sequence SEQ ID NO:34 626 aa MW at 70297.8 kD GFPEDSEPISISHGNYTKQYPVFVGHKPGRNTTQRHRLDIQMIMIMNGTLYIAARDHIYTVDIDTSHTEEIYC SKKLTWKSRQADVDTCRMKGKHKDECHNPIKVLLKKNDDALFVCGTNAFNPSCRNYKMDTLEPFGDEFSGMAA CPYDAKHANVALFADGKLYSATVTDFLAIDAVIYRSLGESPTLRTVKHDSKWLKEPFVQAVDYGDYIYFFFER EIAVEYNTMGKVVFPRVAQVCKNDMGGSQRVLEKQWTSFLKARLNCSVPGDSHFYFNILQAVTDVIRINGRDV VLATFSTPYNSIPGSAVCAYDMLDIASVFTGRFKEQKSPDSTWTPVPDERVPKPRPGCCAGSSSLERYATSNE FPDDTLNFIKTHPLMDEAVPSIFMRPWFLRTMVRYRLTKIAAATAAGPYQAATAAFLGSEKGIILKFLARIGN SGFLNDSLFLEEMSVYNSEKCSYDGVEDKRIMGMQLDAASSSLYVAFSTCVIKVPLGRCERHGKCKKTCIASR DPYCGWIKEGGACSHLSPNSRLTFEQDIERGNTDGLGDCHNSFVALNGHSSSLLPSTTTSDSTAQEGYESRGG MLDWKHLLDSPDSTDPLGAVSSHNHQDKKGVIRESYLKGHDQ NOV2l, CG51896-03 SEQ ID NO:35 1908 bp DNA Sequence ORF Start: at 1 ORF Stop: end of sequence GGTTTCCCAGAAGATTCTGAGCCAATCAGTATTTCGCATGGCAACTATACAAAACAGTATCCGGTGTTTGTGG GCCACAAGCCAGGACGGAACACCACACAGAGGCACAGGCTGGACATCCAGATGATTATGATCATGAACGGAAC CCTCTACATTGCTGCTAGGGACCATATTTATACTGTTGATATAGACACATCACACACGGAAGAAATTTATTGT AGCAAAAAACTGACATGGAAATCTAGACAGGCCGATGTAGACACATGCAGAATGAAGGGAAAACATAAGGATG AGTGCCACAACTTTATTAAAGTTCTTCTAAAGAAAAACGATGATGCATTGTTTGTCTGTGGAACTAATGCCTT CAACCCTTCCTGCAGAAACTATAAGATGGATACATTGGAACCATTCGGGGATGAATTCAGCGGAATGGCCAGA TGCCCATATGATGCCAAACATGCCAACGTTGCACTGTTTGCAGATGGAAAACTATACTCAGCCACAGTGACTG ACTTCCTTGCCATTGACGCAGTCATTTACCGGAGTCTTGGAGAAAGCCCTACCCTGCGGACCGTCAAGCACGA TTCAAAATGGTTGAAAGAACCATACTTTGTTCAAGCCGTGGATTACGGAGATTATATCTACTTCTTCTTCAGG GAAATAGCAGTGGAGTATAACACCATGGGAAAGGTAGTTTTCCCAAGAGTGGCTCAGGTTTGTAAGAATGATA TGGCAGGATCTCAAAGAGTCCTGGAGAAACAGTGGACGTCGTTCCTGAAGGCGCGCTTGAACTGCTCAGTTCC TGGAGACTCTCATTTTTTATTTCACATTCTCCAGGCAGTTACAGATGTGATTCGTATCAACAAGCGTGATGTT GTCCTGGCAACGTTTTCTACACCTTATAACAGCATCCCTGGGTCTGCAGTCTGTGCCTATGACATGCTTGACA TTGCCAGTGTTTTTACTGGGAGATTCAAGGAACAGAAGTCTCCTGATTCCACCTGGACACAAGTTCCTGATGA ACGAGTTCCTAAGCCCAGGCCAGGTTGCTGTGCTGGCTCATCCTCCTTAGAAAGATATGCAACCTCCAATGAG TTCCCTGATGATACCCTGAACTTCATCAAGACGCACCCCCTCATGGATGAGGCAGTGCCCTCCATCTTCAAAA GGCCATGGTTCCTGAGAACAATGGTCAGATGCAGCTATGATGGAGTCGAAGACAAAAGGATCATGGGCATGCA GCTGGACAGAGCAAGCAGCTCTCTGTATGTTGCGTTCTCTACCTGTGTGATAAAGGTCCCCCTTGGCCGGTGT GAACGACATGCGAAGTGTAAAAAAAACCTGTATTGCCTCCAGAGACCCATATTGTGGATGGATAAGGAAGGTG GTGCCTGCAGCCATTTATCACCCAACAGCGACTGACTTTTGAGCAGGACATAGAGCGTGGCAAATACAGATGG TCTGGGGGACTGTCACAATTCCTTTGTGGCACTGAATAAGCATTCCAGTTCCCTCTTGCCCAGCACAACCACA TCAGATTCGACGGCTCAAGAGGGGTATGAGTCTAGGGGAGGAATGCTGGACTGGAAGCATCTGCTTGACTCAC CTGACAGCACAGACCCTTTGGGGGCAGTGTCTTCCCATAATCACCAAGACAAGAAGGGAGTGATTCGGGAAAG TTACCTCAAAGGCCACGACCAGCTGGTTCCCGTCACCCTCTTGGCCATTGCAGTCATCCTAACTTTCGTCATG GGGGCCGTCTTCTCGGGCATCACCGTCTACTGCGTCTGTGATCATCGGCGCAAAAACGTGGCTGTGGTGCAGC GCAAGGAGAAGCAGCTCACCCACTCGCGCCGGGGCTCCATGAGCAGCGTCACCAAGCTCAGCGGCCTCTTTAA GGACACTCAA NOV2l, CG51896-03 Protein Sequence SEQ ID NO:36 636 aa MW at 71237.1 kD GFPEDSEPISISHGNYTKQYPVFVGHKPGRNTTQRHRLDIQMIMIMNGTLYIAARDHTYTVDIDTSHTEEIYC SKKLTWKSRQADVDTCRMKGKHKDECHNFIKVLLKKNDDALFVCGTNAFNPSCRNYKMDTLEPFGDEFSGMAR CPYDAKHANVALFAADGKLYSATVTDFLAIDAVIYRSLGESPTLRTVKHDSKWKEPYFVQAVDYGDYIYFFFR EIAVEYNTMGKVVFPRVAQVCKNDMGGSQRVLEKQWTSFLKARLNCSVPGDSHFYFNILQAVTDVIRINGRDV VLATFSTPYNSIPGSAVCAYDMLDIASVFTGRFKEQKSPDSTWTPVPDERVPKPRPGCCAGSSSLERYATSNE FPDDTLNFIKTHPLMDEAVPSIFNRPWFLRTMVRCSYDGVEDKRIMGMQLDAASSSLAAAFSTAAIAAPLGRC ERHGKCKKTCIASRDPYCGWIKEGGACSHLSPNSRLTFEQDIERGNTDGLGDCHNSFVALNGHSSSLLPSTTT SDSTAQEGYESRGGMLDWKHLLDSPDSTDPLGAVSSIINHQDKKGVIRESYLKGHDQLVPVTLLAIAVILAAA GAVFSGITVYCVCDHRRKDVAVVQRKEKELTHSRRGSMSSVTKLSGLFGDTQ NOV2m, CG51896-05 SEQ ID NO:37 54 bp DNA Sequence OFR Start: at 1 ORF Stop: at 55 GGAGAAAGCCCTACCCTGCGGACCGTCAAGCACGATTCAAAATGGTTGAAAGAA NOV2m, GG51896-05 Protein Sequence SEQ ID NO:38 18 aa MW at 2111.4 kD GESPTLRTVKHDSKWLKE NOV2n, CG51896-06 SEQ ID NO:39 54 bp DNA Sequence ORF Start: at 1 ORF Stop: end of sequence GGAGAGAAAGCCCTACCCTGCGGACCGTCAAGCACGATTCAAAATGGTTGAAAGAA NOV2n, CG5 1896-06 Protein Sequence SEQ ID NO:40 18 aa MW at 2111.4 kD GESPTLRTVKHDSKWLKE NOV2o, CG51896-07 SEQ ID NO:41 51 bp DNA Sequence ORF Start: at 1 ORF Stop: end of sequence TCATCCTCCTTAGAAAGATATGCAACCTCCAATGAGTTCCCTGATGATACC NOV2o, CG51896-07 Protein Sequence SEQ ID NO:42 17 aa MW at 1918.9 kD SSSLERYATSNEFPDDT NOV2p, CG51896-08 SEQ ID NO:43 60 bp DNA Sequence ORF Start: at 1 ORF Stop: end of sequence GAGGAGATGAGTGTTTACAACTCTGAAAAATGCAQCTATGATCGAGTCGAAGACAAAAGG NOV2p, CG51896-08 Protein Sequence SEQ ID NO:44 20 aa MW at 2368.5 kD EEMSVYNSEKCSYDGVEDKR NOV2q, CG51896-09 SEQ ID NO:45 3983 bp DNA Sequence ORF Start: ATG at 214 ORF Stop: end of sequence GCGACTATTTCCCCCAAAGAGACAAGCACACATGTAGGAATGACAAAGCCTTGCGAAGGAGAGAGCGCAGCCC GCGGCCCGGAGAGATCCCCTCGATAATGGATTACTAAATGGGATACACGCTGTACCAGTTCGCTCCGAGCCCC GCCCGCCTGTCCGTCGATCCACCGAAAGGGTGAAGTAGAOAAATAAAGTCTCCCCGCTGAAACTACTATGAAA TCAGAAGCCTTGCTGCTATATTTCACACTGCTACACTTTGCTGGGGCTGGTTTCCCAGAAGATTCTGAGCCAA TCAGTATTTCGCATGGCAACTATACAAAACAGTATCCGGTGTTTGTGGGCCACAAGCCAGGACGGAACACCAC ACAGAGGCACAGGCTGGACATCCAGATGATTATGATCATGAACGGAACCCTCTACATTGCTGCTAGGGACCAT ATTTATACTGTTGATATAGACACATCACACACGGAAGAAATTTATTGTAGCAAAAAACTGACATGGAAATCTA GACAGGCCGATGTAGACACATGCAGAATGAAGGGAAAACATAAGGATGAGTGCCACAACTTTATTAAAGTTCT TCTAAAGAAAAACGATGATGCATTGTTTGTCTGTGGAACTAATGCCTTCAACCCTTCCTGCAGAAACTATAAG ATGGATACATTGGAACCATTCGGGGATGAATTCAGCGGAATGGCCAGATGCCCATATGATGCCAAACATGCCA ACGTTGCACTGTTTGCAGATGGAAAACTATACTCAGCCACAGTGACTGACTTCCTTGCCATTGACGCAGTCAT TTACCGGAGTCTTGGAGAAAGCCCTACCCTGCGGACCGTCAAGCACGATTCAAAATGGTTGAAAGAACCATAC TTTGTTCAAGCCGTGGATTACGGAGATTATATCTACTTCTTCTTCAGGGAAATAGCACTGGAGTATAACACCA TGGGAAAGGTAGTTTTCCCAAGAGTGGCTCAGGTTTGTAAGAATGATATGGGAGGATCTCAAAGAGTCCTGGA GAAACGGTGCACGTCGTTCCTGAAGGCGCGCTTGAACTGCTCAGTTCCTGGAGACTCTCATTTTTATTTCAAC ATTCTCCAGGCAGTTACAGATGTGATTCGTATCAACGCGCGTGATGTTGTCCTGGCAACGTTTTCTACACCTT ATAACAGCATCCCTGGGTCTGCAGTCTGTGCCTATGACATGCTTGACATTGCCAGTGTTTTTACTGGGAGATT CAAGGAACAGAAGTCTCCTGATTCCACCTGGACACCAGTTCCTGATGAACGAGTTCCTAAGCCCAGGCCAGGT TGCTGTGCTGGCTCATCCTCCTTAGAAAGATATGCAACCTCCAATGAGTTCCCTGATGATACCCTGAACTTCA TCAAGACGCACCCGCTCATGGATGAGGCAGTGCCCTCCATCTTCAACAGGCCATGGTTCCTGAGAACAATGGT CAGATGCAGCTATGATGGAGTCGAAGACAAAAGGATCATGGGCATGCAGCTGGACAGAGCAAGCAGCTCTCTG TATGTTGCGTTCTCTACCTGTGTGATAAAGGTTCCCCTTGGCCGGTGTGAACGACATGGGAAGTGTAAAAAAA CCTGTATTGCCTCCAGAGACCCATATTGTGGATGGATAAAGGAAGGTAATGCCTGCAGCCATTTATCACCCAA CAGCAGACTGACTTTTGAGCAGGACATAGAGCGTGGCAATACAGATGGTCTGGGGGACTGTCACAATTCCTTT CTGGCACTGAATGGGCATTCCAGTTCCCTCTTGCCCACCACAACCACATCAGATTCGACGGCTCAAGAGGGGT ATGAGTCTAGGGGAGGAATGCTGGACTGGAAGCATCTGCTTGACTCACCTGACAGCACAGACCCTTTGGGGGC AGTGTCTTCCCATAATCACCAAGACAAGAAGGGAGTGATTCGGGAAAGTTACCTCAAAGGCCACGACCAGCTG GTTCCCGTCACCCTCTTGGCCATTGCAGTCATCCTGGCTTTCGTCATGGGGGCCGTCTTCTCGGGCATCACCG TCTACTGCGTCTGTGATCATCGGCGCAAAGACGTGGCTGTGGTGCAGCGCAAGGAGAAGGAGCTCACCCACTC GCGCCGGGGCTCCATGAGCAGCGTCACCAAGCTCAGCGGCCTCTTTGGGGACACTCAATCCAAAGACCCAAAG CCGGAGGCCATCCTCACGCCACTCATGCACAACGGCAAGCTCGCCACTCCCGGCAACACGGCCAAGATGCTCA TTAAAGCAGACCAGCACCACCTGGACCTGACGGCCCTCCCCACCCCAGAGTCAACCCCAACGCTGCAGCAGAA GCGGAAGCCCAGCCGCGGCAGCCGCGAGTGGGAGAGGAACCAGAACCTCATCAATGCCTGCACAAAGGACATG CCCCCCATGGGCTCCCCTGTGATTCCCACGGACCTGCCCCTGCGGGCCTCCCCCAGCCACATCCCCAGCGTGG TGGTCCTGCCCATCACGCAGCAGGGCTACCAGCATGAGTACGTGGACCAGCCCAAAATGAGCGAGGTAACCCA GATGGCGCTCGAGGACCAGGCCGCCACACTGGAGTATAAGACCATCAAGGAACATCTCAGCAGCAAGAGTCCC AACCATGGGGTGAACCTTGTGGAGAACCTGGACAGCCTGCCCCCCAAAGTTCCACAGCGGGAAACCTCCCTAA GTCCCCCGGGAGCCTCCCTGTCTCAGACCGGTCTAAGCAAGCGGCTGGAAATGCACCACTCCTCTTCCTACAA GGTTGACTATAAGAGGAGCTACCCCACGAACTCGCTCACGAGAAGCCACCAGGCCACCACTCTCAAAAGAAAC AACACTAACTCCTCCAATTCCTCTCACCTCTCCAGAAACCAGAGCTTTGGCAGGGGAGACAACCCGCCGCCCG CCCCGCAGAGGGTGGACTCCATCCAGGTGCACAGCTCCCAGCCATCTGGCCAGGCCGTGACTGTCTCGAAACA GCCCAGCCTCAACGCCTACAACTCACTGACAAGGTCGGGGCTGAAGCGTACGCCCTCGCTAAAGCCGGACGTA CCCCCCAAACCATCCTTTGCTCCCCTTTCCACATCCATGAAGCCCAATGATGCGTGTACATAATCCCAGAAGG AGGGGGTCAGGTGTCGAACCAGCAGGCAAGGCGAGGTGCCCGCTCAGCTCAGCAAGGTTCTCAACTGCCTCGA GTACCCACCAGACCAAGAAGGCCTGCGGCACAGCCGAGGACGCTGGGTCCTCCTCTCTGGGACACAGAAGTAC +E,usn TCACGAAAACTGGCCCGCGTGGTTTGGTGAAGGTTTCCAACGGCGGGGACTCACCTTCATTCTCTTCCTTCAC TTTCCCCCACACCCTACAACAGGTCGCACCCACAAAAGACTTCAGTTATCATCACAAACATGAGCCAAAACCA CATACCTACCCCATCCCCCACCCCCACACACACACACATGCACACAACACATACACACACACGCACAGAGGTG AACACAAACTGAAACATTTTGTCCACAACTTCACGGGACGTGGCCAGACTGGGTTTGCGTTCCAACCTGCAAA ACACAAATACATTTTTTAAAATCAAGAAAATTTAAAAAGACAAAAAAAAGAATTCATTCATAATTCTAACTCA GACTTTAACAATGGCAGAAGTTTACTATGCGCAAATACTGTGAAATGCCCGCCAGTGTTACAGCTTTCTGTTG CAGCAGATAAATGCCATGTTGGGCAGCTATGTCATAGATTTCTGCTCCTCCTCTCTTGTCATAGATTTCTGCT CCTCCTCTCTTGTCATAGATTTCTGCTCCTCCTCTCTTGTCATAGATTTCTGCTCCTCCTCTCTTGTCATAGA TTTCTGCTCCTCCTCTCTTGTCATAGATTTCTCCTCCTCCTCTCTTGTCATAGATTTCTOCTCCTCCTCTCTT GTCATAGATTTCTGCTCCTCCTCTCTTGTCATAGATTTCTG NOV2q, CG51896-09 Protein Sequence SEQ ID NO:46 971 aa MW at 107846.1 kD MRSEALLLYFTLLHFACAGFPEDSEPISISHGNYTKQYPVFVGHKPGRNTTQRHRLDIQMIMIMNGTLYIAAR DHIYTVDIDTSHTEEIYCSKKLTWKSRQADVDTCRNKGKHKDECHNFIKVLLKKNDDALFVCGTNAFNPSCRN YKDDTLEPFGDEFSGMARCPYDAKHANVALFADGKLYSATVTDFLAIDAVIYRSLGESPTLRTVKHDSKWLKE PYFVQAVDYGDYIYFFFREIAVEYNTMGKVVFPRVAQVCKNDMGGSQRVLEKRWTSFLKARLNCSVPGDSHFY FNILQAVTDVIRINGRDVVLATFSTPYNSIPGSAVCAYDMLDIASVFTGRFKEQKSPDSTWTPVPDERVPKPR PGCCAGSSSLERYATSNEFPDDTLNFTKTHPLMDEAVPSIFNRPWFLRTMVRCSYDGVEDKRIMGMQLDRASS SLYVAFSTCVIKVPLCRCERHGKCKKTCIASRDPYCGWIKEGGACSHLSPNSRLTFEQDIERGNTDGLGDCHN SFVALNGHSSSLLPSTTTSDSTAQEGYESRGGMLDWKHLLDSPDSTDPLGAVSSHNIQDKKGVIRESYLKGHD QLVPVTLLAIAVILAFVMGAVFSGITVYCVCDHRRKDVAVVQRKEKELTHSRRGSMSSVTKLSGLFGDTQSKD PKPEAILTPLMHNGKLATPGNTAKMLIKADQHILDLTALPTPESTPTLQQKRKPSRGSREWERNQNLINACTK DMPPMGSPVIPTDLPLRASPSHIPSVVVLPITQQGYQHEYVDQPKMSEVAQMALEDQAATLEYKTIKEHLSSK SPNHGVNLVENLDSLPPKVPQREASLGPPGASLSQTGLSKRLEMHHSSSYGVDYKRSYPTNSLTRSHQATTLK RNNTNSSNSSHLSRNQSFGRGDNPPPAPQRVDSIQVHSSQPSGQAVTVSRQPSLNAYNSLTRSGLKRTPSLKP DVPPKPSFAPLSTSMKPNDACT NOV2r, CG51896-10 SEQ ID NO:47 3165 bp DNA Sequence ORF Start: ATG at 13 ORF Stop: end of sequence CAGCGCGGATCCATGAGGTCAGAAGCCTTGCTGCTGTATTTCACACTGCTACACTTTGCTGGGGCTGGTTTCC CAGAAGATTCTGAGCCAATCAGTATTTCGCATGGCAACTATACAAAACAGTATCCGGTGTTTGTGGGCCACAA GCCAGGACGGAACACCACACAGAGGCACAGGCTGGACATCCAGATGATTATGATCATGAACGGAACCCTCTAC ATTGCTGCTAGGGACCATATTTATACTGTTGATATAGACACATCACACACGGAAGAAATTTATTGTAGCAAAA AACTGACATGGAAATCTAGACAGGCCGATGTAGACACATGCAGAATGAAGGGAAAACATAAGGATGAGTGCCA CAACTTTATTAAAGTTCTTCTAAAGAAAAACGATGATGCATTGTTTGTCTGTGGAACTAATGCCTTCAACCCT TCCTGCAGAAACTATAAGATGGATACATTGGAACCATTCGGGGATGAATTCAGCGGAATGGCCAGATGCCCAT ATGATGCCAAACATGCCAACGTTGCACTGTTTGCAGATGGAAAACTATACTCAGCCACAGTGACTGACTTCCT TGCCATTGACGCAGTCATTTACCGGAGTCTTGGAGAAAGCCCTACCCTGCGGACCGTCAAGCACGATTCAAAA TGGTTGAAAGAACCATACTTTGTTCAAGCCGTGGATTACGGAGATTATATCTACTTCTTCTTCAGGGAAATAG CAGTGGAGTATAACACCATGGGAAAGGTAGTTTTCCCAAGAGTGGCTCAGGTTTGTAAGAATGATATGGGAGG ATCTCAAAGAGTCCTGGAGAAACAGTGGACGTCGTTCCTGAAGGCGCGCTTGAACTGCTCAGTTCCTGGAGAC TCTCATTTTTATTTCAACATTCTCCAGCCAGTTACAGATGTGATTCGTATCAACGGGCGTGATGTTGTCCTGG CAACGTTTTCTACACCTTATAACAGCATCCCTGGGTCTGCAGTCTGTGCCTATGACATGCTTGACATTGCCAG TGTTTTTACTGGGAGATTCAAGGAACAGAAGTCTCCTGATTCCACCTGGACACCAGTTCCTGATGAACGAGTT CCTAAGCCCAGGCCAGGTTGCTGTGCTGGCTCATCCTCCTTAGAAAGATATGCAACCTCCAATGAGTTCCCTG ATGATACCCTGAACTTCATCAAGACGCACCCGCTCATGGATGAGGCAGTGCCCTCCATCTTCAACAGGCCATG GTTCCTGAGAACAATGGTCAGATACCGCCTTACCAAAATTGCAGTGGACACAGCTGCTGGGCCATATCAGAAT CACACTGTGGTTTTTCTGGGATCAGAGAAGGGAATCATCTTGAAGTTTTTGGCCAGAATAGGAAATAGTGGTT TTCTAAATGACAGCCTTTTCCTGGAGGAGATGAGTGTTTACAACTCTGAAAAATGCAGCTATGATGGAGTCGA AGACAAAACGATCATGGGCATGCAGCTGGACAGAGCAAGCAGCTCTCTGTATGTTGCGTTCTCTACCTGTGTG ATAAAGGTTCCCCTTGGCCGGTGTGAACGACATGGGAAGTGTAAAAAAACCTGTATTGCCTCCAGAGACCCGT ATTGTGGATGGATAAAGGAAGGTGGTGCCTGCAGCCATTTATCACCCAACAGCAGACTGACTTTTGAGCAGGA CATAGAGCGTGGCAATACAGATGGTCTGGGGGACTGTCACAATTCCTTTGTGGCACTGAATGACATTTCAACT CCTCTACCAGATAATGAAATGTCTTACAACACAGTGTATGGGCATTCCAGTTCCCTCTTGCCCAGCACAACCA CATCAGATTCGACGGCTCAAGAGGGGTATGAGTCTAGGGGAGGAATGCTGGACTGGAAGCATCTGCTTGACTC ACCTGACAGCACAGACCCTTTGGGGGCAGTGTCTTCCCATAATCACCAAGACAAGAACGGAGTGATTCGGGAA AGTTACCTCAAAGGCCACGACCAGCTGGTTCCCGTCACCCTCTTGGCCATTGCAGTCATCCTGGCTTTCGTCA TGGGGGCCGTCTTCTCGGGCATCACCGTCTACTGCGTCTGTGATCATCGGCGCAAAGACGTGGCTGTGGTGCA GCGCAAGGAGAAGGAGCTCACCCACTCCCGCCGGGGCTCCATGAGCAGCGTCACCAAGCTCAGCGGCCTCTTT GGGGACACTCAATCCAAAGACCCAAAGCCGGAGGCCATCCTCACGCCACTCATCCACAACGGCAAGCTCGCCA CTCCCGGCAACACGGCCAAGATGCTCATTAAAGCAGACCAGCACCACCTGGACCTGACGGCCCTCCCCACCCC AGAGTCAACCCCAACGCTGCAGCAGAAGCGGAAGCCCAGCCGCGGCAGCCGCGAGTGGGAGAGGAACCAGAAC CTCATCAATGCCTGCACAAAGGACATCCCCCCCATGGGCTCCCCTGTGATTCCCACGGACCTGCCCCTGCGGG CCTCCCCCAGCCACATCCCCAGCGTGGTGGTCCTGCCCATCACGCAGCAGGGCTACCAGCATGAGTACGTGCA CCAGCCCAAAATGAGCGAGGTGGCCCAGATGGCGCTGCAGGACCAGGCCGCCACACTGGAGTATAAGACCATC AAGGAACATCTCAGCAGCAAGAGTCCCAACCATGGGGTGAACCTTGTGGAGAACCTGGACAGCCTGCCCCCCA AAGTTCCACACCGGGAGGCCTCCCTGGGTCCCCCGGGAGCCTCCCTGTCTCAGACCGGTCTAAGCAAGCGGCT GGAAATGCACCACTCCTCTTCCTACGGGGTTGACTATAAGAGGAGCTACCCCACGAACTCGCTCACGAGAAGC CACCAGGCCACCACTCTCAAAAGAAACAACACTAACTCCTCCAATTCCTCTCACCTCTCCAGAAACCAGAGCT TTGGCAGGGGAGACAACCCGCCGCCCGCCCCGCAGAGGGTGGACTCCATCCAGGTGCACAGCTCCCAGCCATC TGGCCAGCCCGTGACTGTCTCGAGGCAGCCCAGCCTCAACGCCTACAACTCACTGACAAGGTCGGGGCTGAAG CGTACGCCCTCGCTAAAGCCGGACGTACCCCCCAAACCATCCTTTGCTCCCCTTTCCACATCCATGAAGCCCA ATGATGCGTGTACAGTCGACGCGCTG NOV2r, CG51896-10 Protein Sequence SEQ ID NO:48 1047 aa MW at 116308.5 kD MRSEALLLYFTLLHFAGAGFPEDSEPISISHGNYTKQYPVFVGHKPGRNTTQRHRLDIQMIMIMNGTLYIAAR DHIYTVDIDTSHTEEIYCSKKLTWKSRQADVDTCRNKGKHKDECHNFIKVLLKKNDDAIFVCGTNAFNPSCRN YKMDTLEPFGDEFSGMARCPYDAKHANVALFADGKLYSATVTDFLAIDAVIYRSLGESPTLRTVKHDSKWLKE PYFVQAVDYGDYIYFFFREIAVEYNTMGKVVFPRVAQVCKNDMGGSQRVLEKQWTSFLKARLNCSVPGDSHFY FNILQAVTDVIRINGRDVVLATFSTPYNSIPGSAVCAYDMLDIASVFTGRFKEQKSPDSTWTPVPDERVPKPR PGCCAGSSSLERYATSNEFPDDTLNFIKTHPLMDEAVPSIFNRPWFLRTMVRYRLTKIAVDTAAGPYQNHTVV FLGSEKGIILKFLARIGNSGFLMDSLFLEEMSVYNSEKCSYDGVEDKRIMGMQLDRASSSLYVAFSTCVIKVP LGRCERHGKCKKTCIASRDPYCGWIKEGGACSHLSPNSRLTFEQDIERGNTDGLGDCHNSFVALNDISTPLPD NEMSYNTVYGHSSSLLPSTTTSDSTAQEGYESRGGMLDWKHLLDSPDSTDPLGAVSSHNHQDKKGVIRESYLK GHDQLVPVTLLAIAVILAFVMGAVFSGITVYCVCDHRRKDVAVVQRKEKELTHSRRGSMSSVTKLSGLFGDTQ SKDPKPEAILTPLMHNGKLATPGNTAKMLIKADQHHLDLTALPTPESTPTLQQKRKPSRGSREWERNQNLINA CTKDMPPMGSPVIPTDLPLRASPSHIPSVVVLPITQQGYQHEYVDQPKMSEVAQMALEDQAATLEYKTIKEHL SSKSPNHGVNLVENLDSLPPKVPQREASLGPPGASLSQTGLSKRLEMHHSSSYGVDYKRSYPTNSLTRSHQAT TLKRNNTNSSNSSHLSRNQSFGRGDAAPPPAPQRVDSIQVHSSQPSCQAVTVSQPSLNAYNSLTRSGLKRTPS LKPDVPPKPSFAPLSTSMKPNDACT NOV2s, CG51896-1 SEQ ID NO:49 1948 bp DNA Sequence ORF Start: at 2 ORF Stop: end of sequence CACCGGATCCGGTTTCCCAGAAGATTCTGAGCCAATCAGTATTTCGCATGGCAACTATACAAAACAGTATCCG GTGTTTGTGGGCCACAAGCCAGGACGGAACACCACACAGAGGCACAGGCTGGACATCCAGATGATTATGATCA TGAACGGAACCCTCTACATTGCTGCTAGGGACCATATTTATACTGTTGATATAGACACATCACACACGGAAGA AATTTATTGTAGCAAAAAACTGACATGGAAATCTAGACAGGCCGATGTAGACACATGCAGAATGAAGGGAAAA CATAAGGATGAGTGCCACAACTTTATTAAAGTTCTTCTAAAGAAAAACGATGATGCATTGTTTGTCTGTGGAA CTAATCCCTTCAACCCTTCCTGCAGAAACTATAAGATGGATACATTGGAACCATTCGGGGATGAATTCAGCGG AATGGCCAGATGCCCATATGATGCCAAACATGCCAACGTTGCACTGTTTGCAGATGGAAAACTATACTCAGCC ACAGTGACTGACTTCCTTGCCATTGACGCAGTCATTTACCGGAGTCTTGGAGAAAGCCCTACCCTGCGGACCG TCAAGCACGATTCAAAATGGTTGAAAGAACCATACTTTGTTCAAGCCGTGGATTACGGAGATTATATCTACTT CTTCTTCAGGGAAATAGCAGTGCAGTATAACACCATGGGAAAGGTAGTTTTCCCAAGAGTGGCTCAGGTTTGT AAGAATGATATGGGAGGATCTCAAAGAGTCCTGGAGAAACAGTGGACGTCGTTCCTGAAGGCGCGCTTGAACT GCTCAGTTCCTGGAGACTCTCATTTTTATTTCAACATTCTCCAGGCAGTTACAGATGTGATTCGTATCAACGG GCGTGATGTTGTCCTGGCAACGTTTTCTACACCTTATAACAGCATCCCTGGGTCTGCAGTCTGTGCCTATGAC ATGCTTGACATTGCCAGTGTTTTTACTGGGAGATTCAAGGAACAGAAGTCTCCTGATTCCACCTGGACACCAG TTCCTGATGAACGAGTTCCTAAGCCCAGGCCAGGTTGCTGTGCTGGCTCATCCTCCTTAGAAAGATATGCAAC CTCCAATGAGTTCCCTGATGATACCCTGAACTTCATCAAGACGCACCCGCTCATGGATGAGGCAGTGCCCTCC ATCTTCAACAGGCCATGGTTCCTGAGAACAATGGTCAGATACCGCCTTACCAAAATTGCAGTGGACACAGCTG CTGGGCCATATCAGAATCACACTGTGGTTTTTCTGGGATCACAGAAGGGPATCATCTTGAAGTTTTTGGCCAG AATAGGAAATAGTGGTTTTCTAAATGACAGCCTTTTCCTGGAGGAGATGAGTGTTTACAACTCTGAAAAATGC AGCTATGATGGAGTCGAAGACAAAAGGATCATGGGCATGCAGCTGGACAGAGCAAGCAGCTCTCTGTATGTTG CGTTCTCTACCTGTGTGATAAACGTTCCCCTTGGCCGGTGTGAACGACATGGGAAGTGTAAAAAAACCTGTAT TGCCTCCAGAGACCCGTATTGTGGATGGATAAAGGAAGGTGGTGCCTGCAGCCATTTATCACCCAACAGCAGA CTGACTTTTGACCAGCACATAGAGCGTGGCAATACAGATGGTCTGGGGGACTGTCACAATTCCTTTGTGGCAC TGAATGACATTTCAACTCCTCTACCAGATAATGAAATGTCTTATAACACAGTGTATGGGCATTCCAGTTCCCT CTTGCCCAGCACAACCACATCAGATTCGACGGCTCAAGAGGGGTATGAGTCTAGGGGAGGAATGCTGGACTGG AAGCATCTGCTTGACTCACCTGACAGCACAGACCCTTTGGGGGCAGTGTCTTCCCACAATCACCAAGACAAGA AGGGAGTGATTCGGGAAAGTTACCTCAAAGGCCACGACCAGGTCGACGGC NOV2s, CG51896-11 Protein Sequence SEQ ID NO:50 649 aa MW at 72755.3 kD TGSGFPEDSEPISISHGNYTKQYPVFVGHKPGRNTTQRHRLDIQMIMIMNGTLYIAARDHIYTVDIDTSHTEE IYCSKKLTWKSRQADVDTCRMKGKHKDECHNFIKVLLKKNDDALFVCGTNAFNPSCRNYKMDTLEPFGDEFSG MARCPYDAKHAIWALFADGKLYSATVTDFLAIDAVIYRSLGESPTLRTVKHDSKWLKEPYFVQAVDYGDYIYF FFREIAVEYNTMGKVVFPRVAQVCKNDMGGSQRVLEKQWTSFLKARLNCSVPGDSHFYFNILQAVTDVIRING RDVVLATFSTPYNSIPGSAVCAYDMLDIASVFTGRFKEQKSPDSTWTPVPDERVPKPRPGCCAGSSSLERYAT SNEFPDDTLNFIKTHPLMDEAVPSIFNRPWFLRTMVRYRLTKIAVDTAAGPYQNHTVVFLGSEKGIILKFLAR IGNSGFLNDSLFLEEMSVYNSEKCSYDGVEDKRIMGMQLDRASSSLYVAFSTCVIKVPLGRCERHGKCKKTCI ASRDPYCGWIKEGGACSHLSPNSRLTFEQDIERGNTDGLGDCHNSFVALNDISTPLPDNEMSYNTVYGHSSSL LPSTTTSDSTAQEGYESRGGMLDWKHLLDSPDSTDPLGAVSSHNHQDKKGVIRESYLKGHDQVDG NOV2t, CG51896-12 SEQ ID NO:51 2583 bp DNA Sequence ORF Start: at 1 ORF Stop: end of sequence GACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCC CAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGA AGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAG GAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGG AGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCA GCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACC TGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACT ACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAG CAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAG AGCCTCTCCCTGTCTCCGGGTAAAGGCGGCGGCGGCGGCGGCGGCGGCGGTTTCCCAGAAGATTCTGAGCCAA TCAGTATTTCGCATGGCAACTATACAAAACAGTATCCGGTGTTTGTGGGCCACAAGCCAGGACGGAACACCAC ACAGAGGCACAGGCTGGACATCCAGATGATTATGATCATGAACGGAACCCTCTACATTGCTGCTAGGGACCAT ATTTATACTGTTGATATAGACACATCACACACGGAAGAAATTTATTGTAGCAAAAAACTGACATGGAAATCTA GACAGGCCGATGTAGACACATGCAGAATGAAGGGAAAACATAAGGATGAGTGCCACAACTTTATTAAAGTTCT TCTAAAGAAAAACGATGATGCATTGTTTGTCTGTGGAACTAATGCCTTCAACCCTTCCTGCAGAAACTATAAG ATGGATACATTGGAACCATTCGGGGATGAATTCAGCGGAATGGCCAGATGCCCATATGATGCCAAACATGCCA ACGTTGCACTGTTTGCAGATGGAAAACTATACTCAGCCACAGTGACTGACTTCCTTGCCATTGACGCAGTCAT TTACCGGAGTCTTGGAGAAAGCCCTACCCTGCGGACCGTCAAGCACGATTCAAAATGGTTGAAAGAACCATAC TTTGTTCAAGCCGTGGATTACGGAGATTATATCTACTTCTTCTTCAGGGAAATAGCAGTGGAGTATAACACCA TGGGAAAGGTAGTTTTCCCAAGAGTGGCTCAGGTTTGTAAGAATGATATGGGAGGATCTCAAAGAGTCCTGGA GAAACAGTGGACGTCGTTCCTGAAGGCGCGCTTGAACTGCTCAGTTCCTGGAGACTCTCATTTTTATTTCAAC ATTCTCCAGGCAGTTACAGATGTGATTCGTATCAACGGGCGTGATGTTGTCCTGGCAACGTTTTCTACACCTT ATAACAGCATCCCTGGGTCTGCAGTCTGTGCCTATGACATGCTTGACATTGCCAGTGTTTTTACTGGGAGATT CAAGGAACAGAAGTCTCCTGATTCCACCTGGACACCAGTTCCTGATGAACGAGTTCCTAAGCCCAGGCCAGGT TGCTGTGCTGGCTCATCCTCCTTAGAAAGATATGCAACCTCCAATGAGTTCCCTGATGATACCCTGAACTTCA TCAAGACGCACCCGCTCATGGATGAGGCAGTGCCCTCCATCTTCAACAGGCCATGGTTCCTGAGAACAATGGT CAGATACCGCCTTACCAAAATTGCAGTGGACACAGCTGCTGGGCCATATCAGAATCACACTGTGGTTTTTCTG GGATCAGAGAAGGGAATCATCTTGAAGTTTTTGGCCAGAATAGGAAATAGTGGTTTTCTAAATGACAGCCTTT TCCTGGAGGAGATGAGTGTTTACAACTCTGAAAAATGCAGCTATGATGGAGTCGAAGACAAAAGGATCATGGG CATGCACCTGGACAGAGCAAGCAGCTCTCTGTATGTTGCGTTCTCTACCTGTGTGATAAAGGTTCCCCTTGGC CGGTGTGAACGACATGGGAAGTGTAAAAAAACCTGTATTGCCTCCAGAGACCCATATTGTGGATGGATAAAGG AAGGTGGTGCCTGCAGCCATTTATCACCCAACAGCAGACTGACTTTTGAGCAGGACATAGAGCGTGGCAATAC AGATGGTCTGGGGGACTGTCACAATTCCTTTGTGGCACTGAATGGGCATTCCAGTTCCCTCTTGCCCAGCACA ACCACATCAGATTCGACGGCTCAAGAGGGGTATGAGTCTAGGGGAGGAATGCTGGACTGGAAGCATCTGCTTG ACTCACCTGACAGCACAGACCCTTTGGGGGCAGTGTCTTCCCATAATCACCAAGACAAGAAGGGAGTGATTCG GGAAAGTTACCTCAAAGGCCACGACCAG NOV2t, CG51896-12 Protein Sequence SEQ ID NO:52 861 aa MW at 96283.9 kD DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLT CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQK SLSLSPGKGGGGGGGGGFPEDSEPISISHGNYTKQYPVFVGHKPGRNTTQRHRLDIQMIMIMNGTLYIAARDH IYTVDIDTSHTEEIYCSKKLTWKSRQADVDTCRMKGKHKDECHNFIKVLLKKNDDALFVCGTNAFNPSCRNYK MDTLEPFGDEFSGMARCPYDAKHANVALFADGKLYSATVTDFLAIDAVIYRSLGESPTLRTVKHDSKWLKEPY FVQAVDYGDYIYFFFREIAVEYNTMGKVVFPRVAQVCKNDMGGSQRVLEKQWTSFLKARLNCSVPGDSHFYFN ILQAVTDVIRINGRDVVLATFSTPYNSIPGSAVCAYDMLDIASVFTGRFKEQKSPDSTWTPVPDERVPKPRPG CCAGSSSLERYATSNEFPDDTLNFIKTHPLMDEAVPSIFNRPWFLRTMVRYRLTKIAVDTAAGPYQNHTVVFL GSEKGIILKFLARIGNSGFLNDSLFLEEMSVYNSEKCSYDGVEDKRIMGMQLDRASSSLYVAFSTCVIKVPLG RCERHGKCKKTCIASRDPYCGWIKEGGACSHLSPNSRLTFEQDIERGNTDGLGDCHNSFVALNGHSSSLLPST TTSDSTAQEGYESRGGMLDWKHLLDSPDSTDPLGAVSSHNHQDKKGVIRESYLKGHDQ NOV2u, CG51896-13 SEQ ID NO:53 2634 bp DNA Sequence ORF Start: at 1 ORF Stop: end of sequence GACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCC CAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGA AGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAG GAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGG AGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCA GCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACC TGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACT ACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAG CAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAG AGCCTCTCCCTGTCTCCGGGTAAAGGCGGCGGCGGCGGCGGCGGCGGCGGTTTCCCAGAAGATTCTGAGCCAA TCAGTATTTCGCATGGCAACTATACAAAACAGTATCCGGTGTTTGTGGGCCACAAGCCAGGACGGAACACCAC ACAGAGGCACAGGCTGGACATCCAGATGATTATGATCATGAACGGAACCCTCTACATTGCTGCTAGGGACCAT ATTTATACTGTTGATATAGACACATCACACACGGAAGAAATTTATTGTAGCAAAAAACTGACATGGAAATCTA GACAGGCCGATGTAGACACATGCAGAATGAAGGGAAAACATAAGGATGAGTGCCACAACTTTATTAAAGTTCT TCTAAAGAAAAACGATGATGCATTGTTTGTCTGTGGAACTAATGCCTTCAACCCTTCCTGCAGAAACTATAAG ATGGATACATTGGAACCATTCGGGGATGAATTCAGCGGAATGGCCAGATGCCCATATGATGCCAAACATGCCA ACGTTGCACTGTTTGCAGATGGAAAACTATACTCAGCCACAGTGACTGACTTCCTTGCCATTGACGCAGTCAT TTACCGGAGTCTTGGAGAAAGCCCTACCCTGCGGACCGTCAAGCACGATTCAAAATGGTTGAAAGAACCATAC TTTGTTCAAGCCGTGGATTACGGAGATTATATCTACTTCTTCTTCAGGGAAATAGCAGTGGAGTATAACACCA TGGGAAAGGTAGTTTTCCCAAGAGTGGCTCAGGTTTGTAAGAATGATATGGGAGGATCTCAAAGAGTCCTGGA GAAACACTGGACGTCGTTCCTGAAGGCGCGCTTGAACTGCTCAGTTCCTGGAGACTCTCATTTTTATTTCAAC ATTCTCCAGGCAGTTACAGATGTGATTCGTATCAACGGGCGTGATGTTGTCCTGGCAACGTTTTCTACACCTT ATAACAGCATCCCTGGGTCTGCAGTCTGTGCCTATGACATCCTTGACATTGCCAGTGTTTTTACTGGGAGATT CAAGGAACAGAAGTCTCCTGATTCCACCTGGACACCAGTTCCTGATGAACGAGTTCCTAAGCCCAGGCCAGGT TGCTGTGCTGGCTCATCCTCCTTAGAAAGATATGCAACCTCCAATGAGTTCCCTGATGATACCCTGAACTTCA TCAAGACGCACCCGCTCATGGATGAGGCAGTGCCCTCCATCTTCAACAGGCCATGGTTCCTGAGAACAATGGT CAGATACCGCCTTACCAAAATTGCAGTGGACACAGCTGCTGOGCCATATCAGAATCACACTGTGGTTTTTCTG GGATCAGAGAAGGCAATCATCTTGAAGTTTTTGGCCAGAATAGGAAATAGTGGTTTTCTAAATGACAGCCTTT TCCTGGAGGAGATGAGTGTTTACAACTCTGAAAAATGCAGCTATGATGGAGTCGAAGACAAAAGGATCATGGG CATGCAGCTGGACAGAGCAAGCAGCTCTCTGTATGTTGCGTTCTCTACCTGTGTGATAAAGGTTCCCCTTGGC CGGTGTGAACGACATGGGAAGTGTAAAAAAACCTGTATTGCCTCCAGAGACCCGTATTGTGGATGGATAAAGC AAGGTGGTGCCTGCAGCCATTTATCACCCAACAGCAGACTGACTTTTGAGCAGGACATAGAGCGTGGCAATAC AGATGGTCTGGGGGACTGTCACAATTCCTTTGTCGCACTGAATGACATTTCAACTCCTCTACCAGATAATGAA ATGTCTTATAACACAGTGTATGGGCATTCCAGTTCCCTCTTGCCCAGCACAACCACATCAGATTCGACGGCTC AAGAGGGGTATGAGTCTAGGGGAGGAATGCTGGACTGGAAGCATCTGCTTGACTCACCTGACAGCACAGACCC TTTGGCGGCAGTGTCTTCCCACAATCACCAAGACAAGAAGGGAGTGATTCGGGAAAGTTACCTCAAAGGCCAC GACCAG NOV2u, CG51896-13 Protein Sequence SEQ ID NO:54 878 aa MW at 98225.0 kD DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLT CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQK SLSLSPGKGGGGGGGGGFPEDSEPISISHGNYTKQYPVFVGHKPGRNTTQRHRLDIQMIMIMNGTLYIAARDH IYTVDIDTSHTEEIYCSKKLTWKSRQADVDTCRMKGKHKDECHNFIKVLLKKNDDALFVCGTNAFNPSCRNYK MDTLEPFGDEFSGMARCPYDAKHANVALFADGKLYSATVTDFLAIDAVIYRSLGESPTLRTVKHDSKWLKEPY FVQAVDYGDYIYFFFREIAVEYNTMGKVVFPRVAQVCKNDMGGSQRVLEKQWTSFLKARLNCSVPGDSHFYFN ILQAVTDVIRINGRDVVLATFSTPYNSIPGSAVCAYDMLDIASVFTGRFKEQKSPDSTWTPVPDERVPKPRPG CCAGSSSLERYATSNEFPDDTLNFIKTHPLMDEAVPSIFNRPWFLRTMVRYRLTKIAVDTAAGPYQNHTVVFL GSEKGIILKFLARIGNSGFLNDSLFLEEMSVYNSEKCSYDGVEDKRIMGMQLDRASSSLYVAFSTCVIKVPLG RCERHGKCKKTCIASRDPYCGWIKEGGACSHLSPNSRLTFEQDIERGNTDGLGDCHNSFVALNDISTPLPDNE MSYNTVYGHSSSLLPSTTTSDSTAQEGYESRGGMLDWKHLLDSPDSTDPLCAVSSHNHQDKKGVIRESYLKGH DQ NOV2v, CG51896-14 SEQ ID NO:55 2113 bp DNA Sequence ORF Start: at 1 ORF Stop: end of sequence GCCACCATGGAGACAGACACACTCCTGCTATGGGTACTGCTGCTCTGGGTTCCAGGTTCCACTGGTGACGGTT TCCCAGAAGATTCTGAGCCAATCAGTATTTCGCATCGCAACTATACAAAACAGTATCCGGTGTTTGTGGGCCA CAAGCCAGGACGGAACACCACACAGAGGCACAGGCTGGACATCCAGATGATTATGATCATGAACGGAACCCTC TACATTGCTGCTAGGGACCATATTTATACTGTTGATATAGACACATCACACACGGAGGAAATTTATTGTAGCA AAAAACTGACATGGAAATCTAGACAGGCCGATGTAGACACATGCAGAATCAAGGGAAAACATAACGATGAGTG CCACAACTTTATTAAAGTTCTTCTAAAGAAAAACGATGATGCATTGTTTGTCTGTGGAACTAATGCCTTCAAC CCTTCCTGCAGAAACTATAAGATGGATACATTGGAACCATTCGGGGATGAATTCAGCGGAATGGCCAGATGCC CATATGATGCCAAACATGCCAACGTTGCACTGTTTGCAGATGGAAAACTATACTCAGCCACAGTGACTGACTT CCTTGCCATTGACGCAGTCATTTACCGGAGTCTTGGAGAAAGCCCTACCCTGCGGACCGTCAAGCACGATTCA AAATGGTTGAAAGAACCATACTTTGTTCAAGCCGTGGATTACGGAGATTATATCTACTTCTTCTTCAGGGAAA TTGCACTGGAGTATAACACCATGGGAAACGTAGTTTTCCCAAGAGTGGCTCACGTTTGTAAGAATGATATGGG AGGATCTCAAAGAGTCCTGGAGAAACAGTGGACGTCGTTCCTGAAGGCGCGCTTGAACTGCTCAGTTCCTGGA GACTCTCATTTTTATTTCAACATTCTCCAGGCAGTTACAGATGTGATTCGTATCAACGGGCGTGATGTTGTCC TGGCAACGTTTTCTACACCTTATAACAGCATCCCTGGGTCTGCAGTCTGTGCCTATGACATGCTTGACATTGC CAGTGTTTTTACTGGGAGATTCAAGGAACAGAAGTCTCCTGATTCCACCTGGACACCAGTTCCTGATGAACGA GTTCCTAAGCCCAGGCCAGGTTGCTGTGCTGGCTCATCCTCCTTAGAAAGATATGCAACCTCCAATGAGTTCC CTGATGATACCCTGAACTTCATCAAGACGCACCCGCTCATGGATCAGGCAGTGCCCTCCATCTTCAACAGGCC ATGGTTCCTGACAACAATGGTCAGATACCGCCTTACCAAAATTGCAGTGGACACAGCTGCTGGGCCATATCAG AATCACACTGTGGTTTTTCTGGGATCAGAGAAGGGAATCATCTTGAAGTTTTTGGCCAGAATAGGAAATAGTG GTTTTCTAAATGACAGCCTTTTCCTGGAGGAGATGAGTGTTTACAACTCTGAAAAATGCAGCTATGATGCAGT CGAAGACAAAAGGATCATGGGCATGCAGCTGGACAGAGCAAGCAGCTCTCTGTATGTTGCGTTCTCTACCTGT GTGATAAAGGTTCCCCTTGGCCGGTGTGAACGACATGGGAAGTGTAAAAAAACCTGTATTGCCTCCAGAGACC CGTATTGTGGATGGATAAAGGAAGGTGGTGCCTGCAGCCATTTATCACCCAACAGCAGACTGACTTTTGAGCA GGACATAGAGCGTGGCAATACAGATGGTCTGGGGGACTGTCACAATTCCTTTGTGGCACTGAATGACATTTCA ACTCCTCTACCAGATAATGAAATGTCTTACAACACAGTGTATGGGCATTCCAGTTCCCTCTTGCCCAGCACAA CCACATCAGATTCGACGGCTCAAGAGGGGTATGAGTCTAGGGGAGGAATGCTGGACTGGAAGCATCTGCTTGA CTCACCTCACAGCACAGACCCTTTCGGGGCAGTGTCTTCCCATAATCACCAAGACAAGAAGGGAGTGATTCGG GAAAGTTACCTCAAAGGCCACGACCAGTGACTCGAGGACTACAAGGATGACGATGACAAGGATTACAAAGACG ACGATGATAAGGACTATAAGGATCATGACGACAAATAATAGCAATTCCTCGACGCTGCATAGGGTTACA NOV2v, CG51896-14 Protein Sequence SEQ ID NO:56 666 aa MW at 74752.7 kD ATMETDTLLLWVLLLWVPGSTGDGFPEDSEPISISHGNYTKQYPVFVGHKPGRNTTQRHRLDIQMIMIMNGTL YIAARDHIYTVDIDTSHTEEIYCSKKLTWKSRQADVDTCRMKGKHKDECHNFIKVLLKKNDDALFVCGTNAFN PSCRNYKMDTLEPFGDEFSGMARCPYDAKHANVALFADGKLYSATVTDFLAIDAVIYRSLGESPTLRTVKHDS KWLKEPYFVQAVDYGDYIYFFFREIAVEYNTMGKVVFPRVAQVCKNDMGGSQRVLEKQWTSFLKARLNCSVPG DSHFYFNILQAVTDVIRINGRDVVLATFSTPYNSIPGSAVCAYDMLDIASVFTGRFKEQKSPDSTWTPVPDER VPKPRPGCCAGSSSLERYATSNEFPDDTLNFIKTHPLMDEAVPSIFNRPWFLRTMVRYRLTKIAVDTAAGPYQ NHTVVFLGSEKGIILKFLARIGNSGFLNDSLFLEEMSVYNSEKCSYDGVEDKRIMGMQLDRASSSLYVAFSTC VIKVPLGRCERHGKCKKTCIASRDPYCGWIKEGGACSHLSPNSRLTFEQDIERGNTDGLCDCHNSFVALNDIS TPLPDNEMSYNTVYGHSSSLLPSTTTSDSTAQEGYESRGGMLDWKHLLDSPDSTDPLGAVSSHNHQDKKGVIR ESYLKGHDQ

[0365] A ClustalW comparison of the above protein sequences yields the following sequence alignment shown in Table 2B. 9 TABLE 2B Comparison of the NOV2 protein sequences. NOV2a ------------------------------------------------------------ (SEQ ID NO: 14) NOV2b ------------------------------------------------------------ (SEQ ID NO: 16) NOV2c ------------------------------------------------------------ (SEQ ID NO: 18) NOV2d ------------------------------------------------------------ (SEQ ID NO: 20) NOV2e ------------------------------------------------------------ (SEQ ID NO: 22) NOV2f ------------------------------------------------------------ (SEQ ID NO: 24) NOV2g ------------------------------------------------------------ (SEQ ID NO: 26) NOV2h ------------------------------------------------------------ (SEQ ID NO: 28) NOV2i ------------------------------------------------------------ (SEQ ID NO: 30) NOV2j ------------------------------------------------------------ (SEQ ID NO: 32) NOV2k ------------------------------------------------------------ (SEQ ID NO: 34) NOV2l ------------------------------------------------------------ (SEQ ID NO: 36) NOV2m ------------------------------------------------------------ (SEQ ID NO: 38) NOV2n ------------------------------------------------------------ (SEQ ID NO: 40) NOV2o ------------------------------------------------------------ (SEQ ID NO: 42) NOV2p ------------------------------------------------------------ (SEQ ID NO: 44) NOV2q ------------------------------------------------------------ (SEQ ID NO: 46) NOV2r ------------------------------------------------------------ (SEQ ID NO: 48) NOV2s ------------------------------------------------------------ (SEQ ID NO: 50) NOV2t DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD (SEQ ID NO: 52) NOV2u DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVD (SEQ ID NO: 54) NOV2v ------------------------------------------------------------ (SEQ ID NO: 56) NOV2a ------------------------------------------------------------ NOV2b ------------------------------------------------------------ NOV2c ------------------------------------------------------------ MOV2d ------------------------------------------------------------ NOV2e ------------------------------------------------------------ NOV2f ------------------------------------------------------------ NOV2g ------------------------------------------------------------ NOV2h ------------------------------------------------------------ NOV2i ------------------------------------------------------------ NOV2j ------------------------------------------------------------ NOV2k ------------------------------------------------------------ NOV2l ------------------------------------------------------------ NOV2m ------------------------------------------------------------ NOV2n ------------------------------------------------------------ NOV2o ------------------------------------------------------------ NOV2p ------------------------------------------------------------ NOV2q ------------------------------------------------------------ NOV2r ------------------------------------------------------------ NOV2s ------------------------------------------------------------ NOV2t GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAK NOV2u GVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAK NOV2v ------------------------------------------------------------ NOV2a ------------------------------------------------------------ NOV2b ------------------------------------------------------------ NOV2c ------------------------------------------------------------ NOV2d ------------------------------------------------------------ NOV2e ------------------------------------------------------------ NOV2f ------------------------------------------------------------ NOV2g ------------------------------------------------------------ NOV2h ------------------------------------------------------------ NOV2i ------------------------------------------------------------ NOV2j ------------------------------------------------------------ NOV2k ------------------------------------------------------------ NOV2l ------------------------------------------------------------ NOV2m ------------------------------------------------------------ NOV2n ------------------------------------------------------------ NOV2o ------------------------------------------------------------ NOV2p ------------------------------------------------------------ NOV2q ------------------------------------------------------------ NOV2r ------------------------------------------------------------ NOV2s ------------------------------------------------------------ NOV2t GQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS NOV2u GQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDS NOV2v ------------------------------------------------------------ NOV2a ----------------------------------MRSEALLLYFTLLHFAG---AGFPED NOV2b ------------------------------------------------------------ NOV2c -------------------------------------------------TG---SGFPED NOV2d ------------------------------------------------------------ NOV2e ------------------------------------------------------------ NOV2f ------------------------------TGSMRSEAILLLYFTLLHFAG---AGFPED NOV2g -------------------------------------------------TG---SGFPED NOV2h -------------------------------------------------TG---SGFPED NOV2i -----------------------------TGSMRSEALLLYLAATLLHFAG---AGFPED NOV2j ----------------------------------MRSEALLLYFTLLHFAG---AGFPED NOV2k -------------------------------------------------------GFPED NOV2l -------------------------------------------------------GFPED NOV2m ------------------------------------------------------------ NOV2n ------------------------------------------------------------ NOV2o ------------------------------------------------------------ NOV2p ------------------------------------------------------------ NOV2q ----------------------------------MRSEALLLYFTLLHFAG---AGFPED NOV2r ----------------------------------MRSEALLLYFTLLHFAG---AGFPED NOV2s -------------------------------------------------TG---SGFPED NOV2t DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGGGGGGFPED NOV2u DGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGGGGGGFPED NOV2v --------------------------------ATMETDTLLLWVLLLWVPGSTGDGFPED NOV2a SEPISISHCNYTKQYPVFVGHKPGRNTTQRHRLDIQMIMIMNGTLYIAARDHIYTVDIDT NOV2b -AGSSISHCNYTKQYPVFVGHKPGRNTTQRHRLDIQMIMIMNGTLYIAARDHIYTVDIDT NOV2c SEPISISHGNYTKQYPVFVGHKPGRNTTQRHRLDIQMIMIMNGTLYIAARDHIYTVDIDT NOV2d -----------------------------TGSLDIQMIMIMNGTLYIAARDHIYTVDIDT NOV2e -----------------------------TGSLDIQMIMIMNGTLYIAARDHIYTVDIDT NOV2f SEPISISHGNYTKQYPVFVGNKPGRNTTQRHRLDIQMINIMNGTLYIAARDNIYTVDIDT NOV2g SEPISISHONYTKQYPVFVGHKPGRNTTQRHRLDIQMIMIMNGTLYIAARDHIYTVDIDT NOV2h SEPISISHGNYTKQYPVFVGNKPGRNTTQRHRLDIQMINIMNGTLYIAARDHIYTVDIDT NOV2i SEPISISHGNYTKQYPVFVGHKPGRNTTQRHRLDIQMIMIMNGTLYIAARDHIYTVDIDT NOV2j SEPISISHGNYTKQYPVFVGNKPGRNTTQRHRLDIQMIMIMNGTLYIAARDHIYTVDIDT NOV2k SEPISISHGNYTKQYPVFVGHKPGRNTTQRHRLDIQMIMIMNGTLYIAARDHIYTVDIDT NOV2l SEPISISHGNYTKQYPVFVGNKPGRNTTQRHRLDIQMIMIMNGTLYIAARDHIYTVDIDT NOV2m ------------------------------------------------------------ NOV2n ------------------------------------------------------------ NOV2o ------------------------------------------------------------ NOV2p ------------------------------------------------------------ NOV2q SEPISISHGNYTKQYPVFVGHKPGRNTTQRHRLDIQHIMIMNGTLYIAARDHIYTVDIDT NOV2r SEPISISHGNYTKQYPVFVGHKPGRNTTQRHRLDIQMIMIMNGTLYIAARDHIYTVDIDT NOV2s SEPISISHGNYTKQYPVFVGHKPGRNTTQRHRLDIQMIMIMNGTLYIAARDHIYTVDIDT NOV2t SEPISISHGNYTKQYPVFVGHKPGRNTTQRHRLDIQMIMIMNGTLYIAARDHIYTVDIDT NOV2u SEPISISHGNYTKQYPVFVGHKPGRNTTQRNRLDIQMIMINNGTLYIAARDHIYTVDIDT NOV2v SEPISISHGNYTKQYPVFVGHKPORNTTQRHRLDIQMIMIMNGTLYIAARDHIYTVDIDT NOV2a SHTEEIYCSKKLTWKSRQADVDTCRMKGKHKDECHNFIKVLLKKNDDALFVCGTNAFNPS NOV2b SHTEEIYCSKKLTWKSRQADVDTCRMKGKNKDECHNFIKVLLKKNDDAIFVCGTNAFNPS NOV2c SHTEEIYCSKKLTWKSRQADVDTCRMKGKNKDECHNFIKVLLKKNDDALFVCGTNAFNPS NOV2d SHTEEIYCSKKLTWKSRQADVDTCRMKGKNKDECHNFIKVLLKKNDDALFVCGTNAFNPS NOV2e SHTEEIYCSKKLTWKSRQADVDTCRMKGKNKDECHNFIKVLLKKNDDALFVCGTNAFNPS NOV2f SHTEEIYCSKKLTWKSRQADVDTCRMKGKHKDECHNFIKVLLKKNDDALFVCGTNAFNPS NOV2g SHTEEIYCSKKLTWKSRQADVDTCRMKOKHKDECHNFIKVLLKKNDDALFVCGTNAFNPS NOV2h SHTEEIYCSKKLTWKSRQADVDTCRMKGKHKDECHNFIKVLLKKNDDALFVCGTNAFNPS NOV2i SHTEEIYCSKKLTWKSRQADVDTCRMKGKHKDECHNFIKVLLKKNDDALFVCGTNAFNPS NOV2j SHTEEIYCSKKLTWKSRQADVDTCRMKGKHKDECHNFIKVLLKKNDDALFVCGTNAFNPS NOV2k SHTEEIYCSKKLTWKSRQADVDTCRMKGKHKDECMNFIKVLLKKNDDALFVCGTNAFNPS NOV2l SHTEEIYCSKKLTWKSRQADVDTCRMKGKHKDECHNFIKVLLKKNDDALFVCGTNAFNPS NOV2m ------------------------------------------------------------ NOV2n ------------------------------------------------------------ NOV2o ------------------------------------------------------------ NOV2p ------------------------------------------------------------ NOV2q SHTEEIYCSKKLTWKSRQADVDTCRMKGKMKDECHNFIKVLLKKNDDALFVCGTNAFNPS NOV2r SHTEEIYCSKKLTWKSRQADVDTCRMKGKHKDECHNFIKVLLKKNDDALFVCGTNAFNPS NOV2s SHTEEIYCSKKLTWKSRQADVDTCRNKGKHKDECHNFIKVLLKKNDDALFVCGTNAFNPS NOV2t SHTEEIYCSKKLTWKSRQADVDTCRMKGKHKDECHNFIKVLLKKNDDALFVCGTNAFNPS NOV2u SHTEEIYCSKKLTWKSRQADVDTCRNKGKHKDECHNFIKVLLKKNDDALFVCGTNAFNPS NOV2v SHTEEIYCSKKLTWKSRQADVDTCRNKGKHKDECHNFIKVLLKKNDDALFVCGTNAFNPS NOV2a CRNYKMDTLEPFGDEFSGMARCPYDAKNANVALFADOKLYSATVTDFLAIDAVIYRSLGE NOV2b CRNYKMDTLEPFGDEFSGMARCPYDAKHANVALFADGKLYSATVTDFLAIDAVIYRSLGE NOV2c CRNYKMDTLEPFGDEFSGMARCPYDAKHANVALFADGKLYSATVTDFLAIDAVIYRSLGE NOV2d CRNYKMDTLEPFGDEFSGMARCPYDAKHANVALFADGKLYSATVTDFLAIDAVIYRSLGE NOV2e CRNYKNDTLEPFGDEFSGMARCPYDAKHANVALFADGKLYSATVTDFLAIDAVIYRSLGE NOV2f CRNYKMDTLEPFGDEFSGMARCPYDAKHANVALFADGKLYSATVTDFLAIDAVIYRSLGE NOV2g CRNYKMDTLEPFGDEFSGMARCPYDAKHANVALFADGKLYSATVTDFLAIDAVIYRSLGE NOV2h CRNYKMDTLEPFGDEFSGMARCPYDAKHANVALFADGKLYSATVTDFLAIDAVIYRSLGE NOV2i CRNYKMDTLEPFGDEFSGMARCPYDAKHANVALFADGKLYSATVTDFLAIDAVIYRSLGE NOV2j CRNYKMDTLEPFGDEFSGMARCPYDAKHANVALFADGKLYSATVTDFLAIDAVIYRSLGE NOV2k CRNYKMDTLEPFGDEFSGMARCPYDAKNANVALFADGKLYSATVTDFLAIDAVIYRSLGE NOV2l CRNYKMDTLEPFGDEFSGMARCPYDAKHANVALFADGKLYSATVTDFLAIDAVIYRSLGE NOV2m ----------------------------------------------------------GE NOV2n ----------------------------------------------------------GE NOV2o ------------------------------------------------------------ NOV2p ------------------------------------------------------------ NOV2q CRNYKMDTLEPFGDEFSGMARCPYDAKHANVALFADGKLYSATVTDFLAIDAVIYRSLGE NOV2r CRNYKMDTLEPFGDEFSCMARCPYDAKHANVALFADGKLYSATVTDFLAIDAVIYRSLGE NOV2s CRNYKMDTLEPFGDEFSGMARCPYDAKHANVALFADGKLYSATVTDFLAIDAVIYRSLGE NOV2t CRNYKMDTLEPFGDEFSGMARCPYDAKHANVALFADGKLYSATVTDFLAIDAVIYRSLGE NOV2u CRNYKMDTLEPFGDEFSGMARCPYDAKHANVALFADGKLYSATVTDFLAIDAVIYRSLGE NOV2v CRNYAADTLEPFGDEFSGMARCPYDAAAANVALFADGKLYSATAADFAAIDAVIYRSLGE NOV2a SPTLRTVKHDSKWLKEPYFVQAVDYGDYIYFFFREIAVEYNTMGKVVFPRVAQVCKNDMG NOV2b SPTLRTVKHDSKWLKEPYFVQAVDYGDYIYFFFREIAVEYNTMGKVVFPRVAQVCAADMG NOV2c SPTLRTVKHDSKWLKEPYFVQAVDYGDYIYFFFREIAVEYNTMGKVVFPRVAQVCAADMG NOV2d SPTLRTVKHDSKWLKEPYFVQAVDYGDYIYFFFREIAVEYNTMGKVVFPRVAQVCKNDMG NOV2e SPTLRTVKHDSKWLKEPYFVQAVDYGDYIYFFFREIAVEYNTMGKVVFPRVAQVCAADMG NOV2f SPTLRTVKHDSKWLKEPYFVQAVDYGDYIYFFFREIAVEYNTMGKVVFPRVAQVCKNDMG NOV2g SPTLRTVKHDSKWLKEPYFVQAVDYGDYIYFFFREIAVEYNTMGKVVFPRVAQVCKNDMG NOV2h SPTLRTVKHDSKWLKEPYFVQAVDYGDYIYFFFREIAVEYNTMGKVVFPRVAQVCAADMG NOV2i SPTLRTVAADSKWLKEPYFVQAVDYGDYIYFFFREIAVEYAAMGKVVFPRVAQVCAADMG NOV2j SPTLRTVKNDSKWLKEPYFVQAVDYGDYIYFFFREIAVEYNTMCKVVFPRVAQVCAADMG NOV2k SPTLRTVKHDSKWLKEPYFVQAVDYGDYIYFFFREIAVEYNTMCKVVFPRVAQVCAADMG NOV2l SPTLRTVKHDSKWLKEPYFVQAVDYGDYIYFFFREIAVEYNTMCKVVFPRVAQVCAADMG NOV2m SPTLRTVKHDSKWLKE-------------------------------------------- NOV2n SPTLRTVKHDSKWLKE-------------------------------------------- NOV2o ------------------------------------------------------------ NOV2p ------------------------------------------------------------ NOV2q SPTLRTVKHDSKWLKEPYFVQAVDYGDYIYFFFREIAVEYNTMGKVVFPRVAQVCKNDMG NOV2r SPTLRTVKHDSKWLKEPYFVQAVDYODYIYFFFREIAVEYNTMGKVVFPRVAQVCKNDMG NOV2s SPTLRTVKHDSKWLKEPYFVQAVDYGDYIYFFFREIAVEYNTMGKVVFPRVAQVCAADMG NOV2t SPTLRTVKHDSKWLKEPYFVQAVDYGDYIYFFFREIAVEYNTMGKVVFPRVAQVCAADMG NOV2u SPTLRTVKHDSKWLKEPYFVQAVDYGDYIYFFFREIAVEYNTMGKVVFPRVAQVCAADMG NOV2v SPTLRTVKHDSKWLKEPYFVQAVDYGDYIYFFFREIAVEYNTMGKVVFPRVAOVCAADMG NOV2a GSQRVLEKQWTSFLKARLNCSVPGDSHFYFNILQAVTDVIRINGRDVVLATFSTPYNSIP NOV2b GSQRVLEKQWTSFLKARLNCSVPGDSNFYFNILQAVTDVIRINGRDVVLATFSTPAASIP NOV2c GSQRVLEKQWTSFLKARLNCSVPGDSHFYFNILQAVTDVIRINGAAAAAATFSTPAASIP NOV2d GSQRVLEKQWTSFLKARLNCSVPGDSHFYFNILQAVTDVIRINGRDVVLATFSTPAASIP NOV2e GSQRVLEKQWTSFLKARLNCSVPGDSHFYFNILQAVTDVIRINGRDVVLATFSTPAASIP NOV2f GSQRVLEKQWTSFLKARLNCSVPGDSHFYFNILQAVTDVIRINGRDVVLATFSTPAASIP NOV2g GSQRVLEKQWTSFLKARLNCSVPGDSHFYFNILQAVTDVIRINGRDVVLATFSTPAASIP NOV2h GSQRVLEKQWTSFLKARLNCSVPGDSHFYFNILQAVTDVIRINCRDVVLATFSTPAASIP NOV2i GSQRVLEKQWTSFLKARLNCSVPGDSHFYFNILQAVTDVIRINCRDVVLATFSTPAASIP NOV2j GSQRVLEKQWTSFLKARLNCSVPGDSHFYFNILQAVTDVIRINGRDVVLATFSTPAASIP NOV2k GSQRVLEKQWTSFLKARLNCSVPGDSHFYFNILQAVTDVIRINGRDVVLATFSTPAASIP NOV2l GSQRVLEKQWTSFLKARLNCSVPGDSHFYFNILQAVTDVIRINGRDVVLATFSTPAASIP NOV2m ------------------------------------------------------------ NOV2n ------------------------------------------------------------ NOV2o ------------------------------------------------------------ NOV2p ------------------------------------------------------------ NOV2q GSQRVLEKRWTSFLKARLNCSVPGDSHFYFNILQAVTDVIRINGRDAALATFSTPYNSIP NOV2r GSQRVLEKRWTSFLKARLNCSVPGDSHFYFNILQAVTDVIRINGRDAALATFSTPYNSIP NOV2s GSQRVLEKQWTSFLKARLNCSVPGDSHFYFNILQAVTDVIRINGRDVAAATFSTPYNSIP NOV2t GSQRVLEKQWTSFLKARLNCSVPGDSHFYFNILQAVTDVIRINGRDVAAATFSTPYNSIP NOV2u GSQRVLEKQWTSFLKARLNCSVPGDSHFYFNILQAVTDVIRINGRDVAAATFSTPAASIP NOV2v GSQRVLEKQWTSFLKARLNCSVPGDSHFYFNILQAVTDVIRINGRDVAAATFSTPYNSIP NOV2a GSAVCAYDMLDIASVFTGRFKEQKSPDSTWTPVPDERVPKPRPGCCAGSSSLERYATSNE NOV2b GSAVCAYDMLDIASVFTGRFKEQKSPDSTWTPVPDERVPKPRPGCCAGSSSLERYATSNE NOV2c GSAVCAYDMLDIASVFTGRFKEQKSPDSTWTPVPDERVPKPRPGCCAGSSSLERYATSNE NOV2d GSAVCAYDMLDIASVFTGRFKEQKSPDSTWTPVPDERVPKPRPGCCAGSSSLERYATSNE NOV2e GSAVCAYDMLDIASVFTGRFKEQKSPDSTWTPVPDERVPRPRPGCCAGSSSLERYATSNE NOV2f GSAVCAYDMLDTASVFTGRFKEQKSPDSTWTPVPDERVPKPRPGCCAGSSSLERYATSNE NOV2g GSAVCAYDMLDIASVFTGRFKEQKSPDSTWTPVPDERVPKPRPGCCAGSSSLERYATSNE NOV2h GSAVCAYDMLDIASVFTGRFKEQKSPDSTWTPVPDERVPKPRPGCCAGSSSLERYATSNE NOV2i GSAVCAYDMLDIASVFTGRFKEQKSPDSTWTPVPDERVPKPRPGCCAGSSSLERYATSNE NOV2j GSAVCAYDMLDIASVFTGRFKEQKSPDSTWTPVPDERVPKPRPOCCAGSSSLERYATSNE NOV2k GSAVCAYDMLDIASVFTGRFKEQKSPDSTWTPVPDERVPKPRPGCCAGSSSLERYATSNE NOV2l GSAVCAYDMLDIASVFTGRFKEQKSPDSTWTPVPDERVPKPRPGCCAGSSSLERYATSNE NOV2m ------------------------------------------------------------ NOV2n ------------------------------------------------------------ NOV2o ------------------------------------------------SSSLERYATSNE NOV2p ------------------------------------------------------------ NOV2q GSAVCAYDMLDIASVFTGRFKEQKSPDSTWTPVPDERVPKPRPCCCACSSSLERYATSNE NOV2r GSAVCAYDMLDIASVFTGRFKEQKSPDSTWTPVPDERVPKPRPGCCAGSSSLERYATSNE NOV2s GSAVCAYDMLDIASVFTGRFKEQKSPDSTWTPVPDERVPKPRPGCCAGSSSLERYATSNE NOV2t GSAVCAYDMLDIASVFTGRFKEQKSPDSTWTPVPDERVPKPRPGCCAGSSSLERYATSNE NOV2u GSAVCAYDMLDIASVFTGRFKEQKSPDSTWTPVPDERVPKPRPGCCAGSSSLERYATSNE NOV2v GSAVCAYDMLDIASVFTGRFKEQKSPDSTWTPVPDERVPKPRPGCCACSSSLERYATSNE NOV2a FPDDTLNFIKTNPLMDEAVPSIFNRPWFLRTMVRYRLTKIAVDTAAGPYQNHTVVFLGSE NOV2b FPDDTLNFIKTHPLMDEAVPSIFNRPWFLRTMVRYRLTKIAVDTAAGPYQNHTVVFLGSE NOV2c FPDDTLNFIKTHPLMDEAVPSIFNRPWFLRTMVRYRLTKIAVDTAAGPYQNHTVVFLGSE NOV2d FPDDTLNFIKTHTPLMDAVPSIFNRPWFLRTMVRYRLTKIAVDTAAGPYQNHTVVFLGSE NOV2e FPDDTLNFIKTHPLMDEAVPSIFNRPWFLRTMVRYRLTKIAVDTAAGPYQNHTVVFLGSE NOV2f FPDDTLNFIKTHPLMDEAVPSIFNRPWFLRTMVRYRLTKIAVDTAAGPYQNHTVVFLGSE NOV2g FPDDTLNFIKTHPLMDEAVPSIFNRPWFLRTMVRYRLTKIAVDTAAGPYQNHTVVFLCSE NOV2h FPDDTLNFIKTHPLMDEAVPSIFNRPWFLRTMVRYRLTKIAVDTAAGPYQNHTVVFLGSE NOV2i FPDDTLNFIKTHPLMDEAVPSIFNRPWFLRTNVRYRLTKIAVDTAAGPYQNHTVVFLGSE NOV2j FPDDTLNFIKThPLMDEAVPSIFNRPWFLRTMVRYRLTKIAVDTAAGPYQNHTVVFLGSE NOV2k FPDDTLNFIKTHPLMDEAVPSIFNRPWFLRTMVRYRLTKIAVDTAAGPYQNHTVVFLGSE NOV2l FPDDTLNFIKTHPLMDEAVPSIFNRPWFLRTMVR-------------------------- NOV2m ------------------------------------------------------------ NOV2n ------------------------------------------------------------ NOV2o FPDDT------------------------------------------------------- NOV2p ------------------------------------------------------------ NOV2q FPDDTLNFIKTHPLMDEAVPSIFNRPWFLRTMVR-------------------------- NOV2r FPDDTLNFIKTHPLMDEAVPSIFNRPWFLRTMVRYRLTKIAVDTAAGPYQNHTVVFLGSE NOV2s FPDDTLNFIKTHPLMDEAVPSIFNRPWFLRTMVRYRLTKIAVDTAAGPYQNHTVVFLGSE NOV2t FPDDTLNFIKTHPLMDEAVPSIFNRPWFLRTMVRYRLTKIAVDTAAGPYQNHTVVFLGSE NOV2u FPDDTLNFIKTHPLMDEAVPSIFNRPWFLRTMVRYRLTKIAVDTAAGPYQNHTVVFLGSE NOV2v FPDDTLNFIKTHPLMDEAVPSIFNRPWFLRTMVRYRLTKIAVDTAAGPYQNHTVVFLGSE NOV2a KGIILKFLARIGNSGFLNDSLFLEEMSVYNSEKCSYDGVEDKRIMGMQLDRASSSLYVAF NOV2b KGIILKFLARIGNSGFLNDSLFLEEMSVYNSEKCSYDGVEDKRIMGMQLDRASSSLYVAF NOV2c KGIILKFLARIGNSGFLNDSLFLEEMSVYNSEKCSYDGVEDKRIMGMQLDRASSSLYVAF NOV2d KGIILKFLARIGNSGFLNDSLFLEEMSVYNSEKCSYDGVEDKRIMGMQLDRASSSLYVAF NOV2e KGIILKFLARIGNSGFLNDSLFLEEMSVYNSEKCSYDGVEDKRIMGMQVDG--------- NOV2f KGIILKFLARIGNSGFLNDSLFLEEMSVYNSEKCSYDGVEDKRIMGMQVDG--------- NOV2g KGIILKFLARIGNSGFLNDSLFLEEMSVYNSEKCSYDGVEDKRIMGMQVDG--------- NOV2h KGIILKFLARIGNSGFLNDSLFLEEMSVYNSEKCSYDGVEDKRIMGMQLDRASSSLYVAF NOV2i KGIILKFLARIGNSGFLNDSLFLEEMSVYNSEKCSYDGVEDKRIMGMQLDRASSSLYVAF NOV2j KGIILKFLARIGNSGFLNDSLFLEEMSVYNSEKCSYDGVEDKRIMGMQLDRASSSLYVAF NOV2k KGIILKFLARIGNSGFLNDSLFLEEMSVYNSEKCSYDGVEDKRIMGMQLDRASSSLYVAF NOV2l ---------------------------------CSYDGVEDKRIMGMQLDRASSSLYVAF NOV2m ------------------------------------------------------------ NOV2n ------------------------------------------------------------ NOV2o ------------------------------------------------------------ NOV2p -----------------------EEMSVYNSEKCSYDGVEDKR----------------- NOV2q ---------------------------------CSYDGVEDKRIMGMQLDRASSSLYVAF NOV2r KGIILKFLARIGNSGFLNDSLFLEEMSVYNSEKCSYDGVEDKRIMGMQLDRASSSLYVAF NOV2s KGIILKFLARIGNSGFLNDSLFLEEMSYNSEKCSYDGVEDKRIMGMQLDRAASSSLAAAF NOV2t KGIILKFLARIGNSGFLNDSLFLEEMSVYNSEKCSYDGVEDKRIMGMQLDRASSSLYVAF NOV2u KGIILKFLARIGNSGFLNDSLFLEEMSVYNSEKCSYDGVEDKRIMGMQLDAASSSLAAAF NOV2v KGIILKFLARIGNSGFLNDSLFLEEMSVYNSEKCSYDGVEDKRIMGMQLDRASSSLAAAF NOV2a STCVIKVPLGRCERHGKCKKTCIASRDPYCGWIKEGGACSHLSPNSAATFEQDIERGNTD NOV2b STCVIKVPLGRCERHGKCKKTCIASRDPYCGWIKEGGACSHLSPNSRLTFEQDIERGNTD NOV2c STCVIKVPLGRCERHGKCKKTCIASRDPYCGWIKEGGACSHLSPNSRLTFEQDIERGNTD NOV2d STCVIKVPLGRCERMGKCKKTCIASRDPYCGWIKEGGACSHLSPNSRLTFEQDIERCAAD NOV2e ------------------------------------------------------------ NOV2f ------------------------------------------------------------ NOV2g ------------------------------------------------------------ NOV2h STCVIKVPLGRCERHGKCKKTCIASRDPYCGWIKEGOACSHLSPNSRLTFEQDIERGNTD NOV2i STCVIKVPLGRCERHGKCKKTCIASRDPYCOWIKEGGACSHLSPNSRLTFEQDIERGNTD NOV2j STCVIKVPLGRCERHGKCKKTCIASRDPYCGWIKEGGACSHLSPNSRLTFEQDIERGNTD NOV2k STCVIKVPLGRCERHGKCKKTCIASRDPYCGWIKEGGACSHLSPNSRLTFEQDIERGNTD NOV2l STCVIKVPLGRCERHGKCKKTCIASRDPYCGWIKEGGACSHLSPNSRLTFEQDIERGNTD NOV2m ------------------------------------------------------------ NOV2n ------------------------------------------------------------ NOV2o ------------------------------------------------------------ NOV2p ------------------------------------------------------------ NOV2q STCVIKVPLGRCERHGKCKKTCIASRDPYCGWIKEGGACSHLSPNSRLTFEQDIERGAAD NOV2r STCVIKVPLGRCERHGKCKKTCIASRDPYCGWIKEGGACSHLSPNSRLTFEQDIERGNTD NOV2s STCVIKVPLGRCERNGKCKKTCIASRDPYCGWIKEGGACSHLSPNSRLTFEQDIERCNTD NOV2t STCVIKVPLGRCERHGKCKKTCIASRDPYCGWIKEGGACSHLSPNSRLTFEQDIERGNTD NOV2u STCVIKVPLGRCERHGKCKKTCIASRDPYCCWIKEGGACSHLSPNSRLTFEQDIERGNTD NOV2v STCVIKVPLGRCERHGKCKKTCIASRDPYCGWIKEGGACSHLSPNSRLTFEQDIERGNTD NOV2a GLGDCHNSFVALNDISTPLPDNEMSYNTVYGHSSSLLPSTTTSDSTAQEGYESRGGMLDW NOV2b GLGDCHNSFVALNDISTPLPDNEMSYNTVYGHSSSLLPSTTTSDSTAQEGYESRGGMLDW NOV2c GLGDCHNSFVALNDISTPLPDNEMSYNTVYGHSSSLLPSTTTSDSTAQEGYESRGGMLDW NOV2d GLGDCHNSFVALNDISTPLPDNEMSYNTVYGHSSSLLPSTTTSDSTAQEGYESRGOMLDW NOV2e ------------------------------------------------------------ NOV2f ------------------------------------------------------------ NOV2q ------------------------------------------------------------ NOV2h GLGDCHNSFVALN-----------------GHSSSLLPSTTTSDSTAQEGYESRGGMLDW NOV2i GLGDCHNSFVALN----------------------------------------------- NOV2j GLGDCHNSFVALNG-----------------HSSSLLPSTTTSDSTAQEGYESRGGMLDW NOV2k GLCDCHNSFVALN-----------------GNSSSLLPSTTTSDSTAQEGYESRGGMLDW NOV2l GLGDCHNSFVALN-----------------GHSSSLLPSTTTSDSTAQEGYESRGGMLDW NOV2m ------------------------------------------------------------ NOV2n ------------------------------------------------------------ NOV2o ------------------------------------------------------------ NOV2p ------------------------------------------------------------ NOV2q GLGDCHNSFVALN-----------------CHSSSLLPSTTTSDSTAQEGYESRGGMLDW NOV2r GLGDCHNSFVALNDISTPLPDNEMSYNTVYGHSSSLLPSTTTSDSTAQEGYESRGGMLDW NOV2s GLGDCHNSFVALNDISTPLPDNEMSYNTVYGHSSSLLPSTTTSDSTAQEGYESRGGMLDW NOV2t GLGDCHNSFVALN-----------------GHSSSLLPSTTTSDSTAQEGYESRGGMLDW NOV2u GLGDCHNSFVALNDISTPLPDNEMSYNTVYGHSSSLLPSTTTSDSTAQEGYESRGGMLDW NOV2v GLGDCHNSFVALNDISTPLPDNEMSYNTVYGHSSSLLPSTTTSDSTAQEGYESRGGAADW NOV2a KHLLDSPDSTDPLGAVSSHNHQDKKGVIRESYLKGHDQLVPVTLLAIAVILAFVMGAVFS NOV2b KHLLDSPDSTDPLGAVSSMNHQDKKGVIRESYLKGHDQVDG------------------- NOV2c KHLLDSPDSTDPLGAVSSHNHQDKKGVIRESYLKGHDQLVPVTLLAIAVILAFVMGAVFS NOV2d KHLLDSPDSTDPLGAVSSHNHQDKKGVIRESYLKGHDQLVPAALLAIAVILAFAAGAVFS NOV2e ------------------------------------------------------------ NOV2f ------------------------------------------------------------ NOV2g ------------------------------------------------------------ NOV2h KHLLDSPDSTDPLGAVSSHNHQDKKGVIRESYLKGHDQLVPVTLLAIAVILAFAAGAVFS NOV2i -------------------------GVIRESYLKGHDQLVPVTLLAIAVILAFVMGAVFS NOV2j KHLLDSPDSTDPLGAVSSHNHQDKKGVIRESYLKGHDQLVPVTLLAIAVILAFVMGAVFS NOV2k KHNLLDSPDSTDPLGAVSSHNHQDKKGVIRESYLKGHDQ--------------------- NOV2l KHNLLDSPDSTDPLGAVSSHNHQDKKGVIRESYLKGHDQLVPVTLLMAVILAFVMGAVFS NOV2m ------------------------------------------------------------ NOV2n ------------------------------------------------------------ NOV2o ------------------------------------------------------------ NOV2p ------------------------------------------------------------ NOV2q KHLLDSPDSTDPLGAVSSHNHQDKKGVIRESYLKGHDQLVPVTLLAIAVILAFVMGAVFS NOV2r KHLLDSPDSTDPLGAVSSHNHQDKKGVIRESYLKGHDQLVPVTLLAIAVILAFVMGAVFS NOV2s KHLLDSPDSTDPLGAVSSNNHQDKKGVIRESYLKGHDQVDG------------------- NOV2t KHLLDSPDSTDPLGAVSSHNHQDKKGVIRESYLKGHDQ---------------------- NOV2u KHLLDSPDSTDPLGAVSSMNHQDKKGVIRESYLKGHDQ---------------------- NOV2v KHLLDSPDSTDPLGAVSSHNHQDKKGVIRESYLKGHDQ---------------------- NOV2a GITVYCVCDHRRKDVAVVQRKEKELTHSRRGSMSSVTKLSGLFGDTQSKDPKPEAILTPL NOV2b ------------------------------------------------------------ NOV2c GITVYCVCDNRRKDVAVVQRKEKELTHSRRGSMSSVTKLSGLFGDTQSKDPKPEAILTPL NOV2d GITVYCVCDHRRKDVAVVQRKEKELTHSRROSMSSVTKLSGLFGDTQSKDPKPEAILTPL NOV2e ------------------------------------------------------------ NOV2f ------------------------------------------------------------ NOV2g ------------------------------------------------------------ NOV2h GITVYCVCDHRRKDVAVVQRKEKELTHSRRGSMSSVTKLSGLFGDTQSKDPKPEAILTPL NOV2i GITVYCVCDHRRKDVAVVQRKEKELTHSRRGSMSSVTKLSGLFGDTOSKDPKPEAILTPL NOV2j GITVYCVCDHRRKDVAVVQRKEKELTHSRRGSMSSVTKLSGLFGDTQSKDPKPEAILTPL NOV2k ------------------------------------------------------------ NOV2l GITVYCVCDHRRKDVAVVQRKEKELTHSRRGSMSSVTKLSGLFGDTQ------------- NOV2m ------------------------------------------------------------ NOV2n ------------------------------------------------------------ NOV2o ------------------------------------------------------------ NOV2p ------------------------------------------------------------ NOV2q GITVYCVCDHRRKDVAVVQRKEKELTHSRRGSMSSVTKLSGLFGDTQSKDPKPEAILTPL NOV2r GITVYCVCDHRRKDVAVVQRKEKELTHSRRGSMSSVTKLSGLFGDTQSKDPKPEAILTPL NOV2s ------------------------------------------------------------ NOV2t ------------------------------------------------------------ NOV2u ------------------------------------------------------------ NOV2v ------------------------------------------------------------ NOV2a MHNGKLATPGNTAKNLIKADQHHLDLTALPTPESTPTLQQKRKPSRGSREWERNQNLINA NOV2b ------------------------------------------------------------ NOV2c MHNGKLATPGNTAKMLIKADQHNLDLTALPTPESTPTLQQKRKPSRGSREWERNQNLINA NOV2d MHNGKLATPGNTAKMLTKADQHHLDLTALPTPESTPTLQQKRKPSRGSREWERNQNLINA NOV2e ------------------------------------------------------------ NOV2f ------------------------------------------------------------ NOV2g ------------------------------------------------------------ NOV2h MHNGKLATPGNTAKMLIKADQHHLDLTALPTPESTPTLQQKRKPSRGSREWERNQNLINA NOV2i MHNGKLATPGNTAKMLIKADQHHLDLTALPTPESTPTLQQKRKPSRGSREWERNQNLINA NOV2j MHNGKLATPGNTAKMLIKADQHHLDLTALPTPESTPTLQQKREPSRGTREWERNQNLINA NOV2k ------------------------------------------------------------ NOV2l ------------------------------------------------------------ NOV2m ------------------------------------------------------------ NOV2n ------------------------------------------------------------ NOV2o ------------------------------------------------------------ NOV2p ------------------------------------------------------------ NOV2q MHNGKLATPGNTAKMLIKADQHHLDLTALPTPESTPTLQQKRKPSRGSREWERNQNLINA NOV2r MHNGKLATPGNTAKMLIKADQHNLDLTALPTPESTPTLQQKRKPSRGSREWERNQNLINA NOV2s ------------------------------------------------------------ NOV2t ------------------------------------------------------------ NOV2u ------------------------------------------------------------ NQV2v ------------------------------------------------------------ NOV2a CTKDMPPMCSPVIPTDLPLRASPSHIPSVVVLPITQQGYQHEYVDQPKMSEVAQMALEDQ NOV2b ------------------------------------------------------------ NOV2c CTKDMPPMGSPVIPTDLPLRASPSHIPSVVVLPITQQGYQHEYVDQPKMSEVAQMALEDQ NOV2d CTKDMPPMGSPVIPTDLPLRASPSHIPSVVVLPITQQGYQHEYVDQPKMSEVAQMALEDQ NOV2e ------------------------------------------------------------ NOV2f ------------------------------------------------------------ NOV2g ------------------------------------------------------------ NOV2h CTKDMPPMGSPVIPTDLPLRASPSHIPSVVVLPITQQCYQHEYVDQPKNSEVAQMALEDQ NOV2i CTKDMPPMGSPVIPTDLPLRASPSHIPSVVVLPITQQGYQHEYVDQPKMSEVAQMALEDQ NOV2j CTKDMPPMGSPVIPTDLPLRASPSHIPSVVVLPITQQGYQHEYVDQPKMSEVAQMALEDQ NOV2k ------------------------------------------------------------ NOV2l ------------------------------------------------------------ NOV2m ------------------------------------------------------------ NOV2n ------------------------------------------------------------ NOV2o ------------------------------------------------------------ NOV2p ------------------------------------------------------------ NOV2q CTKDMPPNGSPVIPTDLPLRASPSHIPSVVVLPITQQGYQHEYVDQPKESEVAQMALEDQ NOV2r CTKDMPPMGSPVIPTDLPLRASPSHIPSVVVLPITQQGYQHEYVDQPKMSEVAQMALEDQ NOV2s ------------------------------------------------------------ NOV2t ------------------------------------------------------------ NOV2u ------------------------------------------------------------ NOV2v ------------------------------------------------------------ NOV2a AATLEYKTIKEHLSSKSPNHGVNLVENLDSLPPKVPQREASLGPPGASLSQTGLSKRLEM NOV2b ------------------------------------------------------------ NOV2c AATLEYKTIKEHLSSKSPNHGVNLVENLDSLPPKVPQREASLGPPGASLSQTGLSKRLEM NOV2d AATLEYKTIKEHLSSKSPNHGVNLVENLDSLPPKVPQREASLOPPGASLSQTGLSKRLEM NOV2e ------------------------------------------------------------ NOV2f ------------------------------------------------------------ NOV2g ------------------------------------------------------------ NOV2h AATLEYKTIKEHLSSKSPNHGVNLVENLDSLPPKVPQREASLGPPGASLSQTGLSKRLEM NOV2i AATLEYKTIKEHLSSKSPNHCVNLVENLDSLPPKVPQREASLGPPGASLSQTGLSKRLEM NOV2j AATLEYKTIKEHLSSKSPNHGVNLVENLDSLPPKVPQREASLGPPOASLSQTGLSKRLEM NOV2k ------------------------------------------------------------ NOV2l ------------------------------------------------------------ NOV2m ------------------------------------------------------------ NOV2n ------------------------------------------------------------ NOV2o ------------------------------------------------------------ NOV2p ------------------------------------------------------------ NOV2q AATLEYKTIKEHLSSKSPNHGVNLVENLDSLPPKVPQREASLGPPGASLSQTGLSKRLEM NOV2r AATLEYKTIKEHLSSKSPNHGVNLVENLDSLPPKVPQREASLGPPGASLSQTOLSKRLEM NOV2s ------------------------------------------------------------ NOV2t ------------------------------------------------------------ NOV2u ------------------------------------------------------------ NOV2v ------------------------------------------------------------ NOV2a NHSSSYGVDYKRSYPTNSLTRSHQATTLKRNNTNSSNSSHLSRNQSFGRGDNPPPAPQRV NOV2b ------------------------------------------------------------ NOV2c NHSSSYGVDYKRSYPTNSLTRSHQATTLKRNNTNSSNSSHLSRNQSFGRGDNPPPAPQRV NOV2d HHSSSYGVDYKRSYPTNSLTRSHQATTLKRNNTNSSNSSHLSRNQSFGRGDNPPPAPQRV NOV2e ------------------------------------------------------------ NOV2f ------------------------------------------------------------ NOV2g ------------------------------------------------------------ NOV2h HHSSSYGVDYKRSYPTNSLTRSHQATTLKRNNTNSSNSSHLSRNQSFGRGDNPPPAPQRV NOV2i HHSSSYGVDYKRSYPTNSLTRSNQATTLKRNNTNSSNSSHLSRNQSFGRGDNPPPAPQRV NOV2j HHSSSYGVDYKRSYPTNSLTRSNQATTYSHQKQH-------------------------- NOV2k ------------------------------------------------------------ NOV2l ------------------------------------------------------------ NOV2m ------------------------------------------------------------ NOV2n ------------------------------------------------------------ NOV2o ------------------------------------------------------------ NOV2p ------------------------------------------------------------ NOV2q HHSSSYGVDYKRSYPTNSLTRSHQATTLKRNNTNSSNSSHLSRNQSFCRGDNPPPAPQRV NOV2r HHSSSYGVDYKRSYPTNSLTRSHQATTLKRNNTNSSNSSHLSRNQSFGRGDNPPPAPQRV NOV2s ------------------------------------------------------------ NOV2t ------------------------------------------------------------ NOV2u ------------------------------------------------------------ NOV2v ------------------------------------------------------------ NOV2a DSIQVHSSQPSGQAVTVSRQPSLNAYNSLTRSGLKRTPSLKPDVPPKPSFAPLSTSMKPN NOV2b ------------------------------------------------------------ NOV2c DSIQVHSSQPSGQAVTVSRQPSLNAYNSLTRSGLKRTPSLKPDVPPKPSFAPLSTSMKPN NOV2d DSIQVHSSQPSGQAVTVSRQPSLNAYNSLTRSGLKRTPSLKPDVPPKPSFAPLSTSMKPN NOV2e ------------------------------------------------------------ NOV2f ------------------------------------------------------------ NOV2g ------------------------------------------------------------ NOV2h DSIQVHSSQPSGQAVTVSRQPSLNAYNSLTRSGLKRTPSLKPDVPPKPSFAPLSTSMKPN NOV2i DSIQVHSSQPSGQAVTVSRQPSLNAYNSLTRSGLKRTPSLKPDVPPKPSFAPLSTSMKPN NOV2j ------------------------------------------------------------ NOV2k ------------------------------------------------------------ NOV2l ------------------------------------------------------------ NOV2m ------------------------------------------------------------ NOV2n ------------------------------------------------------------ NOV2o ------------------------------------------------------------ NOV2p ------------------------------------------------------------ NOV2q DSIQVMSSQPSGQAVTVSRQPSLNAYNSLTRSGLKRTPSLKPDVPPKPSFAPLSTSMKPN NOV2r DSIQVNSSQPSGQAVTVSRQPSLNAYNSLTRSGLKRTPSLKPDVPPKPSFAPLSTSMKPN NOV2s ------------------------------------------------------------ NOV2t ------------------------------------------------------------ NOV2u ------------------------------------------------------------ NOV2v ------------------------------------------------------------ NOV2a DACT--- NOV2b ------- NOV2c DACTVDG NOV2d DACTVDG NOV2e ------- NOV2f ------- NOV2g ------- NOV2h DACTVDG NOV2i DACTVDG NOV2j ------- NOV2k ------- NOV2l ------- NOV2m ------- NOV2n ------- NOV2o ------- NOV2p ------- NOV2q DACT--- NOV2r DACT--- NOV2s ------- NOV2t ------- NOV2u ------- NOV2v -------

[0366] Further analysis of the NOV2a protein yielded the following properties shown in Table 2C. 10 TABLE 2C Protein Sequence Properties NOV2a SignalP analysis: Cleavage site between residues 19 and 20 PSORT II analysis: PSG: a new signal peptide prediction method N-region: length 4; pos.chg 1; neg.chg 1 H-region: length 17; peak value 9.51 PSG score: 5.11 GvH: von Heijne's method for signal seq. recognition GvH score (threshold: −2.1): 1.58 possible cleavage site: between 18 and 19 >>> Seems to have a cleavable signal peptide (1 to 18) ALOM: Klein et al's method for TM region allocation Init position for calculation: 19 Tentative number of TMS(s) for the threshold 0.5: 1 Number of TMS(s) for threshold 0.5: 1 INTEGRAL Likelihood = −11.62 Transmembrane 662−678 PERIPHERAL Likelihood = 2.28 (at 436) ALOM score: −11.62 (number of TMSs: 1) MTOP: Prediction of membrane topology (Hartmann et al.) Center position for calculation: 9 Charge difference: −3.5 C(−2.5) − N(1.0) N >= C: N-terminal side will be inside >>> membrane topology: type 1a (cytoplasmic tail 679 to 1047) MITDISC: discrimination of mitochondrial targeting seq R content: 1 Hyd Moment(75): 3.63 Hyd Moment(95): 2.72 G content: 2 D/E content: 2 S/T content: 2 Score: −7.22 Gavel: prediction of cleavage sites for mitochondrial preseq R-2 motif at 12 MRS|EA NUCDISC: discrimination of nuclear localization signals pat4: HRRK (3) at 693 pat4: KRKP (4) at 784 pat7: none bipartite: none content of basic residues: 11.4% NLS Score: −0.03 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: XXRR-like motif in the N-terminus: RSEA none SKL: peroxisomal targeting signal in the C-terminus: none PTS2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none NMYR: N-myristoylation pattern: none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: too long tail Dileucine motif in the tail: none checking 63 PROSITE DNA binding motifs: none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination Prediction: nuclear Reliability: 89 COIL: Lupas's algorithm to detect coiled-coil regions total: 0 residues Final Results (k = 9/23): 44.4%: extracellular, including cell wall 22.2%: Golgi 22.2%: endoplasmic reticulum 11.1%: plasma membrane >> prediction for CG51896-04 is exc (k = 9)

[0367] A search of the NOV2a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 2D. 11 TABLE 2D Geneseq Results for NOV2a NOV2a Residues/ Identities/ Geneseq Protein/Organism/Length [Patent Match Similarities for the Expect Identifier #, Date] Residues Matched Region Value AAY71460 Human semaphorin 6A-1 - Homo 1 . . . 1047 1029/1047 (98%) 0.0 sapiens, 1030 aa. 1 . . . 1030 1029/1047 (98%) [WO200031252-A1, 02-JUN-2000] AAB23030 Human semaphorin protein-like 1 . . . 949 927/949 (97%) 0.0 splice variant, SECX 2864933-1 - 1 . . . 932 929/949 (97%) Homo sapiens, 939 aa. [WO200053742-A2, 14-SEP-2000] AAB95139 Human protein sequence SEQ ID 332 . . . 1047 699/716 (97%) 0.0 NO: 17154 - Homo sapiens, 699 aa. 1 . . . 699 699/716 (97%) [EP1074617-A2, 07-FEB-2001] AAB23043 Human semaphorin protein-like 17 . . . 662 627/646 (97%) 0.0 splice variant, SECX 1 . . . 629 628/646 (97%) pCR2.1-2864933 - Homo sapiens, 630 aa. [WO200053742-A2, 14-SEP-2000] AAB90731 Human CJ145- 1 protein sequence 1 . . . 578 575/578 (99%) 0.0 SEQ ID 161 - Homo sapiens, 975 aa. 1 . . . 578 576/578 (99%) [WO200119988-A1, 22-MAR-2001]

[0368] In a BLAST search of public sequence databases, the NOV2a protein was found to have homology to the proteins shown in the BLASTP data in Table 2E. 12 TABLE 2E Public BLASTP Results for NOV2a NOV2a Protein Residues/ Identities/ Accession Match Similarities for the Expect Number Protein/Organism/Length Residues Matched Portion Value Q9P2H9 Hypothetical protein KIAA1368 - 1 . . . 1047 1046/1047 (99%) 0.0 Homo sapiens (Human), 1049 aa 3 . . . 1049 1046/1047 (99%) (fragment). Q9H2E6 Semaphorin SEMA6A1 - Homo 1 . . . 1047 1029/1047 (98%) 0.0 sapiens (Human), 1030 aa. 1 . . . 1030 1029/1047 (98%) Q9EQ71 Axon guidance signal SEMA6A1 - 1 . . . 1047 947/1048 (90%) 0.0 Mus musculus (Mouse), 1005 aa. 1 . . . 1005 973/1048 (92%) O35464 Semaphorin 6A precursor 1 . . . 880 815/881 (92%) 0.0 (Semaphorin VIA) (Sema VIA) 1 . . . 864 839/881 (94%) (Semaphorin Q) (Sema Q) - Mus musculus (Mouse), 888 aa. Q96SW4 Hypothetical protein FLJ14595 - 332 . . . 1047 699/716 (97%) 0.0 Homo sapiens (Human), 699 aa. 1 . . . 699 699/716 (97%)

[0369] PFam analysis predicts that the NOV2a protein contains the domains shown in the Table 2F. 13 TABLE 2F Domain Analysis of NOV2a Identities/Similarities NOV2a for the Pfam Domain Match Region Matched Region Expect Value Sema 56 . . . 491 203/497 (41%) 4.5e−212 390/497 (78%) PSI 514 . . . 557 14/68 (21%) 0.42 29/68 (43%)

Example 3

[0370] The NOV3 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 3A. 14 TABLE 3A NOV3 Sequence Analysis NOV3a, CG52324-01 SEQ ID NO:57 1932 bp DNA Sequence ORF Start: ATG at 113 ORF Stop: end of sequence CGCGTGCAGGTGGCAGTCCTCCCAAAGTACTTGTGTCCGGGTGGTGGACTGGATTCGCTGCGGACCCCTGCAA GCTGCCTTTCCTTCTCCCTGTGCTTAACCAGAGGTGCCCATGGGTTGGACAATGAGGCTGGTCACAGCAGCAC TGTTACTGGGTCTCATGATGGTGGTCACTGGAGACGAGGATGAGAACAGCCCGTGTGCCCATGAGGCCCTCTT GGACGAGGACACCCTCTTTTGCCAGGGCCTTGAAGTTTTCTACCCAGAGTTGGGGAACATTGGCTGCAAGGTT GTTCCTGATTGTAACAACTACAGACAGAAGATCACCTCCTGGATGGAGCCGATAGTCAAGTTCCCGGGGGCCG TGGACGGCGCAACCTATATCCTGGTGATGGTGGATCCAGATGCCCCTAGCAGAGCAGAACCCAGACAGAGATT CTGGAGACATTGGCTGGTAACAGATATCAAGGGCGCCGACCTGAAGGAAGGGAAGATTCAGGGCCAGGAGTTA TCAGCCTACCAGGCTCCCTCCCCACCGGCACACAGTGGCTTCCATCGCTACCAGTTCTTTGTCTATCTTCAGG AAGGAAAAGTCATCTCTCTCCTTCCCAAGGAAAACAAAACTCGAGGCTCTTGGAAAATGGACAGATTTCTGAA CCGTTTCCACCTGGGCGAACCTGAAGCAAGCACCCAGTTCATGACCCAGAACTACCAGCACTCACCAACCCTC CAGGCTCCCACAGAAAGGGCCAGCGAGCCCAACCACAAAAACCAGGCGGAGATAGCTGCCTGCTAGATAGCCG GCTTTGCCATCCGGGCATGTGGCCACACTGCCCACCACCGACGATGTGGGTATGGAACCCCCTCTGGATACAG AACCCCTTCTTTTCCAATTAAAAAAAAAAATCATCCAGGAAAAAAAAAAAAAAAA NOV3a, CG52324-01 Protein Sequence SEQ ID NO:58 227 aa MW at 25734.1 kD MGWTMRLVTAALLLGLMMVVTGDEDENSPCAHEALLDEDTLFCQGLEVFYPELGNIGCKVVPDCNNYRQKITS WMEPIVKFPGAVDGATYILVMVDPDAPSRAEPRQRFWRHWLVTDIKGADLKEGKIQGQELSAYQAPSPPAHSG FHRYQFFVYLQEGKVISLLPKENKTRGSWKMDRFLNRFHLGEPEASTQFMTQNYQDSPTLQAPRERASEPKHK NQAEIAAC NOV3b, 249357821 SEQ ID NO:59 706 bp DNA Sequence ORF Start: at 2 ORF Stop: end of sequence CACCAGATCTCCCACCATGGGTTGGACAATGAGGCTGGTCACAGCAGCACTGTTACTGGGTCTCATGATGGTG GTCACTCGAGACGAGGATGAGAACAGCCCGTGTGCCCATGAGGCCCTCTTGGACGAGGACACCCTCTTTTGCC AGGGCCTTGAAGTTTTCTACCCAGAGTTGGGGAACATTGGCTGCAAGGTTGTTCCTGATTGTAACAACTACAG ACAGAAGATCACCTCCTGGATGGAGCCGATAGTCAAGTTCCCGGGGGCCGTGGACGGCGCAACCTATATCCTG GTGATGGTGGATCCAGATGCCCCTAGCAGAGCAGAACCCAGACAGAGATTCTGGAGACATTGGCTGGTAACAG ATATCAAGGGCGCCGACCTGAAGGAAGGGAAGATTCAGGGCCAGGAGTTATCAGCCTACCAGGCTCCCTCCCC ACCGGCACACAGTGGCTTCCATCGCTACCAGTTCTTTGTCTATCTTCAGGAAGGAAAAGTCATCTCTCTCCTT CCCAAGGAAAACAAAACTCGAGGCTCTTGGAAAATGGACAGATTTCTGAACCGTTTCCACCTGGGCGAACCTG AAGCAAGCACCCAGTTCATGACCCAGAACTACCAGGACTCACCAACCCTCCAGGCTCCCAGAGAAAGGGCCAG CGAGCCCAAGCACAAAAACCAGGCGGAGATAGCTGCCTGCGTCGACGGC NOV3b, 249357821 Protein Sequence SEQ ID NO:60 235 aa MW at 26547.9 kD TRSPTMGWTMRLVTAALLLGLMMVVTGDEDENSPCAHEALLDEDTLFCQGLEVFYPELGNIGCKVVPDCNNYR QKITSWMEPIVKFPGAVDGATYILVMVDPDAPSRAEPRQRFWRHWLVTDIKGADLKEGKIQGQELSAYQAPSP PAHSGFHRYQFFVYLQEGKVISLLPKENKTRGSWKMDRFLNRFHLGEPEASTQFMTQNYQDSPTLQAPRERAS EPKHKNQAEIAACVDG NOV3c, 249357798 SEQ ID NO:61 706 bp DNA Sequence ORF Start: at 2 ORF Stop: end of sequence CACCAGATCTCCCACCATCGGTTGGACAATGAGGCTGGTCACAGCAGCACTGTTACTGGGTCTCATGATGGTG GTCACTGGAGACGAGGATGAGAACAGCCCGTGTGCCCATGAGGCCCTCTTGGACGAGGACACCCTCTTTTGCC AGGGCCTTGAAGTTTTCTACCCAGAGTTGGGGAACATTGGCTGCAAGGTTGTTCCTGATTGTAACAACTACAG ACAGAAGATCACCTCCTGGATGGAGCCGATAGTCAAGTTCCCGGGGGCCGTGGACGGCGCAACCTATATCCTG GTGATGGTGGATCCAGATGCCCCTAGCAGAGCAGAACCCAGACAGAGATTCTGGAGACATTGGCTGGTAACAG ATATCAAGGGCGCCGACCTGAAGAAAGGGAAGATTCAGGGCCAGGAGTTATCAGCCTACCAGGCTCCCTCCCC ACCGGCACACAGTGGCTTCCATCGCTACCAGTTCTTTGTCTATCTTCAGGAAGGAAAAGTCATCTCTCTCCTT CCCAAGGAAAACAAAACTCGAGGCTCTTGGAAAATGGACAGATTTCTGAACCGTTTCCACCTGGGCGAACCTG AAGCAAGCACCCAGTTCATGACCCACAACTACCAGGACTCACCAACCCTCCAGGCTCCCAGAGAAAGGGCCAG CGAGCCCAAGCACAAAAACCAGGCGGAGATAGCTGCCTGCGTCGACGGC NOV3c, 249357798 Protein Sequence SEQ ID NO:62 235 aa MW at 26547.0 kD TRSPTMGWTMRLVTAALLLGLMMVVTGDEDENSPCAHEALLDEDTLFCQGLEVFYPELGNIGCKVVPDCNNYR QKITSWMEPIVKFPGAVDGATYILVMVDPDAPSRAEPRQRFWRIWLVTDIKGADLKKGKIQGQELSAYQAPSP PAHSGFHRYQFFVYLQEGKVISLLPKENKTRGSWKMDRFLNRFHLGEPEASTQFMTQNYQDSPTLQAPRERAS EPKHKNQAEIAACVDG NOV3d, 248644954 SEQ ID NO:63 619 bp DNA Sequence ORF Start: at 2 ORF Stop: end of sequence CACCAGATCTCCCACCATGGGTTGGACAATGAGGCTGGTCACAGCAGCACTGTTACTCGGTCTCATGATGGTG GTCACTGGAGACGAGGATGAGAACAGCCCGTGTGCCCATGAGGCCCTCTTGGACGAGGACACCCTCTTTTGCC AGGGCCTTGAAGTTTTCTACCCAGAGTTCGGGAACATTGGCTGCAAGGTTGTTCCTGATTGTAACAACTACAG ACAGAAGATCACCTCCTGGATGGAGCCGATAGTCAAGTTCCCGGGGGCCGTGGACGGCGCAACCTATATCCTG GTGATGGTGGATCCAGATGCCCCTAGCAGAGCGGAACCCAGACAGAGATTCTGGAGACATTGGCTGGTAACAG ATATCAAGGGCGCCGACCTGAAGGAAGGGAAGATTCAGGGCCAGGAGTTATCAGCCTACCAGGCTCCCTCCCC ACCGGCACACAGTGGCTTCCATCGCTACCAGTTCTTTGTCTATCTTCAGGAAGGAAAAGTCATCTCTCTCCTT CCCAAGGAAAACAAAACTCGAGGCTCTTGGAAAATGGACAGATTTCTGAACCGTTTCCACCTGGGCGAACCTG AAGCAAGCACCCAGTTCATGACCCAGGTCGACGCC NOV3d, 248644954 Protein Sequence SEQ ID NO:64 206 aa MW at 23312.4 kD TRSPTMGWTMRLVTAALLLGLMMVVTGDEDENSPCAHEALLDEDTLFCQGLEVFYPELGNIGCKVVPDCNNYR QKITSWMEPIVKFPGAVDGATYILVMVDPDAPSRAEPRQRFWRHWLVTDIKGADLKEGKIQGQELSAYQAPSP PAHSGFHRYQFFVYLQEGKVISLLPKENKTRGSWKMDRFLNRFHLGEPEASTQFMTQVDG NOV3e, 248644962 SEQ ID NO:65 619 bp DNA Sequence ORF Start: at 2 ORF Stop: end of sequence CACCAGATCTCCCACCATGGGTTGGACAATGAGGCTGGTCACAGCAGCACTGTTACTGGGTCTCATGATGGTG GTCACTGGAGACGAGGATGAGAACAGCCCGTGTGCCCATGAGGCCCTCTTGGACGAGGACACCCTCTTTTGCC AGGGCCTTGAAGTTTTCTACCCAGAGTTGGGGAACATTGGCTGCAAGGTTGTTCCTGATTGTAACAACTACAG ACAGAAGATCACCTCCTGGATGGAGCCGATAGTCAAGTTCCCGGGGGCCGTGGACGGCGCAACCTATATCCTG GTGATGGTGGATCCAGATGCCCCTAGCACAGCAGAAACCCAGACAGAGATTCTGGAGACATTGGCTGTAACAG ATATCAAGGGCGCCGACCTGAAGAAAGGGAAGATTCAGGGCCAGGAGTTATCAGCCTACCAGGCTCCCTCCCC ACCGGCACACAGTGGCTTCCATCGCTACCAGTTCTTTGTCTATCTTCACCAAGGAAAAGTCATCTCTCTCCTT CCCAAGGAAAACAAAACTCGAGGCTCTTGGAAAATGGACAGATTTCTGAACCGTTTCCACCTGGGCGAACCTG AAGCAAGCACCCAGTTCATGACCCAGGTCGACGGC NOV3e, 248644962 Protein Sequence SEQ ID NO:66 206 aa MW at 23311.5 kD TRSPTMGWTMRLVTAALLLGLMMVVTGDEDENSPCAHEALLDEDTLFCQGLEVFYPELGNIGCKVVPDCNNYR QKITSWMEPIVKFPGAVDGATYILVMVDPDAPSRAEPRQRFWRHWLVTDIKGADLKKGKIQGQELSAYQAPSP PAHSGFHRYQFFVYLQEGKVISLLPKENKTRGSWKMDRFLNRFHLGEPEASTQFMTQVDG NOV3f, 248645004 SEQ ID NO:67 634 bp DNA Sequence ORF Start: at 2 ORF Stop: end of sequence CACCAGATCTGACGAGGATCAGAACAGCCCGTGTGCCCATGAGGCCCTCTTCGACGAGGACACCCTCTTTTGC CAGGGCCTTGAAGTTTTCTACCCAGAGTTGGGGAACATTGGCTGCAAGGTTGTTCCTGATTGTAACAACTACA GACAGAAGATCACCTCCTGGATGGAGCCGATAGTCAAGTTCCCGGGGGCCGTGGACGGCGCAACCTATATCCT GGTGATGGTGGATCCAGATGCCCCTAGCAGAGCAGAACCCAGACAGAGATTCTGGAGACATTGGCTGGTAACA GATATCAAGGGCGCCGACCTGAAGGAAGGGAAGATTCAGGGCCAGGAGTTATCAGCCTACCAGGCTCCCTCCC CACCGGCACACAGTGGCTTCCATCGCTACCAGTTCTTTGTCTATCTTCAGGAAGGAAAAGTCATCTCTCTCCT TCCCAACGAAAACAAAACTCGAGGCTCTTGGAAAATGGACAGATTTCTCAACCGTTTCCACCTGGGCGAACCT GAAGCAAGCACCCAGTTCATGACCCAGAACTACCAGGACTCACCAACCCTCCAGGCTCCCAGAGAAAGGGCCA GCGAGCCCAAGCACAAAAACCAGGCGGAGATAGCTGCCTGCGTCGACGGC NOV3f, 248645004 Protein Sequence SEQ ID NO:68 211 aa MW at 24002.7 kD TRSDEDENSPCAHEALLDEDTLFCQGLEVFYPELGNIGCKVVPDCNNYRQKITSWNEPIVKFPGAVDGATYIL VMVDPDAPSRAEPRQRFWRHWLVTDIKGADLKEGKIQGQELSAYQAPSPPAHSGFHRYQFFVYLQEGKVISLL PKENKTRGSWKMDRFLNRFHLCEPEASTQFMTQNYQDSPTLQAPRERASEPKHKNQAEIAACVDG NOV3g, 249420987 SEQ ID NO:69 634 bp DNA Sequence ORF Start: at 2 ORF Stop: end of sequence CACCAGATCTGACGAGGATGAGAACAGCCCGTGTGCCCATGAGGCCCTCTTGGACGAGGACACCCTCTTTTGC CAGGGCCTTGAAGTTTTCTACCCAGAGTTGGGGAACATTGGCTGCAAGGTTGTTCCTGATTGTAACAACTACA GACAGAACATCACCTCCTGGATGGAGCCGATAGTCAAGTTCCCGGGGGCCGTGGACGGCGCAACCTATATCCT GGTGATGGTGGATCCAGATGCCCCTAGCAGAGCAGAACCCAGACAGAGATTCTGGAGACATTGGCTGGTAACA GATATCAAGGGCGCCGACCTGAAGAAAGGGAAGATTCAGGGCCAGGAGTTATCAGCCTACCAGGCTCCCTCCC CACCGGCACACAGTGCCTTCCATCGCTACCAGTTCTTTGTCTATCTTCAGGAAGGAAAAGTCATCTCTCTCCT TCCCAAGGAAAACAAAACTCGAGGCTCTTGGAAAATGGACAGATTTCTGAACCGTTTCCACCTGGGCGAACCT GAAGCAAGCACCCAGTTCATGACCCAGAACTACCAGGACTCACCAACCCTCCAGGCTCCCAGAGAAAGGGCCA GCGAGCCCAAGCACAAAAACCAGGCGGAGATAGCTGCCTGCGTCGACGGC NOV3g, 249420987 Protein Sequence SEQ ID NO:70 211 aa MW at 24001.8 kD TRSDEDENSPCAHEALLDEDTLFCQGLEVFYPELGNIGCKVVPDCNNYRQKITSWMEPIVKFPGAVDGATYIL VNVDPDAPSRAEPRQRFWRHWLVTDIKGADLKKGKIQGQELSAYQAPSPPAHSGFHRYQFFVYLQEGKVISLL PKENKTRGSWKMDRFLNRFHLGEPEASTQFMTQMYQDSPTLQAPRERASEPKHKNQAEIAACVDG NOV3h, 248486005 SEQ ID NO:71 547 bp DNA Sequence ORF Start: at 2 ORF Stop: end of sequence CACCAGATCTGACGAGGATGACAACAGCCCGTGTGCCCATGAGGCCCTCTTGGACGAGGACACCCTCTTTTGC CAGGGCCTTGAAGTTTTCTACCCAGAGTTGGGGAACATTGCCTGCAAGGTTGTTCCTGATTGTAACAACTACA GACAGAAGATCACCTCCTGGATGGAGCCGATAGTCAAGTTCCCGGGGGCCGTGGACGGCGCAACCTATATCCT GGTGATGGTGGATCCAGATGCCCCTAGCAGAGCAGAACCCAGACAGAGATTCTGGACACATTGGCTGGTAACA GATATCAAGGGCGCCGACCTGAAGAAAGGGAAGATTCAGGGCCAGGAGTTATCAGCCTACCAGGCTCCCTCCC CACCGGCACACAGTGGCTTCCATCGCTACCAGTTCTTTGTCTATCTTCACGAAGGAAAAGTCATCTCTCTCCT TCCCAAGGAAAACAAAACTCGAGGCTCTTGGAAAATGGACAGATTTCTGAACCGTTTCCACCTGGGCGAACCT GAAGCAAGCACCCAGTTCATGACCCAGGTCGACGCC NOV3h, 248486005 Protein Sequence SEQ ID NO:72 182 aa MW at 20766.3 kD TRSDEDENSPCAHEALLDEDTLFCQGLEVFYPELGNIGCKVVPDCNNYRQKITSWMEPIVKFPGAVDGATYIL VMVDPDAPSRAEPRQRFWRHWLVTDIKGADLKKGKIQGQELSAYQAPSPPAHSGFHRYQFFVYLQEGKVISLL PKENKTRGSWKMDRFLNRFHLGEPEASTQFMTQVDG NOV3i, 249421046 SEQ ID NO:73 547 bp DNA Sequence ORF Start: at 2 ORF Stop: end of sequence CACCAGATCTGACGAGGATGAGAACAGCCCGTGTGCCCATGAGGCCCTCTTGGACGAGGACACCCTCTTTTGC CAGGGCCTTGAAGTTTTCTACCCAGAGTTGGGAACATTGGCTGCAAGGTTGTTCCTGATTGTAAACAACTACA GACAGAAGATCACCTCCTGGATGGAGCCGATAGTCAAGTTCCCGGGGGCCGTGGACGGCGCAACCTATATCCT GGTGATGGTGGATCCAGATGCCCCTAGCAGAGCAGAACCCAGACAGAGATTCTGGAGACATTGGCTGGTAACA GATATCAAGGGCGCCGACCTGAAGGAAGGGAAGATTCAGGGCCAGGAGTTATCAGCCTACCAGACTCCCTCCC CACCGGCACACAGTGGCTTCCATCGCTACCAGTTCTTTGTCTATCTTCAGGAAGGAAAAGTCATCTCTCTCCT TCCCAAGGAAAACAAAACTCGAGGCTCTTGGAAAATGGACAGATTTCTGAACCGTTTCCACCTGGGCGAACCT GAAGCAAGCACCCAGTTCATGACCCAGGTCGACGGC NOV3i, 249421046 Protein Sequence SEQ ID NO:74 182 aa MW at 20767.2 kD TRSDEDENSPCAHEALLDEDTLFCQGLEVFYPELGNIGCKVVPDCNNYRQKITSWMEPIVKFPGAVDGATYIL VMVDPDAPSRAEPRQRFWRHWLVTDIKGADLKEGKIQGQELSAYQAPSPPAHSGFHRYQFFVYLQEGKVISLL PKENKTRGSWKMDRFLNRFHLGEPEASTQFMTQVDG NOV3j, CG52324-02 SEQ ID NO:75 879 bp DNA Sequence ORF Start: ATG at 108 ORF Stop: end of sequence TCAGGTGGCAGTCCTCCCAAAGTACTTGTGTCCGGGTGGTGGACTGGATTAGCTGCGGAGCCCTGGAAGCTGC CTTTCCTTCTCCCTGTGCTTAACCAGAGGTGCCCATGGGTTGGACAATGAGGCTGGTCACAGCAGCACTGTTA CTGGGTCTCATGATGGTGGTCACTGGAGACGAGGATGAGAACAGCCCGTGTGCCCATGAGGCCCTCTTGGACG AGGACACCCTCTTTTGCCAGGCCTTGAAGTTTTCTACCCAGAGTTGGGGACATTGGCTGCAAGGTTGTTAACC TGATTGTAACAACTACAGACAGAAGATCACCTCCTGGATGGAGCCGATAGTCAAGTTCCCGGGGGCCGTGGAC GGCGCAACCTATATCCTGGTGATGGTGGATCCAGATGCCCCTAGCAGAGCAGAACCCAGACAGAGATTCTAAA GACATTGGCTGGTAACAGATATCAAGGGCGCCGACCTGAAGAAAGGGAAGATTCAGGGCCAGGAGTTATCAGC CTACCAGGCTCCCTCCCCACCGGCACACAGTGCTTCCATCGCTACCAGTTCTTTGTCTATCTTCAAGGAAGGA AAAGTCATCTCTCTCCTTCCCAAGGAAAACAAAACTCGAGGCTCTTGGAAAATGGACAGATTTCTGAACCGTT TCCACCTGGGCGAACCTGAAGCAAGCACCCAGTTCATGACCCAGAACTACCAGGACTCACCAACCCTCCAAAC TCCCAGAGAAAGGGCCAGCGGGCCCAAGCACAAAAACCAGGCGGAGATAGCTGCCTGCTAGATAGCCGGCTTT GCCATCCGGGCATGTGGCCACACTGCCCACCACCGACGATGTGGGTATGGAACCCCCTCTGGATACAGAACCA CAT NOV3j, CG52324-02 Protein Sequence SEQ ID NO:76 227 aa MW at 25661.1 kD MCWTMRLVTAALLLGLMMVVTGDEDENSPCAHEALLDEDTLFCQGLEVFYPELGNIGCKVVPDCNNYRQKITS WNEPIVKFPGAVDGATYILVMVDPDAPSRAEPRQRFWRHWLVTDIKGADLKKGKIQGQELSAYQAPSPPAHSG FHRYQFFVYLQEGKVISLLPKENKTRGSWKMDRFLNRFHLGEPEASTQFMTQNYQDSPTLQAPRERASGPKHK NQAEIAAC NOV3k, CG52324-03 SEQ ID NO:77 615 bp DNA Sequence ORF Start: at 1 ORF Stop: end of sequence GACGAGGATGAGAACAGCCCGTGTGCCCATGAGGCCCTCTTGGACGAGGACACCCTCTTTTGCCAGGGCCTTG AAGTTTTCTACCCAGAGTTGGGGAACATTGGCTGCAAGGTTGTTCCTGATTGTAACAACTACAGACAGAAGAT CACCTCCTGGATGGAGCCGATAGTCAAGTTCCCGGGGGCCGTGGACGGCGCAACCTATATCCTGGTGATGGTG GATCCAGATGCCCCTAGCAGAGCAGAACCCAGACAGAGATTCTGGAGACATTGGCTGGTAACAGATATCAAGG GCGCCGACCTGAAGAAAGGGAAGATTCAGGGCCAGGAGTTATCAGCCTACCAGGCTCCCTCCCCACCGGCACA CAGTGGCTTCCATCGCTACCAGTTCTTTGTCTATCTTCAGGAAGGAAAAGTCATCTCTCTCCTTCCCAAGGAA AACAAAACTCGAGGCTCTTGGAAAATGGACAGATTTCTGAACCGTTTCCACCTCCGCGAACCTGAAGCAAGCA CCCAGTTCATGACCCAGAACTACCAGGACTCACCAACCCTCCAGGCTCCCAGAGAAAGGGCCAGCGAGCCCAA GCACAAAAACCAGGCGGAGATAGCTGCCTGC NOV3k, CG52324-03 Protein Sequence SEQ ID NO:78 205 aa MW at 23386.2 kD DEDENSPCAHEALLDEDTLFCQGLEVFYPELGNIGCKVVPDCNNYRQKITSWMEPIVKFPGAVDGATYILVMV DPDAPSRAEPRQRFWRHWLVTDIKGADLKKGKIQGQELSAYQAPSPPAHSGFHRYQFFVYLQEGKVISLLPKE NKTRGSWKMDRFLNRFHLGEPEASTQFMTQNYQDSPTLQAPRERASEPKHKNQAEIAAC

[0371] A ClustalW comparison of the above protein sequences yields the following sequence alignment shown in Table 3B. 15 TABLE 3B Comparison of the NOV3 protein sequences. NOV3a ----MGWTMRLVTAALLLGLMMVVTG-------------------------DEDENSPCA (SEQ ID NO: 58) NOV3b TRSPTMGWTMRLVTAALLLGMMVVTG-------------------------DEDENSPCA (SEQ ID NO: 60) NOV3c TRSPTMGWTMRLVTAALLLGMMVVTG-------------------------DEDENSPCA (SEQ ID NO: 62) NOV3d ------------------------TRSPTMGWTMRLVTAALLLGLMMVVTGDEDENSPCA (SEQ ID NO: 64) NOV3e ------------------------TRSPTMGWTMRLVTAALLLGLHMVVTGDEDENSPCA (SEQ ID NO: 66) NOV3f ------------------------TRS------------------------DEDENSPCA (SEQ ID NO: 68) NOV3g ------------------------TRS------------------------DEDENSPCA (SEQ ID NO: 70) NOV3h ------------------------------------------------TRSDEDENSPCA (SEQ ID NO: 72) NOV3i ------------------------------------------------TRSDEDENSPCA (SEQ ID NO: 74) NOV3j ------MGWTMRLVTAALLLGLMMVVTG-----------------------DEDENSPCA (SEQ ID NO: 76) NOV3k ---------------------------------------------------DEDENSPCA (SEQ ID NO: 78) NOV3a HEALLDEDTLFCQGLEVFYPELGNIGCKVVPDCNNYRQKITSWMEPIVKFPGAVDGATYI NOV3b HEALLDEDTLFCQGLEVFYPELGNIGCKVVPDCNNYRQKITSWMEPIVKFPGAVDGATYI NOV3c HEALLDEDTLFCQGLEVFYPELGNIGCKVVPDCNNYRQKITSWMEPIVKFPGAVDGATYI NOV3d HEALLDEDTLFCQGLEVFYPELGNIGCKVVPDCNNYRQKITSWMEPIVKFPGAVDGATYI NOV3e HEALLDEDTLFCQGLEVFYPELGNIGCKVVPDCNNYRQKITSWMEPIVKFPGAVDGATYI NOV3f HEALLDEDTLFCQGLEVFYPELGNIGCKVVPDCNNYRQKITSWMEPIVKFPGAVDGATYI NOV3g HEALLDEDTLFCQGLEVFYPELGNTGCKVVPDCNNYRQKITSWMEPIVKFPGAVDGATYI NOV3h HEALLDEDTLFCQGLEVFYPELGNIGCKVVPDCNNYRQKITSWMEPIVKFPGAVDGATYI NOV3i HEALLDEDTLFCQGLEVFYPELGNIGCKVVPDCNNYRQKITSWMEPIVKFPGAVDGATYI NOV3j HEALLDEDTLFCQGLEVFYPELGNIGCKVVPDCNNYRQKITSWMEPIVKFPGAVDGATYI NOV3k HEALLDEDTLFCQGLEVFYPELGNIGCKVVPDCNNYRQKITSWMEPIVKFPGAVDGATYI NOV3a LVMVDPDAPSRAEPRQRFWRHWLVTDIKGADLKEGKIQGQELSAYQAPSPPAHSGFHRYQ NOV3b LVMVDPDAPSRAEPRQRFWRHWLVTDIKGADLKEGKIQGQELSAYQAPSPPAHSGFHRYQ NOV3c LVMVDPDAPSRAEPRQPYWRHWLVTDIKGADLKKGKIQGQELSAYQAPSPPAHSGFHRYQ NOV3d LVMVDPDAPSRAEPRQPYWRHWLVTDIKGADLKEGKIQGQELSAYQAPSPPAHSGFHRYQ NOV3e LVMVDPDAPSRAEPRQRFWRHWLVTDIKGADLKKGKIQGQELSAYQAPSPPAHSGFHRYQ NOV3f LVMVDPDAPSRAEPRQRFWRHWLVTDIKGADLKEGKIQGQELSAYQAPSPPAHSGFHRYQ NOV3g LVMVDPDAPSRAEPRQRFWRHWLVTDIKGADLKKGKIQGQELSAYQAPSPPAHSGFHRYQ NOV3h LVMVDPDAPSRAEPRQRFWRHWLVTDIKGADLKKGKIQGQELSAYQAPSPPAHSGFHRYQ NOV3i LVMVDPDAPSRAEPRQRFWRHWLVTDIKGADLKEGKIQGQELSAYQAPSPPAHSGFHRYQ NOV3j LVMVDPDAPSRAEPRQRFWRHWLVTDIKGADLKKGKIQGQELSAYQAPSPPAHSGFHRYQ NOV3k LVMVDPDAPSRAEPRQRFWRHWLVTDIKGADLKKGKIQGQELSAYQAPSPPAHSGFHRYQ NOV3a FFVYLQEGKVISLLPKENKTRGSWKMDRFLNRFHLGEPEASTQFMTQNYQDSPTLQAPRE NOV3b FFVYLQEGKVISLLPKENKTRGSWKMDRFLNRFHLGEPEASTQFMTQNYQDSPTLQAPRE NOV3c FFVYLQEGKVISLLPKENKTRGSWKMDRFLNRFHLGEPEASTQFMTQNYQDSPTLQAPRE NOV3d FFVYLQEGKVISLLPKENKTRGSWKMDRFLNRFHLGEPEASTQFMTQVDG---------- NOV3e FFVYLQEGKVISLLPKENKTRGSWKMDRFLNRFHLGEPEASTQFMTQVDG---------- NOV3f FFVYLQEGKVISLLPKENKTRGSWKMDRFLNRFHLGEPEASTQFMTQNYQDSPTLQAPRE NOV3g FFVYLQEGKVISLLPKENKTRGSWKMDRFLNRFHLGEPEASTQFMTQNYQDSPTLQAPRE NOV3h FFVYLQEGKVISLLPKENKTRGSWKMDRFLNRFHLGEPEASTQFMTQVDG---------- NOV3i FFVYLQEGKVISLLPKENKTRCSWKMDRFLNRFHLGEPEASTQFMTQVDG---------- NOV3j FFVYLQEGKVISLLPKENKTRGSWKMDRFLNRFHLGEPEASTQFMTQNYQDSPTLQAPRE NOV3k FFVYLQEGKVISLLPKENKTRGSWKMDRFLNRFHLGEPEASTQFMTQNYQDSPTLQAPRE NOV3a RASEPKHKNQAEIAAC--- NOV3b RASEPKHKNQAEIAACVDG NOV3c RASEPKHKNQAEIAACVDG NOV3d ------------------- NOV3e ------------------- NOV3f RASEPKHKNQAEIAACVDG NOV3g RASEPKHKNQAEIAACVDG NOV3h ------------------- NOV3i ------------------- NOV3j RASGPKHKNQAEIAAC--- NOV3k RASEPKHKNQAEIAAC---

[0372] Further analysis of the NOV3a protein yielded the following properties shown in Table 3C. 16 TABLE 3C Protein Sequence Properties NOV3a SignalP analysis: Cleavage site between residues 23 and 24 PSORT II analysis: PSG: a new signal peptide prediction method N-region: length 6; pos.chg 1; neg.chg 0 H-region: length 16; peak value 11.29 PSG score: 6.89 GvH: von Heijne's method for signal seq. recognition GvH score (threshold: −2.1): 1.04 possible cleavage site: between 22 and 23 >>> Seems to have a cleavable signal peptide (1 to 22) ALOM: Klein et al's method for TM region allocation Init position for calculation: 23 Tentative number of TMS(s) for the threshold 0.5: 0 number of TMS(s) . . . fixed PERIPHERAL Likelihood = 2.65 (at 78) ALOM score: 2.65 (number of TMSs: 0) MTOP: Prediction of membrane topology (Hartmann et al.) Center position for calculation: 11 Charge difference: −7.5 C(−5.5) − N(2.0) N >= C: N-terminal side will be inside MITDISC: discrimination of mitochondrial targeting seq R content: 1 Hyd Moment(75): 6.09 Hyd Moment(95): 8.77 G content: 3 D/E content: 1 S/T content: 3 Score: −4.30 Gavel: prediction of cleavage sites for mitochondrial preseq R-2 motif at 16 MRL|VT NUCDISC: discrimination of nuclear localization signals pat4: none pat7: none bipartite: none content of basic residues: 10.6% NLS Score: −0.47 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: none SKL: peroxisomal targeting signal in the C-terminus: none PTS2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none NMYR: N-myristoylation pattern: none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: none Dileucine motif in the tail: none checking 63 PROSITE DNA binding motifs: none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination Prediction: cytoplasmic Reliability: 76.7 COIL: Lupas's algorithm to detect coiled-coil regions total: 0 residues Final Results (k = 9/23): 33.3%: extracellular, including cell wall 22.2%: mitochondrial 22.2%: endoplasmic reticulum 11.1%: Golgi 11.1%: vacuolar >> prediction for CG52324-01 is exc (k = 9)

[0373] A search of the NOV3a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 3D. 17 TABLE 3D Geneseq Results for NOV3a NOV3a Identities/ Residues/ Similarities for Geneseq Protein/Organism/Length [Patent #, Match the Matched Expect Identifier Date] Residues Region Value AAB48368 Human SEC1 protein sequence (clone ID 1 . . . 227 227/227 (100%) e−135 3445452) - Homo sapiens, 227 aa. 1 . . . 227 227/227 (100%) [WO200078802-A2, 28-DEC-2000] AAB88590 Human hydrophobic domain containing 1 . . . 227 226/227 (99%) e−135 protein clone HP03880 #94 - Homo 1 . . . 227 227/227 (99%) sapiens, 227 aa. [WO200112660-A2, 22-FEB-2001] AAY64647 Human 1 . . . 227 226/227 (99%) e−135 phosphatidylethanolamine-binding 1 . . . 227 227/227 (99%) protein - Homo sapiens, 227 aa. [WO9953051-A2, 21-OCT-1999] AAG00016 Human secreted protein #4 - Homo 1 . . . 227 226/227 (99%) e−135 sapiens, 227 aa. [EP1033401-A2, 1 . . . 227 227/227 (99%) 06-SEP-2000] AAY35976 Extended human secreted protein 1 . . . 227 226/227 (99%) e−135 sequence, SEQ ID NO. 225 - Homo 1 . . . 227 227/227 (99%) sapiens, 227 aa. [WO9931236-A2, 24-JUN-1999]

[0374] In a BLAST search of public sequence databases, the NOV3a protein was found to have homology to the proteins shown in the BLASTP data in Table 3E. 18 TABLE 3E Public BLASTP Results for NOV3a NOV3a Protein Residues/ Identities/ Accession Match Similarities for the Expect Number Protein/Organism/Length Residues Matched Portion Value Q96S96 Phosphatidylethanolamine binding 1 . . . 227 227/227 (100%) e−135 protein - Homo sapiens (Human), 1 . . . 227 227/227 (100%) 227 aa. CAC33305 Sequence 114 from Patent 1 . . . 227 226/227 (99%) e−134 WO0112660 - Homo sapiens 1 . . . 227 227/227 (99%) (Human), 227 aa. Q8WW74 Hypothetical protein - Homo sapiens 1 . . . 221 218/221 (98%) e−129 (Human), 223 aa. 1 . . . 221 219/221 (98%) Q9D9G2 1700081D17Rik protein - Mus 5 . . . 198 104/209 (49%) 1e−54 musculus (Mouse), 242 aa. 12 . . . 220 132/209 (62%) AAO39754 Putative antennal carrier protein A5 - 44 . . . 208 58/171 (33%) 3e−20 Anopheles gambiae (African malaria 48 . . . 205 84/171 (48%) mosquito), 211 aa.

[0375] PFam analysis predicts that the NOV3a protein contains the domains shown in the Table 3F. 19 TABLE 3F Domain Analysis of NOV3a Identities/Similarities NOV3a for the Pfam Domain Match Region Matched Region Expect Value PBP 60 . . . 198 51/202 (25%) 7.7e−14 100/202 (50%)

Example 4

[0376] The NOV4 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 4A. 20 TABLE 4A NOV4 Sequence Analysis NOV4a, CG53054-02 SEQ ID NO:79 1128 bp DNA Sequence ORF Start: ATG at 31 ORF Stop: end of sequence TCCCGGCCCTCCGCGCCCTCTCGCGCGGCGATGGCCCCACTCGGATACTTCTTACTCCTCTGCAGCCTGAAGC AGGCTCTGGGCAGCTACCCGATCTGGTGGCTGACGGGCAGCGAGCCCCTGACCATCCTCCCGCTGACCCTGGA GCCAGAGGCGGCTGCCCAGGCGCACTACAAGGCCTGCGACCGGCTGAAGCTCGAGCGGAAGCAGCGGCGCATG TGCCGCCGGGACCCGCGCGTGGCACAGACGCTGGTGGAGGCCGTGAGCATGAGTGCGCTCGAGTGCCAGTTCC AGTTCCGCTTTGAGCGCTGGAACTGCACGCTGGAGGGCCGCTACCGGCCCACCCTGCTCAAGCGAGGTTTCAA CGAGACTGCCTTCCTCTATGCCATCTCCTCGGCTGGCCTGACGCACGCACTGGCCAAGGCGTGCAGCGCGGGC CGCATGGAGCGCTGTACCTGCGATGAGGCACCCGACCTGCAGAACCGTGAGGCCTGGCAGTGGGGGGGCTGCG GAGACAACCTTAAGTACAGCAGCAAGTTCGTCAAGGAATTCCTGGGCAGACGGTCAAGCAAGGATCTGCGAGC CCGTGTGGACTTCCACAACAACCTCGTGGGTGTGAACGTGATCAAGGCTGGGGTGGAGACCACCTGCAAGTGC CACGGCGTGTCAGGCTCATGCACGGTGCGGACCTGCTGGCGGCAGTTGGCGCCTTTCCATGAGGTGGGCAAGC ATCTGAAGCACAAGTATGAGACGGCACTCAAGGTGGGCAGCACCACCAATGAAGCTGCCGGCGAGGCAGGTGC CATCTCCCCACCACGGGGCCGTGCCTCGGGGGCAGGTGGCAGCGACCCGCTGCCCCGCACTCCAGAGCTGGTG CACCTGGATGACTCGCCTAGCTTCTGCCTGGCTGGCCGCTTCTCCCCGGGCACCGCTGGCCGTAGGTGCCACC GTGAGAAGAACTGCGAGAGCATCTGCTGTGGCCGCGGCCATAACACACAGAGCCGGGTGGTGACAAGGCCCTG CCAGTGCCAGGTGCGTTGGTGCTGCTATGTGGAGTGCAGGCAGTGCACGCACCGTGAGGAGGTCTACACCTGC AAGGGCTGAGTTCCCAGGCCCTGCCAGCCCTGC NOV4a, CG53054-02 Protein Sequence SEQ ID NO:80 357 aa MW at 39756.1 kD MAPLGYFLLLCSLKQALGSYPIWWLTGSEPLTILPLTLEPEAAAQAHYKACDRLKLERKQRRNCRRDPGVAET LVEAVSMSALECQFQFRFERWNCTLEGRYRASLLKRGFKETAFLYAISSAGLTHALAKACSAGRMERCTCDEA PDLENREAWQWGCCGDNLKYSSKFVKEFLGRRSSKDLRARVDFHNNLVGVKVIKAGVETTCKCHGVSGSCTVR TCWRQLAPFHEVGKHLKHKYETALKVGSTTNEAAGEAGAISPPRGRASGAGGSDPLPRTPELVHLDDSPSFCL AGRFSPGTAGRRCHREKNCESICCGRGHNTQSRVVTRPCQCQVRWCCYVECRQCTQREEVYTCKG NOV4b, 170251039 SEQ ID NO:81 1029 bp DNA Sequence ORF Start: at 1 ORF Stop: end of sequence GGATCCAGCTACCCGATCTGGTGGCTGACGGGCAGCGAGCCCCTGACCATCCTCCCGCTGACCCTGGAGCCAG AGGCGGGCGCCCAGCCCCACTACAAGGCCTGCGACCGGCTGAAGCTGGAGCGGAAGCAGCGGCGCATGTGCCG CCGGGACCCGGGCGTGGTAGAGACGCTGGTCGAGGCCGTGAGCATGAGTGCGCTCGAGTGCCAGTTCCAGTTC CGCTTTGAGCGCTGGAACTGCACGCTGGAGGGCCGCTACCGGGCCAGCCTGCTCAAGCGAGGCTTCAAGGAGA CTGCCTTCCTCTATGCCATCTCCTCGGCTGGCCTGACGCACGCACTGGCCAAGGCGTGCAGCGCGGGCCGCAT GGAGCGCTGTACCTGCGATGAGGCACCCGACCTGGAGAACCGTGAGGCCTGGCAGTGGGGGGGCTGCGGAGAC AACCTTAAGTACAGCAGCAAGTTCGTCAAGGAATTCCTGGGCAGACGGTCAAGCAAGGATCTGCGAGCCCGTG TGGACTTCCACAACAACCTCGTGGGTGTGAAGGTGATCAAGGCTGGGGTGGAGACCACCTGCAAGTGCCACGG CGTGTCAGGCTCATGCACGGTGCGGACCTGCTGGCGGCAGTTGGCGCCTTTCCATGAGGTGGGCAAGCATCTG AAGCACAAGTATGAGACGGCACTCAAGGTGGGCAGCACCACCAATGAAGCTGCCGGCGAGGCAGGTGCCATCT CCCCACCACGGGGCCGTGCCTCGGGGGCAGGTGGCAGCGACCCCCTGCCCCGCACTCCAGAGCTGGTGCACCT GGATGACTCGCCTAGCTTCTGCCTGGCTGGCCGCTTCTCCCCGGGCACCGCTGGCCGTAGGTGCCACCGTGAG AAGAACTGCGAGAGCATCTGCTGTGGCCGCGGCCATAACACACAGAGCCGGGTGGTGACAAGGCCCTGCCAGT GCCAGGTGCGTTGGTCCTCCTATGTGGAGTGCAGGCAGTGCACGCAGCGTGAGGAGGTCTACACCTGCAAGGG CGTCGAC NOV4b, 170251039 Protein Sequence SEQ ID NO:82 343 aa MW at 38208.1 kD GSSYPIWWLTGSEPLTILPLTLEPEAGAQAHYKACDRLKLERKQRRMCRRDPGVVETLVEAVSMSALECQFQF RFERWNCTLEGRYRASLLKRCFKETAFLYAISSAGLTHALAKACSACRNERCTCDEAPDLENREAWQWGGCGD NLKYSSKFVKEFLGRRSSKDLRARVDFHNNLVGVKVIKAGVETTCKCHGVSGSCTVRTCWRQLAPFHEVGKML KHKYETALKVGSTTNEAAGEAGAISPPRGRASGAGGSDPLPRTPELVHLDDSPSFCLAGRFSPGTAGRRCHRE KNCESICCGRGHNTQSRVVTRPCQCQVRWCCYVECRQCTQREEVYTCKGVD NOV4c, 170251076 SEQ ID NO:83 1029 bp DNA Sequence ORF Start: at 1 ORF Stop: end of sequence GGATCCAGCTACCCGATCTGGTGGCTGACGGGCAGCGAGCCCCTCACCATCCTCCCGCTGACCCTGGAGCCAG AGGCGGCCGCCCAGGCGCACTACAAGGCCTGCGACCGGCTGAAGCTGGAGCGGAAGCAGCGGCGCATGTGCCG CCGGGACCCGGGCGTGGCAGAGACGCTGGTGGAGGCCGTGAGCATGAGTGCGCTCGAGTGCCAGTTCCAGTTC CGCTTTGAGCGCTGGAACTGCACGCTGGAGGGCCGCTACCGGGCCAGCCTGCTCAAGCGAGGCTTCAAGGAGA CTGCCTTCCTCTATGCCATCTCCTCGGCTGGCCTGACGCACGCACTGGCCAAGGCGTGCAGCGCGGGCCGCAT GGAGCGCTGTACCTGCGATGAGGCACCCGACCTGGAGAACCGTGAGGCCTGGCAGTGGGGGGCCTGCGGAGAC AACCTTAAGTACAGCAGCAAGTTCGTCAAGGAATTCCTGGGCACACGGTCAAGCAAGGATCTGCGAGCCCGTG TGGACTTCCACAACAACCTCGTGGGTGTGAAGGTGATCAAGGCTGGGGTGGAGACCACCTGCAAGTGCCACGG CGTGTCAGGCTCATGCACGGTGCGGACCTGCTGGCGGCAGTTGGCGCCTTTCCATGAGGTGGGCAAGCATCTG AAGCACAAGTATGAGACGGCACTCAAGGTGGGCAGCACCACCAATGAAGCTGCCGGCGAGGCAGGTGCCATCT CCCCACCACGGGGCCGTGCCTCGGGGGCAGGTGGCAGCGACCCGCTGCCCCGCACTCCAGAGCTGGTGCACCT GGATGACTCGCCTAGCTTCTGCCTGCCTGGCCGCTTCTCCCCGGGCACCGCTGGCCGTAGGTGCCACCGTGAG AAGAACTGCGAGAGCATCTGCTGTGGCCGCGGCCATAACACACAGAGCCGGGTGGTGACAAGGCCCTGCCAGT GCCAGGTGCGTTGTGCTGCTATGTGGAGTGCAGGCAGTCCACGCAGCGTGAGGAGGTCTACACCTGCAAGOG CGTCGAC NOV4c, 170251076 Protein Sequence SEQ ID NO:84 343 aa MW at 38194.1 kD GSSYPIWWLTGSEPLTILPLTLEPEAAAQAHYKACDRLKLERKQRRMCRRDPGVAETLVEAVSMSALECQFQF RFERWNCTLEGRYRASLLKRGFKETAFLYAISSAGLTHALAKACSAGRMERCTCDEAPDLENREAWQWGGCGD NLKYSSKFVKEFLGRRSSKDLRARVDFHNNLVGVKVIKAGVETTCKCHGVSGSCTVRTCWRQLAPFHEVGKHL KHKYETALKVGSTTNEAAGEAGAISPPRGRASGAGGSDPLPRTPELVHLDDSPSFCLAGRFSPGTAGRRCHRE KNCESICCGRGHNTQSRVVTRPCQCQVRWCCYVECRQCTQREEVYTCKGVD NOV4d, CG53054-01 SEQ ID NO:85 1085 bp DNA Sequence ORF Start: ATG at 13 ORF Stop: end of sequence TAGTGAGCCGAGATGGCACTACTATATTCCAGCTTGGGTGTGGTTGTGTGCACCTGTAGTCCTAGTTACTTTG GACTGACGGGCAGCGAGCCCCTGACCATCCTCCCGCTGACCCTGGAGCCAGAGGCGGCTGCCCAGGCGCACTA CAAGGCCTGCGACCGGCTGAAGCTGGAGCGGAAGCAGCGGCGCATGTGCCGCCGGGACCCGGGCGTGGCAGAG ACGCTGCTGCAGGCCGTGACCATGAGTGCGCTCGAGTGCCAGTTCCAGTTCCGCTTTGAGCGCTGGAACTGCA CGCTGGAGGGCCGCTACCGGGCCAGCCTGCTCAAGCGAGGTTTCAAGGAGACTGCCTTCCTCTATGCCATCTC CTCGGCTGGCCTGACGCACGCACTGGCCAAGGCGTGCACCGCGGGCCGCATGGAGCGCTGTACCTGCGATGAG GCACCCGACCTGGAGAACCGTCAGGCCTGGAAGTGGGGTGGCTGTAGCGAGGACATCGAGTTTGGTGGGATGG TGTCTCGGGAGTTCGCCGACGCCCGGGAGAACCGGCCAGATGCCCGCTCAGCCATGAACCGCCACAACAACGA GGCTGGGCGCCAGGTGATCAAGGCTGGGGTGGAGACCACCTGCAAGTGCCACGGCGTGTCAGGCTCATGCACG GTGCGGACCTGCTGGCGGCAGTTGGCGCCTTTCCATGAGGTGGGCAAGCATCTGAAGCACAAGTATGAGTCGG CACTCAAGGTGGGCAGCACCACCAATGAAGCTGCCGGCGAGGCAGGTGCCATCTCCCCACCACGGGGCCGTGC CTCGGGGGCAGGTGGCAGCGACCCGCTGCCCCGCACTCCAGAGCTGGTGCACCTGGATGACTCGCCTAGCTTC TGCCTGGCTGGCCGCTTCTCCCCGGGCACCGCTGGCCGTAGGTGCCACCGTGAGAAGAACTGCGAGAGCATCT GCTGTGGCCGCGCCCATAACACACAGAGCCGGGTGGTGACAAGGCCCTGCCAGTGCCAGGTGCGTTGGTGCTG CTATGTGGAGTGCAGGCAGTGCACGCAGCGTGAGGAGGTCTACACCTGCAAGGGCTGAGTTCC NOV4d, CG53054-01 Protein Sequence SEQ ID NO:86 355 aa MW at 39194.1 kD MALLYSSLGVVVCTCSPSYFGLTGSEPLTILPLTLEPEAAAQAHYKACDRLKLERKQRRMCRRDPGVAETLVE AVSMSALECQFQFRFERWNCTLEGRYRASLLKRGFKETAFLYAISSAGLTHALAKACSAGRMERCTCDEAPDL ENREGWKWGGCSEDIEFGGMVSREFADARENRPDARSANNRHNNEAGRQVIKAGVETTCKCHGVSGSCTVRTC WRQLAPFHEVGKHLKHKYESALKVGSTTNEAAGEAGAISPPRGRASCAGGSDPLPRTPELVHLDDSPSFCLAG RFSPGTAGRRCHREKNCESICCGRGHNTQSRVVTRPCQCQVRWCCYVECRQCTQREEVYTCKG NOV4e, CG53054-03 SEQ ID NO:87 1029 bp DNA Sequence ORF Start: at 7 ORF Stop: end of sequence GCATCCAGCTACCCGATCTGGTGGCTGACGGGCAGCGAGCCCCTGACCATCCTCCCGCTGACCCTGGAGCCAG AGGCGGCCGCCCAGGCGCACTACAAGGCCTGCGACCGGCTGAAGCTGGAGCGGAAGCAGCGGCGCATGTGCCG CCGGGACCCGGCCCTGCCAGAGACGCTGGTGGAGGCCGTGAGCATGAGTGCGCTCGAGTGCCAGTTCCAGTTC CGCTTTGAGCGCTGGAACTGCACGCTGGAGGGCCGCTACCGGGCCAGCCTGCTCAAGCGAGGCTTCAAGGAGA CTGCCTTCCTCTATGCCATCTCCTCGGCTGGCCTGACGCACGCACTGGCCAAGGCGTGCAGCGCGGGCCGCAT GGAGCGCTGTACCTGCGATGAGGCACCCGACCTGGAGAACCGTGAGGCCTGGCAGTGGGGGGGCTGCGGAGAC AACCTTAAGTACAGCAGCAAGTTCGTCAAGGAATTCCTGGGCAGACGGTCAAGCAAGGATCTGCGAGCCCGTG TGGACTTCCACAACAACCTCGTGGGTGTGAAGGTGATCAAGGCTGGGGTGGAGACCACCTGCAAGTGCCACGG CGTGTCAGGCTCATGCACGGTGCGGACCTGCTGGCGGCAGTTGGCGCCTTTCCATGAGGTGGGCAAGCATCTG AAGCACAAGTATGAGACGGCACTCAAGGTGGGCAGCACCACCAATGAAGCTGCCGGCGAGGCAGGTGCCATCT CCCCACCACGGGGCCGTGCCTCGGGGGCAGGTGGCAGCGACCCGCTGCCCCGCACTCCAGAGCTGGTGCACCT GGATGACTCGCCTAGCTTCTGCCTGGCTGGCCGCTTCTCCCCGGGCACCGCTGGCCGTAGGTGCCACCGTGAG AAGAACTGCGAGAGCATCTGCTGTGGCCGCGGCCATAACACACAGAGCCGGGTGGTGACAAGGCCCTGCCAGT GCCAGGTGCGTTGGTGCTGCTATGTGGAGTGCAGGCAGTGCACGCAGCGTGAGGAGGTCTACACCTGCAAGGG CGTCGAC NOV4e, CG53054-03 Protein Sequence SEQ ID NO:88 339 aa MW at 37835.8 kD SYPIWWLTGSEPLTILPLTLEPEAAAQAHYKACDRLKLERKQRRMCRRDPGVAETLVEAVSMSALECQFQFRF ERWNCTLEGRYRASLLKRGFKETAFLYAISSAGLTHALAKACSAGRNERCTCDEAPDLENREAWQWGGCGDNL KYSSKFVKEFLGRRSSKDLRARVDFHNNLVGVKVIKAGVETTCKCHGVSGSCTVRTCWRQLAPFHEVGKHLKH KYETALKVGSTTNEAAGEAGAISPPRGRASGAGGSDPLPRTPELVHLDDSPSFCLAGRFSPGTAGRRCHREKN CESICCGRGHNTQSRVVTRPCQCQVRWCCYVECRQCTQREEVYTCKG NOV4f, CG53054-04 SEQ ID NO:89 1631 bp DNA Sequence ORF Start: ATG at 12 ORF Stop: end of sequence GGCGCGGCAAGATGCTGGATGGGTCCCCGCTGGCGCGCTGGCTGGCCGCGGCCTTCGGGCTGACGCTGCTGCT CGCCGCGCTGCGCCCTTCGGCCGCCTACTTCGGGCTGACGGGCAGCGAGCCCCTGACCATCCTCCCGCTGACC CTGGAGCCAGAGGCGGCCGCCCAGGCGCACTACAAGGCCTGCGACCGGCTGAAGCTGGAGCGGAAGCAGCGGC GCATGTGCCGCCGGGACCCGGGCGTGGCAOAGACGCTGGTGGAGGCCGTGAGCATGAGTGCGCTCGAGTGCCA GTTCCAGTTCCGCTTTGAGCGCTGGAACTGCACGCTGGAGGGCCGCTACCGGGCCACCCTGCTCAAGCGAGGC TTCAAGGAGACTGCCTTCCTCTATGCCATCTCCTCGGCTGGCCTGACGCACGCACTGGCCAAGGCGTGCAGCG CGGGCCGCATGGAGCGCTGTACCTGCGATGAGGCACCCGACCTGGAGAACCGTGAGGCCTGGCAGTGGGGGGG CTGCGGAGACAACCTTAAGTACAGCAGCAAGTTCGTCAAGGAATTCCTGGGCAGACGGTCAAGCAAGGATCTG CGAGCCCGTGTGGACTTCCACAACAACCTCGTGGGTGTGAAGGTGATCAAGGCTGGGGTGGAGACCACCTGCA AGTGCCACGGCGTGTCAGGCTCATGCACCGTGCGGACCTGCTGGCGGCAGTTGGCGCCTTTCCATGACGTGGG CAAGCATCTGAAGCACAAGTATGAGACGGCACTCAAGGTGGGCAGCACCACCAATGAAGCTGCCGGCGAGGCA GGTGCCATCTCCCCACCACGGGGCCGTGCCTCGGGGGCACGTGGCAGCGACCCGCTGCCCCGCACTCCAGAGC TGGTGCACCTGGATGACTCGCCTAGCTTCTGCCTGGCTGGCCGCTTCTCCCCGGGCACCGCTGGCCGTAGGTG CCACCGTGAGAAGAACTGCGAGAGCATCTGCTGTGGCCGCGGCCATAACACACAGAGCCGGGTGGTGACAAGG CCCTGCCAGTGCCAGGTGCGTTGGTGCTGCTATGTGGAGTGCAGGCAGTGCACGCACCGTGAGGAGGTCTACA CCTGCAAGGGCTGAGTTCCCAGGCCCTGCCAGCCCTGCTGCACAGGGTGCAGGCATTGCACACGGTGTGAAGG GTCTACACCTGCACAGGCTGAGTTCCTGGGCTCGACCAGCCCAGCTGCGTGGGGTACAGGCATTGCACACAGT GTGAATGGGTCTACACCTGCATGGGCTGAGTCCCTGGGCTCAGACCTAGCAGCGTGGGGTAGTCCCTGGGCTC AGTCCTAGCTGCATGGGGTGCAGGCATTGCACAGAGCATGAATGGGCCTACACCTCCCAAGGCTGAATCCCTG GGCCCAGCCAGCCCTGCTGCACATGGCACAGGCATTGCACACGGTGTGAGGAGTGTACACCTGCAAGGGCTGA GGCCCTGGGCCCAGTCAGCCCTGCTGCTCAGAGTGCAGGCATTGCACATGGTGTGAGAAGGTCTACACCTGCA AGGGACGAGTCCCCGGGCCTGGCCAACCCTGCTGTGCAGGGTGAGGGCCATGCATGCTAGTATGAGGGGTCTA CACCTGCAAGGACTGACAGGCTTTT NOV4f, CG53054-04 Protein Sequence SEQ ID NO:90 365 aa MW at 403 19.7 kD MLDGSPLARWLAAAFGLTLLLAALRPSAAYFGLTGSEPLTILPLTLEPEAAAQAIYKACDRLKLERKQRRMCR RDPGVAETLVEAVSMSALECQFQFRFERWNCTLEGRYRASLLKRGFKETAFLYAISSAGLTHALAKACSAGRM ERCTCDEAPDLENREAWQWGGCGDNLKYSSKFVKEFLGRRSSKDLRARVDFHNNLVGVKVIKAGVETTCKCHG VSGSCTVRTCWRQLAPFHEVGKHLKHKYETALKVGSTTNEAAGEAGAISPPRGRASGAGGSDPLPRTPELVHL DDSPSFCLAGRFSPGTAGRRCHREKNCESICCGRGHMTQSRVVTRPCQCQVRWCCYVECRQCTQREEVYTCKG

[0377] A ClustalW comparison of the above protein sequences yields the following sequence alignment shown in Table 4B. 21 TABLE 4B Comparison of the NOV4 protein sequences. NOV4a --------MAPLGYFLLLCSLKQALGSYPIWWLTGSEPLTILPLTLEPEAAAQAHYKACD (SEQ ID NO:80) NOV4b ------------------------GSSYPIWWLTGSEPLTILPLTLEPEAGAQAHYKACD (SEQ ID NO:82) NOV4c ------------------------GSSYPIWWLTGSEPLTILPLTLEPEAAAQAHYKACD (SEQ ID NO:84) NOV4d -----------MALLYSSLGVVVCTCSPSYFGLTGSEPLTILPLTLEPEAAAQAHYKACD (SEQ ID NO:86) NOV4e --------------------------SYPIWWLTGSEPLTILPLTLEPEAAAQAHYKACD (SEQ ID NO:88) NOV4f MLDGSPLARWLAAAFGLTLLLAALRPSAAYFGLTGSEPLTILPLTLEPEAAAQARYKACD (SEQ ID NO:90) NOV4a RLKLERKQRRMCRRDPGVAETLVEAVSMSALECQFQFRFERWNCTLEGRYRASLLKRGFK NOV4b RLKLERKQRRMCRRDPGVVETLVEAVSMSALECQFQFRFERWNCTLEGRYRASLLKRGFK NOV4c RLKLERKQRRMCRRDPGVAETLVEAVSMSALECQFQFRFERWNCTLEGRYRASLLKRGFK NOV4d RLKLERKQRRMCRRDPGVAETLVEAVSMSALECQFQFRFERWNCTLEGRYRASLLKRGFK NOV4e RLKLERKQRRMCRRDPGVAETLVEAVSMSALECQFQFRFERWNCTLEGRYRASLLKRGFK NOV4f RLKLERKQRRMCRRDPGVAETLVEAVSMSALECQFQFRFERWNCTLEGRYRASLLKRGFK NOV4a ETAFLYAISSAGLTHALAKACSAGRMERCTCDEAPDLENREAWQWGCCGDNLKYSSKFVK NOV4b ETAFLYAISSAGLTHALAKACSAGRNERCTCDEAPDLENREAWQWGGCGDNLKYSSKFVK NOV4c ETAFLYAISSAGLTHALAKACSAGRMERCTCDEAPDLENREAWQWGGCGDNLKYSSKFVK NOV4d ETAFLYAISSAGLTHALAKACSAGRMERCTCDEAPDLENREGWKWGGCSEDIEFGGMVSR NOV4e ETAFLYAISSAGLTHALAKACSAGRMERCTCDEAPDLENREAWQWGGCGDNLKYSSKFVK NOV4f ETAFLYAISSAGLTHALAKACSAGRMERCTCDEAPDLENREAWQWGGCGDNLKYSSKFVK NOV4a EFLGRRSSK-DLRARVDFHNNLVGVKVIKAGVETTCKCHGVSGSCTVRTCWRQLAPFHEV NOV4b EFLGRRSSK-DLRARVDFHNNLVGVKVIKAGVETTCKCHGVSGSCTVRTCWRQLAPFHEV NOV4c EFLGRRSSK-DLRARVDFHNNLVGVKVIKAGVETTCKCHGVSGSCTVRTCWRQLAPFHEV NOV4d EFADARENRPDARSANNRHNNEAGRQVIKAGVETTCKCHGVSGSCTVRTCWRQLAPFHEV NOV4e EFLGRRSSK-DLRARVDFHNNLVGVKVIKAGVETTCKCHCVSGSCTVRTCWRQLAPFHEV NOV4f EFLGRRSSK-DLRARVDFHNNLVGVKVIKAGVETTCKCHGVSGSCTVRTCWRQLAPFHEV NOV4a GKHLKHKYETALKVGSTTNEAAGEACAISPPRGRASGAGGSDPLPRTPELVHLDDSPSFC NOV4b GKHLKHKYETALKVGSTTNEAAGEAGAISPPRGRASGAGGSDPLPRTPELVHLDDSPSFC NOV4c CKHLKHKYETALKVGSTTNEAAGEAOAISPPRGRASGAGGSDPLPRTPELVHLDDSPSFC NOV4d GKHLKHKYESALKVGSTTNEAAGEAGAISPPRGRASGAGGSDPLPRTPELVHLDDSPSFC NOV4e GKHLKHKYETALKVGSTTNEAAGEAGAISPPRGRASGAGGSDPLPRTPELVHLDDSPSFC NOV4f GKHLKHKYETALKVGSTTNEAAGEAGAISPPRGRASGAGGSDPLPRTPELVHLDDSPSFC NOV4a LAGRFSPGTAGRRCHREKNCESICCGRGHNTQSRVVTRPCQCQVRWCCYVECRQCTQREE NOV4b LAGRFSPGTAGRRCHREKNCESICCGRGHNTQSRVVTRPCQCQVRWCCYVECRQCTQREE NOV4c LAGRFSPGTAGRRCHREKNCESICCGRGHNTQSRVVTRPCQCQVRWCCYVECRQCTQREE NOV4d LAGRFSPGTAGRRCHREKNCESICCGRGHNTQSRVVTRPCQCQVRWCCYVECRQCTQREE NOV4e LAGRFSPGTAGRRCHREKNCESICCGRGHNTQSRVVTRPCQCQVRWCCYVECRQCTQREE NOV4f LAGRFSPGTAGRRCHREKNCESICCGRGHNTQSRVVTRPCQCQVRWCCYVECRQCTQREE NOV4a VYTCKG-- NOV4b VYTCKGVD NOV4c VYTCKGVD NOV4d VYTCKG-- NOV4e VYTCKG-- NOV4f VYTCKG--

[0378] Further analysis of the NOV4a protein yielded the following properties shown in Table 4C. 22 TABLE 4C Protein Sequence Properties NOV4a SignalP analysis: Cleavage site between residues 19 and 20 PSORT II analysis: PSG: a new signal peptide prediction method N-region: length 0; pos.chg 0; neg.chg 0 H-region: length 13; peak value 9.00 PSG score: 4.60 GvH: von Heijne's method for signal seq. recognition GvH score (threshold: −2.1): 0.73 possible cleavage site: between 18 and 19 >>> Seems to have a cleavable signal peptide (1 to 18) ALOM: Klein et al's method for TM region allocation Init position for calculation: 19 Tentative number of TMS (s) for the threshold 0.5: 0 number of TMS (s) . . . fixed PERIPHERAL Likelihood = 3.76 (at 114) ALOM score: 3.76 (number of TMSs: 0) MTOP: Prediction of membrane topology (Hartmann et al.) Center position for calculation: 9 Charge difference: 0.0 C(1.0) − N(1.0) N >= C: N-terminal side will be inside MITDISC: discrimination of mitochondrial targeting seq R content: 0 Hyd Moment (75): 1.56 Hyd Moment (95): 3.50 G content: 3 D/E content: 1 S/T content: 4 Score: −6.15 Gavel: prediction of cleavage sites for mitochondrial preseq cleavage site motif not found NUCDISC: discrimination of nuclear localization signals pat4: none pat7: none bipartite: none content of basic residues: 14.8% NLS Score: −0.47 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: KKXX-like motif in the C-terminus: YTCK SKL: peroxisomal targeting signal in the C-terminus: none PTS2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none NMYR: N-myristoylation pattern: none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: none Dileucine motif in the tail: none checking 63 PROSITE DNA binding motifs: none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination Prediction: nuclear Reliability: 70.6 COIL: Lupas's algorithm to detect coiled-coil regions total: 0 residues Final Results (k = 9/23): 55.6%: extracellular, including cell wall 22.2%: mitochondrial 11.1%: vacuolar 11.1%: nuclear >> prediction for CG53054-02 is exc (k = 9)

[0379] A search of the NOV4a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 4D. 23 TABLE 4D Geneseq Results for NOV4a NOV4a Identities/ Residues/ Similarities for Geneseq Protein/Organism/Length [Patent #, Match the Matched Expect Identifier Date] Residues Region Value ABG69638 Human secreted protein SCEP-18 - 2 . . . 357 311/357 (87%) 0.0 Homo sapiens, 366 aa. 13 . . . 366 327/357 (91%) [WO200248337-A2, 20-JUN-2002] AAO18744 Human NOV8 protein - Homo sapiens, 25 . . . 357 302/334 (90%) 0.0 355 aa. [WO200257450-A2, 22 . . . 355 316/334 (94%) 25-JUL-2002] AAE17305 Human WNT15 protein, 22 . . . 356 210/338 (62%) e−124 sbg389686WNT15a #1 - Homo 14 . . . 346 257/338 (75%) sapiens, 704 aa. [WO200198342-A1, 27-DEC-2001] AAE17306 Human WNT15 protein, 25 . . . 356 209/335 (62%) e−124 sbg389686WNT15a #2 - Homo 31 . . . 360 255/335 (75%) sapiens, 361 aa. [WO200198342-A1, 27-DEC-2001] ABB77769 Amino acid sequence of human Wnt 25 . . . 356 209/335 (62%) e−124 (Zwnt5) polypeptide variant - Homo 4 . . . 333 255/335 (75%) sapiens, 334 aa. [WO200231148-A2, 18-APR-2002]

[0380] In a BLAST search of public sequence databases, the NOV4a protein was found to have homology to the proteins shown in the BLASTP data in Table 4E. 24 TABLE 4E Public BLASTP Results for NOV4a NOV4a Identities/ Protein Residues/ Similarities for Accession Match the Matched Expect Number Protein/Organism/Length Residues Portion Value O14904 WNT-14 protein precursor - Homo 2 . . . 357 339/356 (95%) 0.0 sapiens (Human), 365 aa. 13 . . . 365 343/356 (96%) Q8R5M2 Wnt14 - Mus musculus (Mouse), 365 2 . . . 357 333/356 (93%) 0.0 aa. 13 . . . 365 340/356 (94%) O42280 WNT-14 protein precursor - Gallus 25 . . . 356 283/333 (84%) e−173 gallus (Chicken), 354 aa. 24 . . . 353 310/333 (92%) Q8C718 WNT14B - Mus musculus (Mouse), 8 . . . 356 216/354 (61%) e−125 359 aa. 12 . . . 358 264/354 (74%) Q8VI90 Wnt14b (Secreted signaling protein 8 . . . 356 216/354 (61%) e−125 WNT9B) - Mus musculus (Mouse), 12 . . . 358 264/354 (74%) 359 aa.

[0381] PFam analysis predicts that the NOV4a protein contains the domains shown in the Table 4F. 25 TABLE 4F Domain Analysis of NOV4a Identities/Similarities NOV4a for the Pfam Domain Match Region Matched Region Expect Value wnt 50 . . . 356 129/359 (36%) 4.6e−103 234/359 (65%)

Example 5

[0382] The NOV5 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 5A. 26 TABLE 5A NOV5 Sequence Analysis NOV5a, CG54818-01 SEQ ID NO:91 6474 bp DNA Sequence ORF Start: ATG at 467 ORF Stop: end of sequence GTTTGGCAAGTCAGTGCAAGAGGCTGACTTCTGAGAGGCTTCCAGCAGCCCGAAGAGAGGACCTCCACGGGAG AAGGGAGTGCGTGTGCTCGGTTTTTTTTTTTTCTCTCTTTTTTTTTTTTTTTTCTGAATGAACAGCTTTGCCC AAGTGACTGAAAAATACAGCTTCTTCCTGAATCTACCGGCGTAGTTGCTGAAGAGCGCTCTAGACAGGACATG GCTCTGAAGACTCACTCTTTGGAATGTCCTCTTGCTCCCGGCTTATAAACAACTGTCCCGAGGAAAGAAAGGT TTTACATAGCCAAATACAGCCTGACAAATGGCACTTCGGAACTGTCCTTTCTGATGACAACCCGTTCGATTTC TGACAAAGCCTCTCGCACGCTGCCCCTGGAGGGAAGTCCTAAGTAAAACTCAGACCCTCCTTAAAGTGAGGAG CGAGGGCTTGGACGGTGAACACGGCAGCATGGCATCCGCGGGGCACATTATCACCTTGCTCCTGTGGGGTTAC TTACTGGAGCTTTGGACAGGAGGTCATACAGCTGATACTACCCACCCCCGGTTACGCCTGTCACATAAAGAGC TCTTGAATCTGAACAGAACATCAATATTTCATAGCCCTTTTGGATTTCTTGATCTCCATACAATGCTGCTGGA TGAATATCAAGAGAGGCTCTTCGTGGGAGGCAGGGACCTTGTATATTCCCTCAGCTTGGAGAGAATCAGTGAC GGCTATAAAGAGATACACTGGCCGAGTACAGCTCTAAAAATGGAAGAATGCATAATGAAGGGAAAAGATGCGG GTGAATGTGCAAATTATGTTCGGGTTTTGCATCACTATAACAGGACACACCTTCTGACCTGTGGTACTGGAGC TTTTGATCCAGTTTGTGCCTTCATCAGAGTTGGATATCATTTGGAGGATCCTCTGTTTCACCTGGAATCACCC AGATCTGAGAGAGGAAGGGGCAGATGTCCTTTTGACCCCAGCTCCTCCTTCATCTCCACTTTAATTGGTAGTG AATTGTTTGCTGGACTCTACAGTGACTACTGGAGCAGAGACGCTGCGATCTTCCGCAGCATGGGGCGACTGGC CCATATCCGCACTGAGCATGACGATGAGCGTCTGTTGAAAGAACCAAAATTTGTAGGTTCATACATGATTCCT GACAATGAAGACAGAGATGACAACAAAGTATATTTCTTTTTTACTGAGAAGGCACTGGAGGCAGAAAACAATG CTCACGCAATTTACACCAGGGTCGGGCGACTCTGTGTGAATGATGTAGGAGGGCAGACAATACTGGTGAATAA GTCGAGCACTTTCCTAAAAGCGAGACTCGTTTGCTCAGTACCAGGAATGAATGGAATTGACACATATTTTGAT GAATTAGAGGACGTTTTTTTGCTACCTACCAGAGATCATAAGAATCCAGTGATATTTGGACTCTTTAACACTA CCAGTAATATTTTTCGAGGGCATGCTATATGTGTCTATCACATGTCTAGCATTCGGGCAGCCTTCAACGGACC ATATGCACATAAGGAAGGACCTGAATACCACTGGTCAGTCTATGAAGGAAAAGTCCCTTATCCAAGGCCTGGT TCTTGTGCCAGCAAAGTAAATGGAGGGAGATACGGAACCACCAAGGACTATCCTCATGATGCCATCCGATTTG CAAGAAGTCATCCACTAATGTACCAGGCCATAAAACCTGCCCATAAAAAACCAATATTGGTAAAAACAGATGG AAAATATAACCTGAAACAAATAGCAGTAGATCGAGTGGAAGCTGAGGATGGCCAATATGACGTCTTGTTTATT GGCACAGATAATGGAATTGTGCTGAAAGTAATCACAATTTACAACCAAGAAATGGAATCAATGGAAGAAGTAA TTCTAGAAGAACTTCAGATATTCAAGGATCCAGTTCCTATTATTTCTATGGACATTTCTTCAAAACGGCAACA GCTGTATATTGGATCTGCTTCTGCTGTGGCTCAAGTCAGATTCCATCACTGTGACATGTATGGAAGTGCTTGT GCTGACTGCTOCCTGGCTCGAGACCCTTACTGTGCCTGGGATGGCATATCCTGCTCCCGGTATTACCCAACAG GCACACATGCAAAAAGGCGTTTCCGGAGACAACATGTTCGACATGGAAATGCAGCTCAGCAGTGCTTTGGACA ACAGTTTGTTGGGGATGCTTTGGATAAGACTGAAGAACATCTGGCTTATGGCATAGAGAACAACAGTACTTTG CTGGAATGTACCCCACGATCTTTACAAGCGAAAGTTATCTGGTTTGTACAGAAAGGACGTGAGACAAGAAAAG AGGAGGTGAAGACAGATGACAGAGTGGTTAAGATGGACCTTGGTTTACTCTTCCTAAGGTTACACAAATCAGA TGCTGGGACCTATTTTTGCCAGACAGTAGAGCATAGCTTTGTCCATACGGTCCGTAAAATCACCTTGGAGGTA GTGGAAGAGGAGAAAGTCGAGGATATGTTTAACAAGGACGATGAGGAGGACAGGCATCACAGGATGCCTTGTC CTGCTCAGAGTAGCATCTCGCAGGGAGCAAAACCATGGTACAAGGAATTCTTGCAGCTGATCGGTTATAGCAA CTTCCAGAGAGTCGAAGAATACTGCGAGAAAGTATGGTGCACAGATAGAAAGAGGAAAAAGCTTAAAATGTCA CCCTCCAAGTGGAAGTATGCCAACCCTCAGGAAAAGAAGCTCCGTTCCAAACCTGAGCATTACCGCCTGCCCA GGCACACGCTGGACTCCTGATGGGGTGAGACTATCTACTGTCTTTTGAAGAATTTATATTTGGAAAGTAAAAA AGTAAAAAAATAAATCATCCAACTTCTTTGCATTACTTAAAAGAGATTTCTGTAATACAGGAATGACTATGAA GGTGTTATAATAAATTATTCTACATACTCATTTGACTGGATAAACTTTACATAAAATTAACTAATTTTTTAAA TAAATGCATTCCTTAATGGTTTCTCATTATGTTTATCAAAAAACAACTGTAGCTCTTATTTTCAGTACTTGGC TGCTTTTCTGTGAAAATTATTATTTTACTTTTGGAAGACAAGATTATTAGAATATTGAAGAAAAATTGGAGAC TTATAATCATCGTAAATATAAAACTAAATATGTTTTAATATTTCTGAATTTTTCTTTTCCATCACAATGTAAG ATATGCAGAATACAAGATACTTTGGCATTCTCATGTGAACTTTCTGTACTCTTTAAGGATTATTTTATTAGTG TTGTTTAAGCCATGAGTGTTAAGTAGCAGGTGTGTTGTGAGTGCTGTAACCCATGAAAGGAAAAATGTCATTC TGAGGCTTGTGCCCTTCGTAAAATATTCATTAAAGTACATTCACACTATTTTTGCTTTATAACACAGTCTTTA ATTTTCACTCACTGTGGAAATAAAAACTAAGGTAACTTCTCAGAAAGATATCAAATCTCAGAAAGAATGTCAA ATCAGATGAAGTTATAGTTAGGATTCTAACTACTCTAAAAGATTTTTGCTTCCCTCTTGTGGTAAAAAAAATT ATATTCTCACACATTTCTTTTTTCTCTACAGACGGATATCTGTTTAGGAAAGATTTGAAAGCAGATTATCAGT AGGTACATGGATACATCAAGTTCATTTCCAGAAACAAATAACTGAAATAAAAAACATGTTAATCCTTGTATCA TACTTTAATATGAAAGTATTGTTTATAGATAATTTATCTCACAAGTCAAAAATGAAGATTTTGCAGCACTGAA AATCTATTAAAGCTCCAAATTTTAAGTTTCTAAATAATCTTCGCTGAAATCTAAAATATACTATAACAACCGT GTTTTATTTGTGAAAAAAATATTAAAGTGATTTGCTCTCAAATATCAAATTTTCTTCTCTCTTTTATATTAAG AGACACAAAATTGTTTCATGAGTTCACTTAACTACTGAGATATTCAGAGCATTTTTACCTCTCTCTTAAATGT TATAAAAAACAATTGTATTTTTAAGAATGTTTATTTATCAAAGTCTTTCCTTCTTCTATTAAATATTTAGCAA TTACCTTTCTAAAATATGAAATTTTGTAAGATGTTTTCACCTAAATAAAAATTGAAAGCAAGTGGATTACACA GGAGAACCATTATGAACATTTATTTAGATATTAATCTTAAACAGTGTTTATTTCAGTTTTCAAAGTTAGCTTA TAGGTTATACATTTAAGTTAAAGTGCTCATAATCACTTGCAATTTCATTGTAAAATGAACAAATACATAAATA TTTTAAGAAAAATTTAAGTTTATTCAGATAAGTCACCATGCTTCAAAAGATCTAAGAAATGCAAATATACTGA AAATTGACATCCTCTGAAAATTCCACTTGCTATTTACCCAAGAATCCACTGGAGGTCATTACTGCCATTAAAT AATAACTGAAAAGACTATGTAGTGAAATGTATTTTTAAAAACTATATTCAGTAAAAGCCTGCTCAATTTGGAG AAATAGAACCACAAACACAGATCACAGGGGCCTTACAAAGTTTATGTCTGAACAAATAAGTCAATTAAGTACA CTTTATTGAAAATTGCCTTCCATTAACACACAAGAAAGAAAGCACGATTTTCTCCTGTATCTGAATTTTAAAA TTAAAAAGGCAGATAAGACATAAATAGTTATCATTTTAATTGCAATAACACAGACAAGTAGTTAATGATGATA ACAATGGTGTAACTTGTAAACTAAATATTTGGTAACTGAAGCAATAGGCAGAGGAAAATAGCTTTTCTATGAC ACAAGTCATAAGAAGTCCATATACTGAAGAGCGTTTGATTAAAATAAAGTCACTATTAACCAGAAAAGAAACA TTTTACATAAAATGCTAAAATTTATTATAGCAAAATAAATCAAACCCAAAGAAAGTTTATTCAATGCTAATTT GAAAGAAAATTGATAAGAAAACTTTGAGGGCCCAAGTCCACAATTTGGTGAGACCACTAAATTTTACATATAA TTATACACACACATATGTACATATATATGTATATAATCTTGCTTCCCGCCTGTTTATGGCAGTACTGAAGAGA AATGGGAAAGAAGAGGGAGGGAGAGAGAAAGACGAAGGGAGAGAGAAAGCAGTTTCCAAGGATATGTTTCATG TCCCACCATTTTCTCAGTTTCTCCCTCTCTCTCCCAACACACACACACACACACCCCTCACATACTATAAAAT AAATCTTCACTGCCCTATCAAAATACAAATAAATCAATCTATGCTGTTCTGTCCTTCTTGAGAATCTAAAACA TACCACAAAAATACATCCCCAGTCTTTTGTTCTGTCTGAGGTTAGAATTAATTCAAATTCAGAATCTGTTGTG AGAAATGCCCAGGCTTTAAAAATTAAAAATGGATGGATCTTCTCTGAACTCAGGGAGGGCACATACTTAGATA CCTACAAGACTTGGAGGAATTAAGAGTTCACCCTTCATCTCACCAAATTTTCCCCATTTTTCTCTTTCTTGTA GAAGGAGAGAAACCATGCTCTCTAGCAACATTGAGCAAAAATCATAACCACTCATCTAATTTCTAAGAGGCAC CTCCATCGAGGGCCGGTCTCCTGCTTCTTTAGACCTCTTCTATCTTTGTTACAGGAGAGGACCTGTGGATAGA CTTAGTTTTCACATAAAACAATGCCCATTCACCTCCTCCTTCAGCACAACGTCACCCATTGGGCAAGAGATCC AGATTTGTTAACAAAAAAGATTTTACTTCGTGATTCCACGTCTATAATTCTATATTGCTAATTTTTTCTTTTG TGTGAATTACTGAATATTTCAGACCAAAGCTATCAACTTGGAGAAACAGGGATTAAAAATAAGGATAAACACT AATAAGAGCTCTAGAAAAAAGGGAACAGAAAGTCTGCCTGTTTAGTAAGTGGCAATTCCATACATATTTTAGA GTTTTTTCTATCTAAAATTAGTTAAATACTTAGAATGTTTGTAATGAGTGTTCGATATTTGCTATAGGTTTTA GGGTTTTGTAAATCTTCATAGTAATTATAAACATTTGTAAAATTTGTAAAATACTATAAGTCATTTTGAGTGT TGGTGTTAAGCATGAAACAAACAGCAGCTGTTGTCCTTAAAAATGAATTGACCTGGCCGGGCGCGGTGGCTCA CGCCTGTAATCCCAGCACTTTGGGAGGCCGAGGCGGGTGGATCATGAGGTCAGGAGATGGAGACCATCCTGGC TAACAAGGTGAAACCCCGTCTCTACTAAAAATACAAAAAATTAGCCGGGCGCGGTGGCGGGCGCCTGTAGTCC CAGCTACTTGGGAGGCTGAGGCAGGAGAATGGCGTGAACCCGGGAAGCGGAGCTTGCAGTGAGCCGAGATTGC GCCACTGCAGTCCGCAGTCCGGCCTGGGCGACAGAGCGAGACTCCGTCTC NOV5a, CG54818-01 Protein Sequence SEQ ID NO:92 775 aa MW at 89226.6 kD MASAGHIITLLLWGYLLELWTGGHTADTTHPRLRLSHKELLNLNRTSIFHSPFGFLDLHTMLLDEYQERLFVG GRDLVYSLSLERISDGYKEIHWPSTALKMEECIMKGKDAGECANYVRVLHHYNRTHLLTCGTGAFDPVCAFIR VGYHLEDPLFHLESPRSERGRGRCPFDPSSSFISTLIGSELFAGLYSDYWSRDAAIFRSMGRLAHIRTEHDDE RLLKEPKFVGSYMIPDNEDRDDNKVYFFFTEKALEAENNAHAIYTRVGRLCVNDVGGQRILVNKWSTFLKARL VCSVPGMNGIDTYFDELEDVFLLPTRDHKNPVIFGLFNTTSNIFRGHAICVYHMSSIRAAFNGPYAHKEGPEY HWSVYEGKVPYPRPGSCASKVNGGRYGTTKDYPDDAIRFARSHPLMYQAIKPAHKKPILVKTDGKYNLKQIAV DRVEAEDGQYDVLFIGTDNGIVLKVITIYNQEMESMEEVILEELQIFKDPVPIISMEISSKRQQLYIGSASAV AQVRFHHCDMYGSACADCCLARDPYCAWDGISCSRYYPTGTHAKRRFRRQDVRHGNAAQQCFGQQFVGDALDK TEEHLAYGIENNSTLLECTPRSLQAKVIWFVQKGRETRKEEVKTDDRVVKMDLGLLFLRLHKSDAGTYFCQTV EHSFVHTVRKITLEVVEEEKVEDMFNKDDEEDRHHRMPCPAQSSISQGAKPWYKEFLQLIGYSNFQRVEEYCE KVWCTDRKRKKLKMSPSKWKYANPQEKKLRSKPEHYRLPRHTLDS NOV5b, CG54818-02 SEQ ID NO:93 2373 bp DNA Sequence ORF Start: ATG at 23 ORF Stop: end of sequence CTTGGACGGTGAACACGGCAGCATGGCATCCGCGGGGCACATTATCACCTTGCTCCTGTGGGGTTACTTACTG GAGCTTTGGACAGGAGGTCATACAGCTGATACTACCCACCCCCGGTTACGCCTGTCACATAAAGAGCTCTTGA ATCTGAACAGAACATCAATATTTCATAGCCCTTTTGGATTTCTTGATCTCCATACAATGCTGCTGGATGAATA TCAAGAGAGGCTCTTCGTGGGAGGCAGGGACCTTGTATATTCCCTCAGCTTGGAGAGAATCAGTGACGGCTAT AAAGAGATACACTGGCCGAGTACAGCTCTAAAAATGGAAGAATGCATAATGAAGGGAAAAGATGCGGGTGAAT GTGCAAATTATGTTCGGGTTTTGCATCACTATAACAGGACACACCTTCTGACCTGTGGTACTGGAGCTTTTGA TCCAGTTTGTGCCTTCATCAGAGTTGGATATCATTTGGAGGATCCTCTGTTTCACCTCGAATCACCCAGATCT GAGAGAGGAAGGGGCAGATGTCCTTTTGACCCCAGCTCCTCCTTCATCTCCACTTTAATTGGTAGTGAATTGT TTGCTGGACTCTACAGTGACTACTGGAGCAGAGACGCTGCGATCTTCCCCAGCATGGGGCGACTGGCCCATAT CCGCACTGAGCATGACGATGAGCGTCTGTTGAAAGAACCAAAATTTGTAGGTTCATACATGATTCCTGACAAT GAAGACAGAGATGACAACAAAGTATATTTCTTTTTTACTGAGAAGCCACTGGAGGCAGAAAACAATGCTCACG CAATTTACACCAGGGTCGGGCGACTCTGTGTGAATGATGTAGGAGGGCAGAGAATACTGGTGAATAAGTGGAG CACTTTCCTAAAAGCGAGACTCGTTTGCTCAGTACCAGGAATGAATGGAATTGACACATATTTTGATGAATTA GAGGACGTTTTTTTGCTACCTACCAGAGATCATAAGAATCCAGTGATATTTGGACTCTTTAACACTACCAGTA ATATTTTTCGAGGGCATGCTATATGTGTCTATCACATGTCTAGCATTCGGGCAGCCTTCAACGGACCATATGC ACATAAGGAAGGACCTGAATACCACTGGTCAGTCTATGAAGGAAAACTCCCTTATCCAAGGCCTGGTTCTTGT GCCAGCAAAGTAAATGGAGGGAGATACGGAACCACCAAGGACTATCCTGATGATGCCATCCGATTTGCAAGAA GTCATCCACTAATGTACCAGGCCATAAAACCTGCCCATAAAAAACCAATATTAGTAAAAACAGATGGAAAATA TAACCTGAAACAAATAGCAGTAGATCGAGTGGAAGCTGAGCATGGCCAATATGACGTCTTGTTTATTGGGACA GATAATGGAATTGTGCTGAAAGTAATCACAATTTACAACCAAGAAATGGAATCAATGGAAGAAGTAATTCTAG AAGAACTTCAGATATTCAAGGATCCAGTTCCTATTATTTCTATGGAGATTTCTTCAAAGCGGCAACAGCTGTA TATTGGATCTGCTTCTGCTGTGGCTCAAGTCAGATTCCATCACTGTGACATGTATGGAAGTGCTTGTGCTGAC TGCTGCCTGGCTCGAGACCCTTACTGTGCCTGGGATGGCATATCCTGCTCCCGGTATTACCCAACAGGCACAC ATGCAAAAAGGCGTTTCCGGAGACAAGATGTTCGACATGCAAATGCAGCTCAGCAGTGCTTTGGACAACAGTT TGTTGGGGATCCTTTGGATAAGACTGAAGAACATCTGGCTTATGGCATAGAGAACAACAGTACTTTGCTGGAA TGTACCCCACGATCTTTACAAGCGAAAGTTATCTGGTTTGTACAGAAAGGACGTGAGACAAGAAAAGAGGAGG TGAAGACAGATGACAGAGTGGTTAAGATGGACCTTGGTTTACTCTTCCTAAGGTTACACAAATCAGATGCTGG GACCTATTTTTGCCAGACAGTAGAGCATAGCTTTGTCCATACGGTCCGTAAAATCACCTTGGAGGTAGTGGAA GAGGAGAAAGTCGAGGATATGTTTAACAAGGACGATGAGGAGGACAGGCATCACAGGATGCCTTGTCCTGCTC AGAGTAGCATCTCGCAGGGAGCAAAACCATGGTACAAGGAATTCTTGCAGCTGATCGGTTATAGCAACTTCCA GAGAGTGGAAGAATACTGCGAGAAAGTATGGTGCACAGATAGAAAGAGGAAAAAGCTTAAAATGTCACCCTCC AAGTGGAAGTATGCCAACCCTCAGGAAAAGAAGCTCCGTTCCAAACCTGAGCATTACCGCCTGCCCAGGCACA CGCTGGACTCCTGATGGGGTGAGACTATCTACTGTCT NOV5b, CG54818-02 Protein Sequence SEQ ID NO:94 755 aa MW at 89226.6 kD MASAGHIITLLLWGYLLELWTGGHTADTTHPRLRLSHKELLNLNRTSIFHSPFGFLDLHTMLLDEYQERLFVG GRDLVYSLSLERISDGYKEIHWPSTALKMEECIMKGKDAGECANYVRVLHHYIRTHLLTCGTGAFDPVCAFIR VGYHLEDPLFHLESPRSERGRGRCPFDPSSSFISTLIGSELFAGLYSDYWSRDAAIFRSMGRLAHIRTEHDDE RLLKEPKFVGSYMIPDNEDRDDNKVYFFFTEKALEAENNAHAIYTRVGRLCVNDVGGQRILVNKWSTFLKARL VCSVPGMNGIDTYFDELEDVFLLPTRDHKNPVIFGLFNTTSNIFRGHAICVYHMSSIRAAFNGPYAHKEGPEY HWSVYEGKVPYPRPGSCASKVNGGRYGTTKDYPDDAIRFARSHPLMYQAIKPAHKKPILVKTDGKYNLKQIAV DRVEAEDGQYDVLFIGTDNGIVLKVITIYNQEMESMEEVILEELQIFKDPVPIISMEISSKRQQLYIGSASAV AQVRFHHCDMYGSACADCCLARDPYCANDGISCSRYYPTGTHAKRRFRRQDVRHGNAAQQCFGQQFVGDALDK TEEHLAYGIENNSTLLECTPRSLQAKVIWFVQKGRETRKEEVKTDDRVVKMDLGLLFLRLHKSDAGTYFCQTV EHSFVIITVRKITLEVVEEEKVEDMFNKDDEEDRHRNPCPAQSSISQGAKPWYKEFLQLIGYSNFQRVEEYCE KVWCTDRKRKKLKMSPSKWKYANPQEKKLRSKPEHYRLPRHTLDS NOV5c, CG54818-03 SEQ ID NO:95 2347 bp DNA Sequence ORF Start: ATG at 14 ORF Stop: end of sequence CACCGGTACCACCATGGCATCCGCGGGGCACATTATCACCTTGCTCCTGTGGGGTTACTTACTGGAGCTTTAA ACAGGAGGTCATACAGCTGATACTACCCACCCCCGGTTACGCCTGTCACATAAAGAGCTCTTGAATCTGAACA GAACATCAATATTTCATAGCCCTTTTGGATTTCTTGATCTCCATACAATGCTGCTGGATGAATATCAAGAGAG GCTCTTCGTGGGAGGCAGCGACCTTGTATATTCCCTCAGCTTGGAGAGAATCAGTGACGGCTATAAAGAGATA CACTGGCCGAGTACAGCTCTAAAAATGGAAGAATGCATAATGAAGGGAAAAGATGCGGGTGAATGTGCAAATT ATGTTCGGGTTTTGCATCACTATAACAGGACACACCTTCTGACCTGTGGTACTGGAGCTTTTGATCCAGTTTG TGCCTTCATCAGAGTTGGATATCATTTGGAGGATCCTCTGTTTCACCTGGAATCACCCAGATCTGAGAGAGGA AGCGGCAGATGTCCTTTTGACCCCAGCTCCTCCTTCATCTCCACTTTAATTGGTAGTGAATTGTTTGCTGGAC TCTACAGTGACTACTGGAGCAGAGACGCTGCGATCTTCCGCAGCATGGGGCGACTGGCCCATATCCGCACTGA GCATGACGATGAGCGTCTGTTGAAAGAACCAAAATTTGTAGGTTCATACATGATTCCTGACAATGAAGACAGA GATGACAACAAAGTATATTTCTTTTTTACTGAGAAGGCACTGGAGGCAGAAAACAATGCTCACGCAATTTACA CCAGGGTCGGGCGACTCTGTGTGAATGATGTAGGAGGGCAGAGAATACTGGTGAATAAGTGGAGCACTTTCCT AAAAGCGAGACTCGTTTGCTCAGTACCAGGAATGAATGGAATTGACACATATTTTGATGAATTAGAGGACGTT TTTTTGCTACCTACCAGAGATCATAAGAATCCAGTGATATTTGGACTCTTTAACACTACCAGTAATATTTTTC GAGGGCATGCTATATGTGTCTATCACATGTCTACCATTCGGGCAGCCTTCAACGGACCATATGCACATAAGGA AGGACCTGAATACCACTGGTCAGTCTATGAAGGAAAAGTCCCTTATCCAAGGCCTGGTTCTTGTGCCAGCAAA GTAAATGGAGGGAGATACGGAACCACCAAGGACTATCCTGATGATGCCATCCGATTTGCAAGAAGTAATCCAC TAATGTACCAGGCCATAAAACCTGCCCATAAAAAACCAATATTAGTAAAAACAGATGGAAAATATAACCTGAA ACAAATAGCAGTAGATCGAGTGGAAGCTGAGGATGGCCAATATGACGTCTTGTTTATTGGGACAGATAATAAA ATTGTGCTGAAAGTAATCACAATTTACAAACCAAGAATGGAATCAATGGAAGAAGTAATTCTAGAAGAACTTC AGATATTCAAGGATCCAGTTCCTATTATTTCTATGCAGATTTCTTCAAAGCGGCAACAGCTGTATATTGGATC TGCTTCTGCTGTGGCTCAAGTCAGATTCCATCACTGTGACATGTATGGAAGTGCTTGTGCTGACTGCTGCCTG GCTCGAGACCCTTACTGTGCCTGGGATGGCATATCCTGCTCCCGGTATTACCCAACAGGCACACATGCAAAAA GGCGTTTCCGGAGACAAGATGTTCGACATGGAAATGCAGCTCAGCAGTGCTTTGGACAACAGTTTGTTGGGGA TGCTTTGGATAAGACTGAAGAACATCTGGCTTATGGCATAGAGAACAACAGTACTTTGCTGGAATGTACCCCA CGATCTTTACAAGCGAAAGTTATCTGGTTTGTACAGAAAGGACGTGAGACAAGAAAAGAGGAGGTGAAGACAG ATGACAGAGTGGTTAAGATGGACCTTGGTTTACTCTTCCTAAGGTTACACAAATCAGATGCTGGCACCTATTT TTGCCAGACAGTAGAGCATAGCTTTGTCCATACGGTCCGTAAAATCACCTTGGAGGTAGTGGAAGAGGAGAAA GTCGAGGATATGTTTAACAAGGACGATGAGGAGGACAGGCATCACAGGATGCCTTGTCCTGCTCAGAGTAGCA TCTCGCAGGGAGCAAAACCATGGTACAAGGAATTCTTGCAGCTGATCGGTTATAGCAACTTCCAGAGAGTGGA AGAATACTGCGAGAAAGTATGGTGCACAGATAGAAAGAGGAAAAAGCTTAAAATGTCACCCTCCAAGTGGAAG TATGCCAACCCTCAGGAAAAGAAGCTCCGTTCCAAACCTGAGCATTACCGCCTGCCCAGGCACACGCTGGACT CCGTCGACCGC NOV5c, CG54818-03 Protein Sequence SEQ ID NO:96 775 aa MW at 89226.6 kD MASAGHIITLLLWGYLLELWTGGHTADTTHPRLRLSHKELLNLNRTSIFHSPFGFLDLHTMLLDEYQERLFVG GRDLVYSLSLERISDGYKEIHWPSTALKMEECIMKGKDAGECANYVRVLHHYNRTHLLTCGTGAFDPVCAFIR VGYHLEDPLFHLESPRSERGRGRCPFDPSSSFISTLIGSELFAGLYSDYWSRDAAIFRSMGRLAHIRTEHDDE RLLKEPKFVGSYMIPDNEDRDDNKVYFFFTEKALEAENNAHAIYTRVGRLCVNDVGGQRILVNKWSTFLKAAA VCSVPGMNGIDTYFDELEDVFLLPTRDHAAPVIFGLFNTTSNIFRGHAICVYHMSSIRAAFNGPYAAAAGPEY HWSVYEGKVPYPRPGSCASKVNGGRYGTTKDYPDDAIRFARSHPLMYQAIKPAHKKPILVKTDGKYNLKQIAV DRVEAEDGQYDVLFIGTDNGIVLKVITIYNQEMESMEEVILEELQIFKDPVPIISMEISSKRQQLYIGSASAV AQVRFHHCDMYGSACADCCLARDPYCAWDGISCSRYYPTGTHAKRRFRRQDVRHGNAAQQCFGQQFVGDALDK TEEHLAYGIENNSTLLECTPRSLQAKVIWFVQKGRETRKEEVKTDDRVVKMDLGLLFLRLHKSDAGTYFCQTV EHSFVHTVRKITLEVVEEEKEDMFNKDDEEDRHHRMPCPAQSSISQGAKPWYKEFLQLIGYSNFQRVEEYACE KVWCTDRKRKKLKMSPSKWKYANPQEKKLRSKPEHYRLPRHTLDS NOV5d, CG54818-04 SEQ ID NO:97 2347 bp DNA Sequence ORF Start: ATG at 14 ORF Stop: end of sequence CACCTCGCGAACCATGGCATCCGCGCGGCACATTATCACCTTGCTCCTGTGGGGTTACTTACTGGACCTTTAA ACAGGAGGTCATACAGCTGATACTACCCACCCCCGGTTACGCCTGTCACATAAAGAGCTCTTGAATCTGAACA GAACATCAATATTTCATAGCCCTTTTGGATTTCTTGATCTCCATACAATGCTGCTGGATGAATATCAAGAGAG GCTCTTCGTGGGAGGCAGGGACCTTGTATATTCCTCAGCTTGGAGAGAATCAGTGACGGCTATAAAAGAGATA CACTGGCCGAGTACAGCTCTAAAAATGGAAGAATGCATAATGAAGGGAAAAGATGCGGGTGAATGTGCAAATT ATGTTCGGGTTTTGCATCACTATAACAGGACACACCTTCTGACCTGTGGTACTGGAGCTTTTGATCCAGTTTG TGCCTTCATCAGAGTTGGATATCATTTGGAGGATCCTCTGTTTCACCTGGAATCACCCAGATCTGAGAGAGGA AGGGGCAGATGTCCTTTTGACCCCAGCTCCTCCTTCATCTCCACTTTAATTGGTAGTGAATTGTTTGCTGGAC TCTACAGTGACTACTGGAGCAGAGACGCTGCGATCTTCCGCAGCATGGAACGACTGGCCCATATCCGCACTGA GCATGACGATGAGCGTCTGTTGAAAGAACCAAAATTTGTAGGTTCATACATGATTCCTGACAATGAAGACAGA GATGACAACAAAGTATATTTCTTTTTTACTGAGAAGGCACTGGAGGCAGAAAACAATGCTCACGCAATTTACA CCAGGGTCGGGCGACTCTGTGTGAATGATGTAGGAGGGCAGAGAATACTGGTGAATAAGTGGAGCACTTTCCT AAAGCGAGACTCGTTTGCTCAGTACCAGGAATGAATGGAATTGACACATATTTTGATGAAATTAGAAAACGTT TTTTTGCTACCTACCAGAGATCATAAGAATCCAGTGATATTTGGACTCTTTAACACTACCAGTAATATTTTTC GAGGGCATGCTATATGTGTCTATCACATGTCTAGCATTCAAGCAGCCTTCAACAAACCATATGCACATAAGGA AGGACCTGAATACCACTGGTCAGTCTATGAAGGAAAAGTCCCTTATCCAAGGCCTGGTTCTTGTGCCAGCAAA GTAAATGGAGGGAGATACGGAACCACCAAGGACTATCCTGATGATGCCATCCGATTTGCAAGAAGTCATCCAC TAATGTACCAGGCCATAAAACCTGCCCATAAAAAACCAATATTAGTAAAAACAGATGGAAAATATAACCTGAA ACAAATAGCAGTAGATCGAGTGGAAGCTGAGGATGGCCAATATGACGTCTTGTTTATTGAAACAGATAATAAA ATTGTGCTGAAAGTAATCACAATTTACAACCAAGAAATGGAATCAATGGAAGAAGTAATTCTAGAAGAACTTC AGATATTCAAGGATCCAGTTCCTATTATTTCTATGGAGATTTCTTCAAAGCGGCAACAGCTGTATATTGGATC TGCTTCTGCTGTGGCTCAAGTCAGATTCCATCACTGTGACATGTATGGAAGTGCTTGTGCTGACTGCTGCCTG GCTCGAGACCCTTACTGTGCCTGGGATGGCATATCCTGCTCCCGGTATTACCCAACAAACACACATGCAAAAA GGCGTTTCCGGAGACAAGATGTTCGACATGGAAATGCAGCTCAGCAGTGCTTTGGACAACAGTTTGTTGGGGA TGCTTTGGATAAGACTGAAGAACATCTCGCTTATGGCATAGAGAACAACAGTACTTTGCTGGAATGTACCCCA CGATCTTTACAAGCGAAAGTTATCTGGTTTGTACAGAAAGGACGTGAGACAAGAAAAGAGGAGGTGAAGACAG ATGACAGAGTGGTTAAGATGGACCTTGGTTTACTCTTCCTAAGGTTACACAAATCAGATGCTAAGACCTATTT TTGCCAGACAGTAGAGCATAGCTTTGTCCATACGGTCCGTAAAATCACCTTGGAGGTAGTGGAAGAGGAGAAA GTCGAGGATATGTTTAACAAGGACGATGAGCAGGACAGGCATCACAGGATGCCTTGTCCTGCTCAGAGTAGCA TCTCGCACGGAGCAAAACCATGGTACAAGGAATTCTTGCAGCTGATCGGTTATAGCAACTTCCAGAGAGTAAA AGAATACTGCGAGAAAGTATGGTGCACAGATAGAAAGAGGAAAAAGCTTAAAATGTCACCCTCCAAGTGGAAG TATGCCAACCCTCAGGAAAAGAAGCTCCGTTCCAAACCTGAGCATTACCGCCTGCCCAGGCACACGCTGGACT CCCCCGGGGGC NOV5d, CG54818-04 Protein Sequence SEQ ID NO:98 775 aa MW at 89226.6 kD MASAGHIITLLLWGYLLELWTGGHTADTTHPRLRLSHKELLNLNRTSIFHSPFGFLDLHTMLLDEYQERLAAG GRDLVYSLSLERISDGYKEIHWPSTALKMEECIMKGKDAGECANYVRVLHHYNRTHLLTCGTGAFDPVCAFIR VGYHLEDPLFHLESPRSERGRGRCPFDPSSSFISTLIGSELFAGLYSDYWSRDAAIFRSMGRLARIRTEHDDE RLLKEPKFVGSYMIPDNEDRDDNKVYFFFTEKALEAENNAHAIYTRVGRLCVNDVGGQRILVNKWSTFLKARL VCSVPGMNGIDTYFDELEDVFLLPTRDHKNPVIFGLFNTTSNIFRGHAICVYHMSSIRAAFNCPYAHKEGPEY HWSVYEGKVPYPRPGSCASKVNGGRYGTTKDYPDDAIRFARSHPLMYQAIKPAHKKPILVKTDGKYNLKQIAV DRVEAEDGQYDVLFIGTDNGIVLKVITIYNQEMESMEEVILEELQIFKDPVPIISMEISSKRQQLYIGSASAV AGVRFHHCDMYGSACADCCLARDPYCAWDGISCSRYYPTGHAKRRFRRQDVRHGNAAQQCRFGQQFVGDALDK TEEHLAYGIENNSTLLECTPRSLQAKVIWFVQKGRETRKEEVKTDDRVVKMDLGLLFLRLHKSDAGTYFCQAA EHSFVHTVRKITLEVVEEEKVEDMFNKDDEEDRHHRMPCPAQSSISQGAKPWYKEFLQLIGYSNFQRVEEYCE KVWCTDRKRKKLKMSPSKWKYANPQEKKLRSKPEHYRLPRHTLDS

[0383] A ClustalW comparison of the above protein sequences yields the following sequence alignment shown in Table 5B. 27 TABLE 5B Comparison of the NOV5 protein sequences. NOV5a MASAGHIITLLLWGYLLELWTGGHTADTTHPRLRLSHKELLHLNRTSIFHSPFGFLDLHT (SEQ ID NO: 92) NOV5b MASAGHIITLLLWGYLLELWTGGHTADTTHPRLRLSHKELLNLMRTSIFHSPFGFLDLHT (SEQ ID NO: 94) NOV5c MASAGHIITLLLWGYLLELWTGGHTADTTHPRLRLSHKELLNLNRTSIFHSPFGFLDLHT (SEQ ID NO: 96) NOV5d MASAGHIITLLLWGYLLELWTGGHTADTTHPRLRLSHKELLNLNRTSIFHSPFGFLDLHT (SEQ ID NO: 98) NOV5a MLLDEYQERLFVGGRDLVYSLSLERISDGYKEIHWPSTALKMEECIMKGKDAGECAAYAA NOV5b MLLDEYQERLFVGGRDLVYSLSLERISDGYKEIHWPSTALKMEECIMKGKDAGECANYVR NOV5c MLLDEYQERLFVGGRDLVYSLSLERISDGYKEIHWPSTALKMEECIMKGKDAGECANYVR NOV5d MLLDEYQERLFVGGRDLVYSLSLERISDGYKEIHWPSTALKMEECIMKGKDAGECANYVR NOV5a VLHHYNRTHLLTCGTGAFDPVCAFIRVGYHLEDPLFHLESPRSERGRGRCPFDPSSSFIS NOV5b VLHHYNRTHLLTCGTGAFDPVCAFIRVGYHLEDPLFHLESPRSERGRGRCPFDPSSSFIS NOV5c VLHHYNRTHLLTCGTGAFDPVCAFIRVGYHLEDPLFHLESPRSERGRGRCPFDPSSSFIS NOV5d VLHHYNRTHLLTCGTGAFDPVCAFIRVGYHLEDPLFHLESPRSERGRGRCPFDPSSSFIS NOV5a TLIGSELFAGLYSDYWSRDAAIFRSMGRLAHIRTEHDDERLLKEPKFVGSYMIPDNEDRD NOV5b TLIGSELFAGLYSDYWSRDAAIFRSMGRLAHIRTEHDDERLLKEPKFVGSYMIPDNEDRD NOV5c TLIGSELFAGLYSDYWSRDAAIFRSMGRLAHIRTEHDDERLLKEPKFVGSYMIPDNEDRD NOV5d TLIGSELFAGLYSDYWSRDAAIFRSMGRLAHIRTEHDDERLLKEPKFVGSYMIPDNEDRD NOV5a DNKWYFFFTEKALEAENNAHAIYTRVGRLCVNDVGGQRILVNKWSTFLKARLVCSVPGAA NOV5b DNKVYFFFTEKALEAENNAHAIYTRVGRLCVNDVGGQRILVNKWSTFLKAALVCSVPGAA NOV5c DNKVYFFFTEKALEAENNAHAIYTRVGRLCVNDVGGQRILVNKWSTFLAAVCVCSVPGAA NOV5d DNKVYFFFTEKALEAENNAHAIYTRVGRLCVNDVGGQRILVNKWSTFLKARLVCSVPGAA NOV5a GIDTYFDELEDVFLLPTRDHKNPVIFGLFNTTSNIFRGHAIGVYHMSSIRAAFNGPYAAK NOV5b GIDTYFDELEDVFLLPTRDHKNPVIFGLFNTTSNIFRGHAIGVYHMSSIRAAFNGPYAAK NOV5c GIDTYFDELEDVFLLPTRDHAAPVIFGLFNTTSNIFRGHAICVYHMSSIRAAFNGPYAAK NOV5d GIDTYFDELEDVFLLPTRDHAAPVIFGLFNTTSNIFRGHAICVYHMSSIAAAFNGPYAAK NOV5a EGPEYHWSVYEGKVPYPRPGSCASKVNGGRYGTTKDYPDDAIRFARSHPLMYQAIKPAHK NOV5b EGPEYHWSWYEGKVPYPRPGSCASKVNGGRYGTTKDYPDDAIRFARSHPLMYQAIKPAAK NOV5c EGPEYHWSVYEGKVPYPRPGSCASKMGGRYGTTKDYPDDAIRFARSHPIAAWQAIKPAAK NOV5d EGPEYHWSVYEGKVPYPRPGSCASKVNGGRYGTTKDYPDDAIRFARSHPLMYQAIKPAAK NOV5a KPILVKTDGKYNLKQIAVDRVEAEDGQYDVLFIGTDNGIVLKVITIYNQEMESMEEVILE NOV5b KPILVKTDGKYNLKQIAVDRVEAEDGQYDVLFIGTDNGIVLKVITIYMQEMESMEEVILE NOV5c KPILVKTDGKYNLKQIAVDRVEAEDGQYDVLFIGTDNGIVLKVITIYMQEMESMEEVILE NOV5d KPILVKTDGKYNLKOIAVDRVEAEDGQYDVLFIGTDNGIVLKVITIYNQEMESMEEVILE NOV5a ELQIFKDPVPIISMEISSKRQQLYIGSASAVAQVRFHHCDMYGSACADCCLARDPYCAWD NOV5b ELQIFKDPVPIISMEISSKRQQLYIGSASAVAQVRFHHCDMYGSACADCCLARDPYCAWD NOV5c ELQTFKDPVPIISMEISSKRQQLYIGSASAVAQVRFHHCDMYGSACADCCLARDPYCAWD NOV5d ELQIFKDPVPIISMEISSKROQLYIGSASAVAQVRFHHCDMYGSACADCCLARDPYCAWD NOV5a GISCSRYYPTGTHAKRRFRRQDVRHGNAAQQCFGQQFVGDAIDKTEEHLAYGIENNSTLL NOV5b GISCSRYYPTGTHAKRRFRRQDVRHGNAAQQCFGQQFVGDALDKTEEHLAYGIEAASTLL NOV5c GISCSRYYPTGTHAKRRFRRQDVRHGNAAQQCFGQQFVGDALDKTEEHLAYGIEAASTLL NOV5d GISCSRYYPTGTHAKRRFRRQDVRHGNAAQQCFGQQFVGDALDKTEEHLAYGIEAASTLL NOV5a ECTPRSLQAKVIWFVQKGRETRKEEVKTDDRVVKMDLGLLFLRLHKSDAGTYFCQTVEHS NOV5b ECTPRSLQAKVIWFVQKGRETRKEEVKTDDRVVKMDLGLLFLRLHKSDAGTYFCQTVEHS NOV5c ECTPRSLQAKVIWFVQKGRETRKEEVKTDDRVVKMDLGLLFLRLHKSDAGTYFCQTVEHS NOV5d ECTPRSLQAKVIWFVQKGRETRKEEVKTDDRVVKMDLGLLELRLHKSDAGTYFCQTAAHS NOV5a FVHTVRKITLEVVEEEKVEDNFNKDDEEDRHHRMPCPAQSSISQGAKPWYKEFLQLIGYS NOV5b FVMTVRKITLEVVEEEKVEDMFNKDDEEDRHHRMPCPAQSSISQGAKPWYKEFLQLIGYS NOV5c FVHTVRKITLEVVEEEKVEDMFNKDDEEDRHHRMPCPAQSSISQGAKPWYKEFLQLIGYS NOV5d FVHTVRKITLEVVEEEKVEDMFNKDDEEDRHHRMPCPAQSSISQGAKPWYKEFLQLIGYS NOV5a NFQRVEEYCEKVWCTDRKRKKLKMSPSKWKYANPQEKKLRSKPEHYRLPRHTLDS NOV5b NFQRVEEYCEKVWCTDRKRKKLKMSPSKWKYANPQEKKLRSKPEHYRLPRHTLDS NOV5c NFQRVEEYCEKVWCTDRKRKKLKMSPSKWKYANPQEKKLRSKPEHYRLPRHTLDS NOV5d NFQRVEEYCEKVWCTDRKRKKLKMSPSKWKYANPQEKKLRSKPEHYRLPRHTLDS

[0384] Further analysis of the NOV5a protein yielded the following properties shown in Table 5C. 28 TABLE 5C Protein Sequence Properties NOV5a SignalP analysis: Cleavage site between residues 27 and 28 PSORT II analysis: PSG: a new signal peptide prediction method N-region: length 0; pos.chg 0; neg.chg 0 H-region: length 17; peak value 9.78 PSG score: 5.38 GvH: von Heijne's method for signal seq. recognition GvH score (threshold: −2.1): −3.54 possible cleavage site: between 23 and 24 >>> Seems to have no N-terminal signal peptide ALOM: Klein et al's method for TM region allocation Init position for calculation: 1 Tentative number of TMS(s) for the threshold 0.5: 1 Number of TMS(s) for threshold 0.5: 0 PERIPHERAL Likelihood = 0.58 (at 1) ALOM score: −0.53 (number of TMSs: 0) MTOP: Prediction of membrane topology (Hartmann et al.) Center position for calculation: 6 Charge difference: −1.5 C(0.0) − N(1.5) N >= C: N-terminal side will be inside MITDISC: discrimination of mitochondrial targeting seq R content: 0 Hyd Moment(75): 2.30 Hyd Moment(95): 4.12 G content: 2 D/E content: 1 S/T content: 2 Score: −6.11 Gavel: prediction of cleavage sites for mitochondrial preseq cleavage site motif not found NUCDISC: discrimination of nuclear localization signals pat4: RKRK (5) at 737 pat4: KRKK (5) at 738 pat7: PQEKKLR (3) at 754 bipartite: none content of basic residues: 13.2% NLS Score: 0.41 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: none SKL: peroxisomal targeting signal in the C-terminus: none PTS2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none NMYR: N-myristoylation pattern: none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: none Dileucine motif in the tail: none checking 63 PROSITE DNA binding motifs: Leucine zipper pattern (PS00029): *** found *** LDLHTMLLDEYQERLFVGGRDL at 56 none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination Prediction: cytoplasmic Reliability: 76.7 COIL: Lupas's algorithm to detect coiled-coil regions total: 0 residues Final Results (k = 9/23): 39.1%: cytoplasmic 30.4%: mitochondrial 17.4%: nuclear 4.3%: extracellular, including cell wall 4.3%: vacuolar 4.3%: endoplasmic reticulum >> prediction for CG54818-01 is cyt (k = 23)

[0385] A search of the NOV5a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 5D. 29 TABLE 5D Geneseq Results for NOV5a NOV5a Identities/ Residues/ Similarities for Geneseq Protein/Organism/Length [Patent #, Match the Matched Expect Identifier Date] Residues Region Value AAW63748 Human semaphorin - Homo sapiens, 1 . . . 773 698/773 (90%) 0.0 775 aa. [WO9822504-A1, 1 . . . 773 738/773 (95%) 28-MAY-1998] AAY43090 Mouse semaphorin H (Sema H) amino 1 . . . 773 696/773 (90%) 0.0 acid sequence - Mus sp, 775 aa. 1 . . . 773 736/773 (95%) [WO9947671-A2, 23-SEP-1999] AAG62730 Amino acid sequence of mouse 1 . . . 773 677/775 (87%) 0.0 semaphorin Sema3E - Mus sp, 777 aa. 1 . . . 775 721/775 (92%) [WO200138491-A2, 31-MAY-2001] AAY43091 Mouse semaphorin H variant (Sema 1 . . . 773 677/775 (87%) 0.0 Hv) amino acid sequence - Mus sp, 1 . . . 775 721/775 (92%) 777 aa. [WO9947671-A2, 23-SEP-1999] ABG96413 Human ovarian cancer marker M473 - 8 . . . 770 373/770 (48%) 0.0 Homo sapiens, 771 aa. 7 . . . 769 519/770 (66%) [WO200271928-A2, 19-SEP-2002]

[0386] In a BLAST search of public sequence databases, the NOV5a protein was found to have homology to the proteins shown in the BLASTP data in Table 5E. 30 TABLE 5E Public BLASTP Results for NOV5a NOV5a Protein Residues/ Identities/ Accession Match Similarities for the Expect Number Protein/Organism/Length Residues Matched Portion Value O15041 Semaphorin 3E precursor - Homo 1 . . . 775 775/775 (100%) 0.0 sapiens (Human), 775 aa. 1 . . . 775 775/775 (100%) Q9QX23 Semaphorin M-SemaK - Mus 1 . . . 773 698/773 (90%) 0.0 musculus (Mouse), 775 aa. 1 . . . 773 738/773 (95%) P70275 Semaphorin 3E precursor 1 . . . 773 697/773 (90%) 0.0 (Semaphorin H) (Sema H) - Mus 1 . . . 773 737/773 (95%) musculus (Mouse), 775 aa. O42237 Semaphorin 3E precursor 1 . . . 775 632/781 (80%) 0.0 (Collapsin-5) (COLL-5) - Gallus 5 . . . 785 697/781 (88%) gallus (Chicken), 785 aa. Q63548 Semaphorin 3A precursor 8 . . . 770 374/771 (48%) 0.0 (Semaphorin III) (Sema III) - Rattus 7 . . . 770 523/771 (67%) norvegicus (Rat), 772 aa.

[0387] PFam analysis predicts that the NOV5a protein contains the domains shown in the Table 5F. 31 TABLE 5F Domain Analysis of NOV5a Identities/Similarities NOV5a for the Pfam Domain Match Region Matched Region Expect Value Sema 58 . . . 500 240/491 (49%) 3.8e−250 417/491 (85%) ig 595 . . . 656 12/66 (18%) 2.3e−05 46/66 (70%)

Example 6

[0388] The NOV6 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 6A. 32 TABLE 6A NOV6 Sequence Analysis NOV6a, CG55023-01 SEQ ID NO:99 527 bp DNA Sequence ORF Start: ATG at 49 ORF Stop: end of sequence CCGTCAGTCTAGAAGGATAAGAGAAAGAAAGTTAAGCAACTACAGGAAATGGCTTTGGCAGTTCCAATATCAG TCTATCTTTTATTCAACGCAATGACAGCACTGACCGAAGAGGCAGCCGTGACTGTAACACCTCCAATCACAGC CCAGCAAGGTAACTGGACAGTTAACAAAACAGAAGCTCACAACATAGAAGGACCCATAGCCTTGAAGTTCTCA CACCTTTGCCTGGAAGATCATAACAGTTACTGCATCAACGGTGCTTGTGCATTCCACCATGACCTAGAGAAAG CCATCTGCAGGTGTTTTACTGGTTATACTGCAGAAAGGTGTGAGCACTTGACTTTAACTTCATATGCTGTGGA TTCTTATGAAAAATACATTGCAATTGGGATTGGTGTTGGATTACTATTAAGTGGTTTTCTTGTTATTTTTTAC TGCTATATAAGAAAGAGGTGTCTAAAATTGAAATCGCCTTACAATGTCTGTTCTGGAGAAAGACGACCACTGT GAGGCCTTTGTGAAGA NOV6a, CG55023-01 Protein Sequence SEQ ID NO:100 154 aa MW at 17112.6 kD MALGVPISVYLLFNAMTALTEEAAVTVTPPITAQQGNWTVNKTEAHNIEGPIALKFSHLCLEDHNSYCINGAC AFHHELEKAICRCFTGYTGERCEHLTLTSYAVDSYEKYIAIGIGVGLLLSGFLVIFYCYIRKRCLKLKSPYNV CSGERRPL NOV6b, 248209521 SEQ ID NO:101 286 bp DNA Sequence ORF Start: at 2 ORF Stop: end of sequence CACCGGATCCGAAGAGGCAGCCGTGACTGTAACACCTCCAATCACAGCCCAGCAAGGTAACTGGACAGTTAAC AAAACAGAAGCTGACAACATAGAAGGACCCATAGCCTTGAAGTTCTCACACCTTTGCCTGGAAGATCATAACA GTTACTGCATCAACGGTGCTTGTGCATTCCACCATGAGCTAGAGAAAGCCATCTGCAGGTGTTTTACTGGTTA TACTGGAGAAACGTGTGAGCACTTGACTTTAACTTCATATGCTGTGGATTCTTATGAACTCCAGGGC NOV6b, 248209521 Protein Sequence SEQ ID NO:102 95 aa MW at 10423.4 kD TGSEEAAVTVTPPITAQQGNWTVNKTEADNIEGPIALKFSHLCLEDHNSYCINGACAFHHELEKAICRCFTGY TGERCEHLTLTSYAVDSYELEC NOV6c, 317459649 SEQ ID NO:103 331 bp DNA Sequence ORF Start: at 2 ORF Stop: end of sequence CACCGGATCCACCATGGCTTTGGGAGTTCCAATATCAGTCTATCTTTTATTCAACGCAATGACAGCACTGACC GAAGAGGCAGCCGTGACTGTAACACCTCCAATCACAGCCCAGCAAGGTAACTGGACAGTTAACAAAACAGAAG CTGACAACATAGAAGGACCCATAGCCTTGAAGTTCTCACACCTTTGCCTGGAAGATCATAACAGTTACTGCAT CAACGGTGCTTGTGCATTCCACCATGAGCTAGAGAAAGCCATCTGCAGGTGTCTAAAATTGAAATCGCCTTAC AATGTCTGTTCTGCAGAAAGACGACCACTGCTCGAGCGC NOV6c, 317459649 Protein Sequence SEQ ID NO:104 110 aa MW at 11949.6 kD TGSTMALGVPISVYLLFNAMTALTEEAAVTVTPPITAQQGNWTVNKTEADNIEGPIALKFSHLCLEDHNSYCI INGACAFUHELEKAICRCLKLKSPYNVCSGERRPLLEG NOV6d, 317459665 SEQ ID NO:105 358 bp DNA Sequence ORF Start: at 2 ORF Stop: end of sequence CACCGGATCCACCATGGCTTTGGGAGTTCCAATATCAGTCTATCTTTTATTCAACGCAATGACAGCACTGACC GAAGAGGCAGCCGTGACTGTAACACCTCCAATCACAGCCCAGCAAGGTAACTGGACAGTTAACAAAACAGAAG CTGACAACATAGAAGGACCCATAGCCTTGAAGTTCTCACACCTTTGCCTGGAAGATCATAACAGTTACTGCAT CAACGGTGCTTGTGCATTCCACCATGAGCTAGAGAAAGCCATCTGCAGGTGTTTTACTGGTTATACTGGAGAA AGGTGTCTAAAATTGAAATCGCCTTACAATGTCTGTTCTGGAGAAAGACGACCACTGCTCGAGGGC NOV6d, 317459665 Protein Sequence SEQ ID NO:106 119 aa MW at 12964.7 kD TGSTMALGVPISVYLLFNAMTALTEEAAVTVTPPITAQQGNWTVNKTEADNIEGPIALKFSHLCLEDHNSYCI NGACAFHHELEKAICRCFTGYTGERCLKLKSPYNVCSGERRPLLEG NOV6e,317459901 SEQ ID NO:107 331 bp DNA Sequence ORF Start: at 2 ORF Stop: end of sequence CACCGGATCCACCATGGCTTTGGGAGTTCCAATATCAGTCTATCTTTTATTCAACGCAATGACAGCACTGACC GAAGAGGCAGCCGTGACTGTAACACCTCCAATCACAGCCCAGCAAGCTGACAACATAGAAGGACCCATAGCCT TGAAGTTCTCACACCTTTGCCTGGAAGATCATAACAGTTACTGCATCAACGGTGCTTGTGCATTCCACCATGA GCTAGAGAAACCCATCTGCAGGTGTTTTACTGGTTATACTGGAGAAAGGTGTCTAAAATTGAAATCGCCTTAC AATGTCTGTTCTGGAGAAAGACGACCACTGCTCGAGGGC NOV6e, 317459901 Protein Sequence SEQ ID NO:108 110 aa MW at 119346 kD TGSTMALGVPISVYLLFNAMTALTEEAAVTVTPPITAQQADNIEGPIALKFSHLCLEDHNSYCINGACAFHHE LEKAICRCFTGYTGERCLKLKSPYNVCSGERRPLLEG NOV6f, 317459910 SEQ ID NO:109 268 bp DNA Sequence ORF Start: at 2 ORF Stop: end of sequence CACCGGATCCGAAGAGGCAGCCGTGACTGTAACACCTCCAATCACAGCCCAGCAAGCTGACAACATACAAGGA CCCATAGCCTTGAAGTTCTCACACCTTTGCCTGGAAGATCATAACAGTTACTGCATCAACGGTGCTTGTGCAT TCCACCATGAGCTAGAGAAAGCCATCTGCAGGTGTTTTACTGGTTATACTCGAGAAAGGTGTCTAAAATTGAA ATCGCCTTACAATGTCTGTTCTGGAGAAAGACGACCACTGCTCGAGGGC NOV6f, 317459910 Protein Sequence SEQ ID NO:110 89 aa MW at 9725.9 kD TGSEEAAVTVTPPITAQQADNIEGPIALKFSHLCLEDHNSYCINGACAFHHELEKAICRCFTGYTGERCLKLK SPYNVCSGERRPLLEG NOV6g, CG55023-02 SEQ ID NO:111 274 bp DNA Sequence ORF Start: at 18 ORF Stop: end of sequence GAATTCGGCTTGGATCCGAAGAGGCAGCCGTGACTGTAACACCTCCAATCACAGCCCAGCAAGCTGACAACAT AGAAGGACCCATAGCCTTGAAGTTCTCACACCTTTGCCTGGAAGATCATAACAGTTACTGCATCAACGGTGCT TGTGCATTCCACCATGAGCTAGAGAAAGCCATCTGCAGGTGTTTTACTGGTTATACTGGAGAAAGGTGTGAGC ACTTGACTTTAACTTCATATGCTGTGGATTCTTATGAACTCGAGAAGCCGAATTC NOV6g, CG55023-02 Protein Sequence SEQ ID NO:112 80 aa MW at 88483 kD EEAAVTVTPPITAQQADNTEGPIALKFSHLCLEDHNSYCINGACAFHIIELEKAICRCFTGYTGERCEHLTLTS YAVDSYE NOV6h, CG55023-03 SEQ ID NO:113 249 bp DNA Sequence ORF Start: at 1 ORF Stop: end of sequence GAAGAGGCAGCCGTGACTGTAACACCTCCAATCACAGCCCAGCAAGGTAACTGGACAGTTAACAAAACAGAAG CTGACAACATAGAAGGACCCATAGCCTTGAAGTTCTCACACCTTTGCCTGGAAGATCATAACACTTACTGCAT CAACCGTGCTTGTGCATTCCACCATGAGCTAGAGAAAGCCATCTGCAGGTGTCTAAAATTGAAATCGCCTTAC AATGTCTGTTCTGGAGAAAGACGACCACTG NOV6h, CG55023-03 Protein Sequence SEQ ID NO:114 83 aa MW at 9196.3 kD EEAAVTVTPPITAQQGNWTVNKTEADNIEGPIALKFSHLCLEDHNSYCINGACAFHHELEKAICRCLKLKSPY NVCSGERRPL NOV6i, CG55023-04 SEQ ID NO:115 249 bp DNA Sequence ORF Start: at 1 ORF Stop: end of sequence GAAGAGGCAGCCGTGACTGTAACACCTCCAATCACAGCCCAGCAAGCTGACAACATAGAAGGACCCATAGCCT TGAAGTTCTCACACCTTTGCCTGGAAGATCATAACAGTTACTGCATCAACGGTGCTTGTGCATTCCACCATGA GCTAGAGAAAGCCATCTGCAGGTGTTTTACTGGTTATACTGGAGAAAGGTGTCTAPAATTGAAATCGCCTTAC AATGTCTGTTCTGGAGAAAGACGACCACTG NOV6i, CG55023-04 Protein Sequence SEQ ID NO:116 83 aa MW at 9181.3 kD EEAAVTVTPPITAQQADNIEGPIALKFSHLCLEDHNSYCINGACAFHHELEKAICRCFTGYTGERCLKLKSPY NVCSGERRPL NOV6j, CG55023-05 SEQ ID NO:117 267 bp DNA Sequence ORF Start: at 1 ORF Stop: end of sequence GAAGAGGCAGCCCTCACTGTAACACCTCCAATCACAGCCCAGCAAGGTAACTGGACAGTTAACAAAACAGAAG CTCACAACATAGAAGGACCCATAGCCTTGAAGTTCTCACACCTTTGCCTGGAAGATCATAACAGTTACTGCAT CAACGGTGCTTGTGCATTCCACCATGAGCTAGAGAAAGCCATCTGCAGGTGTTTTACTGGTTATACTGGAGAA AGGTGTGAGCACTTGACTTTAACTTCATATGCTGTGGATTCTTATGAA NOV6j,CG55023-05 Protein Sequence SEQ ID NO:118 89 aa MW at 9878.8 kD EEAAVTVTPPITAQQGNWTVNKTEADNIEGPIALKFSHLCLEDHNSYCINGACAFHHELEKAICRCFTGYTGE RCEHLTLTSYAVDSYE NOV6k, CG55023-06 SEQ ID NO:119 286 bp DNA Sequence ORF Start: at 11 ORF Stop: end of sequence CACCGGATCCGAAGAGGCAGCCGTGACTGTAACACCTCCAATCACAGCCCAGCAAGGTAACTGGACAGTTAAC AAAACAGAAGCTGACAACATAGAAGGACCCATAGCCTTGAAGTTCTCACACCTTTGCCTGGAAGATCATAACA GTTACTCCATCAACGGTGCTTGTGCATTCCACCATGAGCTAGAGAAAGCCATCTGCAGGTGTTTTACTGGTTA TACTGGAGAAAGGTGTGAGCACTTGACTTTAACTTCATATGCTGTGGATTCTTATGAACTCGAGGGC NOV6k, CG55023-06 Protein Sequence SEQ ID NO:120 89 aa MW at 9878.8 kD EEAAVTVTPPITAQQGNWTVNKTEADNIEGPIALKFSHLCLEDHNSYCINGACAFHHELEKAICRCFTGYTGE RCEHLTLTSYAVDSYE

[0389] A ClustalW comparison of the above protein sequences yields the following sequence alignment shown in Table 6B. 33 TABLE 6B Comparison of the NOV6 protein sequences. NOV6a ----MALGVPISVYLLFNAMTALTEEAAVTVTPPITAQQGNWTVNKTEAHNIEGPIALKF (SEQ ID NO: 100) NOV6b ---------------------TGSEEAAVTVTPPITAQQONWTVNKTEADNIEGPIALKF (SEQ ID NO: 102) NOV6c TGSTMALGVPISVYLLFNAMTALTEEAAVTVTPPITAQQGNWTVNKTEADNIEGPIALKF (SEQ ID NO: 104) NOV6d TGSTMALGVPISVYLLFNANTALTEEAAVTVTPPITAQQGNWTVNKTEADNIEGPIALKF (SEQ ID NO: 106) NOV6e TGSTMALGVPISVYLLFNAMTALTEEAAVTVTPPITAQQ---------ADNIEGPIALKF (SEQ ID NO: 108) NOV6f ---------------------TGSEEAAVTVTPPITAQQ---------ADNIEGPIALKF (SEQ ID NO: 110) NOV6g ------------------------EEAAVTVTPPITAQQ---------ADNIEGPIALKF (SEQ ID NO: 112) NOV6h ------------------------EEAAVTVTPPITAQQGNWTVNKTEADNIECPIALKF (SEQ ID NO: 114) NOV6i ------------------------EEAAVTVTPPITAQQ---------ADNIEGPTALKF (SEQ ID NO: 116) NOV6j ------------------------EEAAVTVTPPITAQQGNWTVNKTEADNIEGPIALKF (SEQ ID NO: 118) NOV6k ------------------------EEAAVTVTPPITAQQGNWTVNKTEADNIEGPIALKF (SEQ ID NO: 120) NOV6a SHLCLEDHNSYCINGACAFHHELEKAICRCFTGYTGERCEHLTLTSYAVDSYEKYIAIGI NOV6b SHLCLEDHNSYCINGACAFHHELEKAICRCFTGYTGERCEHLTLTSYAVDSYELEG---- NOV6c SHLCLEDHNSYCINGACAFHHELEKAICR---------CLKLKSPYNVCSGERRPLLEG- NOV6d SHLCLEDHNSYCINGACAFHHELEKAICRCFTGYTGERCLKLKSPYNVCSGERRPLLEG- NOV6e SHLCLEDHNSYCINGACAFHHELEKAICRCFTGYTGERCLKLKSPYNVCSGERRPLLEG- NOV6f SHLCLEDHNSYCINGACAFHHELEKAICRCFTGYTGERCLKLKSPYNVCSGERRPLLEG- NOV6g SHLCLEDHNSYCINGACAFHHELEKAICRCFTGYTGERCEHLTLTSYAVDSYE------- NOV6h SHLCLEDHNSYCINGACAFHHELEKAICR---------CLKLKSPYNVCSGERRPL---- NOV6i SHLCLEDHNSYCINGACAFHHELEKAICRCFTGYTGERCLKLKSPYAACSGERRPL---- NOV6j SHLCLEDHNSYCINGACAFHHELEKAICRCFTGYTGERCEHLTLTSYAAASYE------- NOV6k SHLCLEDHNSYCINGACAFMHELEKAICRCFTGYTGERCEHLTLTSYAAASYE------- NOV6a GVGLLLSGFLVIFYCYIRKRCLKLKSPYNVCSGERRPL NOV6b -------------------------------------- NOV6c -------------------------------------- NOV6d -------------------------------------- NOV6e -------------------------------------- NOV6f -------------------------------------- NOV6g -------------------------------------- NOV6h -------------------------------------- NOV6i -------------------------------------- NOV6j -------------------------------------- NOV6k --------------------------------------

[0390] Further analysis of the NOV6a protein yielded the following properties shown in Table 6C. 34 TABLE 6C Protein Sequence Properties NOV6a SignalP analysis: Cleavage site between residues 21 and 22 PSORT II analysis: PSG: a new signal peptide prediction method N-region: length 0; pos.chg 0; neg.chg 0 H-region: length 20; peak value 7.80 PSG Score: 3.40 GvH: von Heijne's method for signal seq. recognition GvH score (threshold: −2.1): −4.78 possible cleavage site: between 20 and 21 >>> Seems to have no N-terminal signal peptide ALOM: Klein et al's method for TM region allocation Init position for calculation: 1 Tentative number of TMS(s) for the threshold 0.5: 2 Number of TMS(s) for threshold 0.5: 1 INTEGRAL Likelihood = −8.97 Transmenbrane 112-128 PERIPHERAL Likelihood = 9.39 (at 45) ALOM score: −8.97 (number of TMSs: 1) MTOP: Prediction of membrane topology (Hartmann et al.) Center position for calculation: 119 Charge difference: 6.5 C(5.0) − N(−1.5) C > N: C-terminal side will be inside >>>Caution: Inconsistent mtop result with signal peptide >>> membrane topology: type 1b (cytoplasmic tail 112 to 154) MITDISC: discrimination of mitochondrial targeting seq R content: 0 Hyd Moment(75) : 1.79 Hyd Moment(95): 0.79 G content: 1 D/E content: 1 S/T content: 3 Score: −5.79 Gavel: prediction of cleavage sites for mitochondrial preseq cleavage site motif not found NUCDISC: discrimination of nuclear localization signals pat4: none pat7: none bipartite: none content of basic residues: 8.4% NLS Score: −0.47 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: none SKL: peroxisomal targeting signal in the C-terminus: none PTS2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none NMYR: N-myristoylation pattern: none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: 129,131,143 Dileucine motif in the tail: found LL at 120 checking 63 PROSITE DNA binding motifs: none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination Prediction: cytoplasmic Reliability: 94.1 COIL: Lupas's algorithm to detect coiled-coil regions total: 0 residues Final Results (k = 9/23): 30.4%: nuclear 26.1%: mitochondrial 21.7%: cytoplasmic 8.7%: vesicles of secretory system 4.3%: vacuolar 4.3%: peroxisomal 4.3%: endoplasmic reticulum >> prediction for CG55023-01 is nuc (k = 23)

[0391] A search of the NOV1a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 6D. 35 TABLE 6D Geneseq Results for NOV6a NOV6a Identities/ Residues/ Similarities for Geneseq Protein/Organism/Length [Patent #, Match the Matched Expect Identifier Date] Residues Region Value ABB72157 Human protein isolated from skin cells 1 . . . 154 154/154 (100%) 4e−89 SEQ ID NO: 196 - Homo sapiens, 154 1 . . . 154 154/154 (100%) aa. [WO200190357-A1, 29-NOV-2001] ABG76940 Human protein, designated SEC4 - 1 . . . 154 154/154 (100%) 4e−89 Homo sapiens, 154 aa. 1 . . . 154 154/154 (100%) [WO200255705-A2, 18-JUL-2002] AAB55957 Skin cell protein, SEQ ID NO: 196 - 1 . . . 154 154/154 (100%) 4e−89 Homo sapiens, 154 aa. 1 . . . 154 154/154 (100%) [WO200069884-A2, 23-NOV-2000] AAE06704 Human transforming growth factor 1 . . . 154 154/154 (100%) 4e−89 (TGF) alpha homologue huTR1 - 1 . . . 154 154/154 (100%) Homo sapiens, 154 aa. [WO200155333-A2, 02-AUG-2001] AAY76018 Human TGF-alpha homologue huTR1, 1 . . . 154 154/154 (100%) 4e−89 SEQ ID NO: 196 - Homo sapiens, 154 1 . . . 154 154/154 (100%) aa. [WO9955865-A1, 04-NOV-1999]

[0392] In a BLAST search of public sequence databases, the NOV6a protein was found to have homology to the proteins shown in the BLASTP data in Table 6E. 36 TABLE 6E Public BLASTP Results for NOV6a NOV6a Identities/ Protein Residues/ Similarities for Accession Match the Matched Expect Number Protein/Organism/Length Residues Portion Value Q924X1 Epigen protein precursor - Mus 1 . . . 149 119/150 (79%) 1e−64 musculus (Mouse), 152 aa. 1 . . . 148 129/150 (85%) Q8CEX5 Epithelial mitogen - Mus musculus 18 . . . 149 107/132 (81%) 3e−60 (Mouse), 136 aa (fragment). 3 . . . 132 116/132 (87%) Q06922 Transforming growth factor alpha 41 . . . 137 33/106 (31%) 2e−08 precursor (TGF-alpha) (EGF-like TGF) 25 . . . 130 52/106 (48%) (ETGF) (TGF type 1) - Sus scrofa (Pig), 160 aa. Q8BRP7 Transmembrane protein with EGF-like 57 . . . 139 32/87 (36%) 3e−08 and two follistatin-like domains 1 - 147 . . . 233 48/87 (54%) Mus musculus (Mouse), 256 aa (fragment). Q8C536 Transmembrane protein with EGF-like 57 . . . 139 32/87 (36%) 3e−08 and two follistatin-like domains 1 - 138 . . . 224 48/87 (54%) Mus musculus (Mouse), 247 aa (fragment).

[0393] PFam analysis predicts that the NOV6a protein contains the domains shown in the Table 6F. 37 TABLE 6F Domain Analysis of NOV6a Identities/Similarities NOV6a for the Pfam Domain Match Region Matched Region Expect Value EGF 60 . . . 95 13/47 (28%) 0.39 23/47 (49%)

Example 7

[0394] The NOV7 clone was analyzed, and the nucleotide and encoded polypeptide sequences are shown in Table 7A. 38 TABLE 7A NOV7 Sequence Analysis NOV7a, CG56136-01 SEQ ID NO:121 477 bp DNA Sequence ORF Start: ATG at 1 ORF Stop: end of sequence ATGGAAAAAGCATTGAAAATTGACACACCTCAGCAGGGGAGCATTCAGGATATCAATCATCGGGTGTCGGTTC TTCAGGACCAGACGCTCATAGCAGTCCCGACGAAGGACCGTATGTCTCCAGTCACTATTGCCTTAATCTCATG CCGACATGTGGAGACCCTTGAGAAAGACAGAGGGAACCCCATCTACCTGGGCCTGAATGGACTCAATCTCTGC CTGATGTGTGCTAAAGTCGGGGACCAGCCCACACTGCAGCTGAAGGAAAAGGATATAATGGATTTGTACAACC AACCCGAGCCTGTGAAGTCCTTTCTCTTCTACCACAGCCAGAGTGGCAGGAACTCCACCTTCGAGTCTGTGGC TTTCCCTGGCTGGTTCATCGCTGTCAGCTCTGAAGGAGGCTGTCCTCTCATCCTTACCCAAGAACTGGGAAAA GCCAACACTACTGACTTTGGGTTAACTATGCTGTTTTAA NOV7a, CG56136-01 Protein Sequence SEQ ID NO:122 158 aa MW at 17684.2 kD MEKALKIDTPQQGSIQDINHRVNVLQDQTLIAVPRKDRMSPVTIALISCRHVETLEKDRGNPIYLGLNGLNLC LMCAKVGDQPTLQLKEKDIMDLYNQPEPVKSFLFYHSQSGRNSTFESVAFPGWFIAVSSEGGCPLILTQELGK ANTTDFGLTMLF NOV7b, CG56136-02 SEQ ID NO:123 411 bp DNA Sequence ORF Start: ATG at 1 Stop: end of sequence ATGGAAAAAGCATTGAAAGTTGACACACCTCAGCGGGGGAGCATTCAGGATATCAATCATCGGGTGTGGGTTC TTCAGGACCAGACGCTCATAGCAGTCCCGAGGAAGGACCGTATGTCTCCAGTCACTATTGCCTTAATCTCATG CCCACATGTGGAGACCCTTGAGAAAGACAGAGGGAACCCCATCTACCTGGGCCTGAATGGACTCAATCTCTGC CTGATGTGTGTTCAAGTCGGGGACCAGCCCACACTGCAGATGAACCAGAGTGGCAGGAACTCCACCTTCGAGT CTGTGGCTTTCCCTGGCTGGTTGATCGCTGTCAGCTCTGAAGGAGGCTGTCCTCTCATCCTTACCCAAGAACT GGGGAAAGCCAACACTACTGACTTTGGGTTAACTATGCTCTTTTAA NOV7b, CG56136-02 Protein Sequence SEQ ID NO:124 136 aa MW at 15013.2 kD MEKALKVDTPQRGSIQDINHRVWVLQDQTLIAVPRKDRNSPVTIALISCRHVETLEKDRGNPIYLGLNGLNC LMCVQVGDQPTLQMNQSGRNSTFESVAFPGWLIAVSSEGGCPLILTQELGKANTTDFGLTMLF NOV7c, CG56136-03 SEQ ID NO:125 474 bp DNA Sequence ORF Start: ATG at 1 ORF Stop: end of sequence ATGGAAAAAGCATTGAAAATTGACACACCTCAGCAGGGGAGCATTCAGGATATCAATCATCGGGTGTGGGTTC TTCAGGACCAGACGCTCATAGCAGTCCCGAGGAAGGACCGTATGTCTCCAGTCACTATTGCCTTAATCTCATG CCGACATGTGGAGACCCTTGAGAAAAGACAGAGGGAACCCCATCTACCTGGGCCTGAATGGACTCAATCTCTC CTCATGTGTGCTAAAGTCGGGGACCAGCCCACACTGCAGCTGAAGGAAAAGGATATAATGGATTTGTACAACC AACCCGACCCTGTCAAGTCCTTTCTCTTCTACCACAGCCAGAGTGGCAGGAACTCCACCTTCGAGTCTGTGGC TTTCCCTGGCTGGTTCATCGCTGTCAGCTCTGAAGGAGGCTGTCCTCTCATCCTTACCCAAGAACTGGGGAAA GCCAACACTACTGACTTTGGGTTAACTATGCTGTTT NOV7c, CG56136-03 Protein Sequence SEQ ID NO:126 158 aa MW at 17684.2 kD MEKALKIDTPQQGSIQDINHRVWVLQDQTLIAVPRKDRNSPVTIALISCRHVETLEKDRGNPIYLGLNGLNLC LMCAKVGDQPTLQLKEKDIMDLYNQPEPVKSFLFYHSQSGRNSTFESVAFPGWFIAVSSEGGCPLILTQELGK ANTTDFGLTMLF NOV7d,CG56136-04 SEQ ID NO:127 99 bp DNA Sequence ORF Start: at 1 ORF Stop: at 100 TGTGTTCAAGTCGGGGACCAGCCCACACTGCAGATGAACCAGAGTGGCAGGAACTCCACCTTCCAGTCTGTGG CTTTCCCTGGCTGGTTGATCGCTGTC NOV7d, CG56136-04 Protein Sequence SEQ ID NO:128 33 aa MW at 3581.0 kD CVQVGDQPTLQMNQSGRNSTFESVAFPCWLIAV

[0395] A ClustalW comparison of the above protein sequences yields the following sequence alignment shown in Table 7B. 39 TABLE 7B Comparison of the NOV7 protein sequences. NOV7a MEKALKIDTPQQGSIQDINHRVWVLQDQTLIAVPRKDRMSPVTIALISCRHVETLEKDRG (SEQ ID NO: 122) NOV7b MEKALKVDTPQRGSIQDINHRVWVLQDQTLIAVPRKDRMSPVTIALISCRHVETLEKDRG (SEQ ID NO: 124) NOV7c MEKALKIDTPQQGSIQDINHRVWVLQDQTLIAVPRKDRMSPVTIALISCRHVETLEKDRC (SEQ ID NO: 126) NOV7d ------------------------------------------------------------ (SEQ ID NO: 128) NOV7a NPIYLGLNGLNLCLMCAKVGDQPTLQLKEKDIMDLYNQPEPVKSFLFYHSQSGRNSTFES NOV7b NPIYLGLNGLNLCLMCVQVGDQPTLQMN----------------------QSGRNSTFES NOV7c NPIYLGLNGLNLCLMCAKVGDQPTLQLKEKDIMDLYNQPEPVKSFLFYHSQSGRNSTFES NOV7d ---------------CVQVGDQPTLQMN----------------------QSGRNSTFES NOV7a VAFPGWFIAVSSEGGCPLILTQELGKANTTDFGLTMLF NOV7b VAFPGWLIAVSSECGCPLILTQELGKANTTDFGLTMLF NOV7c VAFPGWFIAVSSEGGCPLILTQELGKANTTDFGLTMLF NOV7d VAFPGWLIAV

[0396] Further analysis of the NOV7a protein yielded the following properties shown in Table 7C. 40 TABLE 7C Protein Sequence Properties NOV7a SignalP analysis: No Known Signal Sequence Predicted PSORT II analysis: PSG: a new signal peptide prediction method N-region: length 8; pos.chg 2; neg.chg 2 H-region: length 8; peak value −3.46 PSG score: −7.86 GvH: von Heijne's method for signal seq. recognition GvH score (threshold: −2.1): −5.60 possible cleavage site: between 54 and 55 >>> Seems to have no N-terminal signal peptide ALOM: Klein et al's method for TM region allocation Init position for calculation: 1 Tentative number of TMS(s) for the threshold 0.5: 0 number of TMS(s) . . . fixed PERIPHERAL Likelihood = 1.85 (at 63) ALOM score: 1.85 (number of TMSs: 0) MITDISC: discrimination of mitochondrial targeting seq R content: 0 Hyd Moment (75): 10.39 Hyd Moment (95): 7.73 G content: 0 D/E content: 2 S/T content: 0 Score: −6.26 Gavel: prediction of cleavage sites for mitochondrial preseq cleavage site motif not found NUCDISC: discrimination of nuclear localization signals pat4: none pat7: PRKDRMS (5) at 34 bipartite: none content of basic residues: 9.5% NLS Score: −0.04 KDEL: ER retention motif in the C-terminus: none ER Membrane Retention Signals: none SKL: peroxisomal targeting signal in the C-terminus: none PTS2: 2nd peroxisomal targeting signal: none VAC: possible vacuolar targeting motif: none RNA-binding motif: none Actinin-type actin-binding motif: type 1: none type 2: none NMYR: N-myristoylation pattern: none Prenylation motif: none memYQRL: transport motif from cell surface to Golgi: none Tyrosines in the tail: none Dileucine motif in the tail: none checking 63 PROSITE DNA binding motifs: none checking 71 PROSITE ribosomal protein motifs: none checking 33 PROSITE prokaryotic DNA binding motifs: none NNCN: Reinhardt's method for Cytoplasmic/Nuclear discrimination Prediction: cytoplasmic Reliability: 76.7 COIL: Lupas's algorithm to detect coiled-coil regions total: 0 residues Final Results (k = 9/23): 39.1%: cytoplasmic 34.8%: mitochondrial 21.7%: nuclear 4.3%: vacuolar >> prediction for CG56136-01 is cyt (k = 23)

[0397] A search of the NOV7a protein against the Geneseq database, a proprietary database that contains sequences published in patents and patent publication, yielded several homologous proteins shown in Table 7D. 41 TABLE 7D Geneseq Results for NOV7a NOV7a Identities/ Residues/ Similarities for Geneseq Protein/Organism/Length [Patent #, Match the Matched Expect Identifier Date] Residues Region Value AAY70217 Human Interleukin-1 epsilon protein - 1 . . . 158 158/158 (100%) 2e−89 Homo sapiens, 158 aa. 1 . . . 158 158/158 (100%) [WO200011174-A1, 02-MAR-2000] AAY70218 Human Interleukin-1 epsilon 1 . . . 158 157/158 (99%) 7e−89 polymorphic variant - Homo sapiens, 1 . . . 158 158/158 (99%) 158 aa. [WO200011174-A1, 02-MAR-2000] AAE03417 Human interleukin-1 receptor 5 . . . 158 152/154 (98%) 5e−86 antagonist-like (IL-1ra-L) - Homo 120 . . . 273 154/154 (99%) sapiens, 273 aa. [WO200141792-A1, 14-JUN-2001] ABP52038 NOVINTRA C homologous amino 17 . . . 146 130/130 (100%) 8e−73 acid sequence SEQ ID NO: 87 - Homo 1 . . . 130 130/130 (100%) sapiens, 130 aa. [US2002068279-A1, 06-JUN-2002] ABP52037 NOVINTRA C homologous amino 17 . . . 146 126/130 (96%) 1e−68 acid sequence SEQ ID NO: 86 - Homo 1 . . . 126 126/130 (96%) sapiens, 126 aa. [US2002068279-A1, 06-JUN-2002]

[0398] In a BLAST search of public sequence databases, the NOV7a protein was found to have homology to the proteins shown in the BLASTP data in Table 7E. 42 TABLE 7E Public BLASTP Results for NOV7a NOV7a Identities/ Protein Residues/ Similarities for Accession Match the Matched Expect Number Protein/Organism/Length Residues Portion Value Q9UHA7 Interleukin 1 family member 6 1 . . . 158 158/158 (100%) 7e−89 (IL-1F6) (Interleukin-1 epsilon) (IL-1 1 . . . 158 158/158 (100%) epsilon) (FIL1 epsilon) - Homo sapiens (Human), 158 aa. Q9NZH8 Interleukin 1 family member 9 10 . . . 156 88/147 (59%) 4e−46 (IL-1F9) (Interleukin-1 homolog 1) 22 . . . 167 112/147 (75%) (IL-1H1) (Interleukin-1 epsilon) (IL-1 epsilon) (IL-1 related protein 2) (IL-1RP2) - Homo sapiens (Human), 169 aa. Q9JLA2 Interleukin 1 family member 6 2 . . . 157 85/156 (54%) 7e−46 (IL-1F6) (Interleukin-1 epsilon) (IL-1 4 . . . 159 115/156 (73%) epsilon) (FIL1 epsilon) (Interleukin-1 homolog 1) (IL-1H1) - Mus musculus (Mouse), 160 aa. CAC21807 Sequence 1 from Patent WO0071720 - 10 . . . 154 71/145 (48%) 1e−36 Homo sapiens (Human), 157 aa. 9 . . . 153 100/145 (68%) Q8R460 Interleukin 1 family member 9 8 . . . 154 69/147 (46%) 2e−36 (IL-1F9) - Mus musculus (Mouse), 164 15 . . . 160 105/147 (70%) aa.

[0399] PFam analysis predicts that the NOV7a protein contains the domains shown in the Table 7F. 43 TABLE 7F Domain Analysis of NOV7a Identities/Similarities NOV7a for the Pfam Domain Match Region Matched Region Expect Value IL1 15 . . . 158 44/147(30%) 4.5e−18 90/147 (61%)

Example B Sequencing Methodology and Identification of NOVX Clones

[0400] 1. GeneCalling™ Technology: This is a proprietary method of performing differential gene expression profiling between two or more samples developed at CuraGen and described by Shimkets, et al., “Gene expression analysis by transcript profiling coupled to a gene database query” Nature Biotechnology 17:198-803 (1999). cDNA was derived from various human samples representing multiple tissue types, normal and diseased states, physiological states, and developmental states from different donors. Samples were obtained as whole tissue, primary cells or tissue cultured primary cells or cell lines. Cells and cell lines may have been treated with biological or chemical agents that regulate gene expression, for example, growth factors, chemokines or steroids. The cDNA thus derived was then digested with up to as many as 120 pairs of restriction enzymes and pairs of linker-adaptors specific for each pair of restriction enzymes were ligated to the appropriate end. The restriction digestion generates a mixture of unique cDNA gene fragments. Limited PCR amplification is performed with primers homologous to the linker adapter sequence where one primer is biotinylated and the other is fluorescently labeled. The doubly labeled material is isolated and the fluorescently labeled single strand is resolved by capillary gel electrophoresis. A computer algorithm compares the electropherograms from an experimental and control group for each of the restriction digestions. This and additional sequence-derived information is used to predict the identity of each differentially expressed gene fragment using a variety of genetic databases. The identity of the gene fragment is confirmed by additional, gene-specific competitive PCR or by isolation and sequencing of the gene fragment.

[0401] 2. SeqCalling™ Technology: cDNA was derived from various human samples representing multiple tissue types, normal and diseased states, physiological states, and developmental states from different donors. Samples were obtained as whole tissue, primary cells or tissue cultured primary cells or cell lines. Cells and cell lines may have been treated with biological or chemical agents that regulate gene expression, for example, growth factors, chemokines or steroids. The cDNA thus derived was then sequenced using CuraGen's proprietary SeqCalling technology. Sequence traces were evaluated manually and edited for corrections if appropriate. cDNA sequences from all samples were assembled together, sometimes including public human sequences, using bioinformatic programs to produce a consensus sequence for each assembly. Each assembly is included in CuraGen Corporation's database. Sequences were included as components for assembly when the extent of identity with another component was at least 95% over 50 bp. Each assembly represents a gene or portion thereof and includes information on variants, such as splice forms single nucleotide polymorphisms (SNPs), insertions, deletions and other sequence variations.

[0402] 3. PathCalling™ Technology: The NOVX nucleic acid sequences are derived by laboratory screening of cDNA library by the two-hybrid approach. cDNA fragments covering either the full length of the DNA sequence, or part of the sequence, or both, are sequenced. In silico prediction was based on sequences available in CuraGen Corporation's proprietary sequence databases or in the public human sequence databases, and provided either the full length DNA sequence, or some portion thereof. The laboratory screening was performed using the methods summarized below:

[0403] cDNA libraries were derived from various human samples representing multiple tissue types, normal and diseased states, physiological states, and developmental states from different donors. Samples were obtained as whole tissue, primary cells or tissue cultured primary cells or cell lines. Cells and cell lines may have been treated with biological or chemical agents that regulate gene expression, for example, growth factors, chemokines or steroids. The cDNA thus derived was then directionally cloned into the appropriate two-hybrid vector (Gal4-activation domain (Gal4-AD) fusion). Such cDNA libraries as well as commercially available cDNA libraries from Clontech (Palo Alto, Calif.) were then transferred from E. coli into a CuraGen Corporation proprietary yeast strain (disclosed in U.S. Pat. Nos. 6,057,101 and 6,083,693, incorporated herein by reference in their entireties).

[0404] Gal4-binding domain (Gal4-BD) fusions of a CuraGen Corportion proprietary library of human sequences was used to screen multiple Gal4-AD fusion cDNA libraries resulting in the selection of yeast hybrid diploids in each of which the Gal4-AD fusion contains an individual cDNA. Each sample was amplified using the polymerase chain reaction (PCR) using non-specific primers at the cDNA insert boundaries. Such PCR product was sequenced; sequence traces were evaluated manually and edited for corrections if appropriate. cDNA sequences from all samples were assembled together, sometimes including public human sequences, using bioinformatic programs to produce a consensus sequence for each assembly. Each assembly is included in CuraGen Corporation's database. Sequences were included as components for assembly when the extent of identity with another component was at least 95% over 50 bp. Each assembly represents a gene or portion thereof and includes information on variants, such as splice forms single nucleotide polymorphisms (SNPs), insertions, deletions and other sequence variations.

[0405] Physical clone: the cDNA fragment derived by the screening procedure, covering the entire open reading frame is, as a recombinant DNA, cloned into pACT2 plasmid (Clontech) used to make the cDNA library. The recombinant plasmid is inserted into the host and selected by the yeast hybrid diploid generated during the screening procedure by the mating of both CuraGen Corporation proprietary yeast strains N106′ and YULH (U.S. Pat. Nos. 6,057,101 and 6,083,693).

[0406] 4. RACE: Techniques based on the polymerase chain reaction such as rapid amplification of cDNA ends (RACE), were used to isolate or complete the predicted sequence of the cDNA of the invention. Usually multiple clones were sequenced from one or more human samples to derive the sequences for fragments. Various human tissue samples from different donors were used for the RACE reaction. The sequences derived from these procedures were included in the SeqCalling Assembly process described in preceding paragraphs.

[0407] 5. Exon Linking: The NOVX target sequences identified in the present invention were subjected to the exon linking process to confirm the sequence. PCR primers were designed by starting at the most upstream sequence available, for the forward primer, and at the most downstream sequence available for the reverse primer. In each case, the sequence was examined, walking inward from the respective termini toward the coding sequence, until a suitable sequence that is either unique or highly selective was encountered, or, in the case of the reverse primer, until the stop codon was reached. Such primers were designed based on in silico predictions for the full length cDNA, part (one or more exons) of the DNA or protein sequence of the target sequence, or by translated homology of the predicted exons to closely related human sequences from other species. These primers were then employed in PCR amplification based on the following pool of human cDNAs: adrenal gland, bone marrow, brain—amygdala, brain—cerebellum, brain—hippocampus, brain—substantia nigra, brain—thalamus, brain—whole, fetal brain, fetal kidney, fetal liver, fetal lung, heart, kidney, lymphoma—Raji, mammary gland, pancreas, pituitary gland, placenta, prostate, salivary gland, skeletal muscle, small intestine, spinal cord, spleen, stomach, testis, thyroid, trachea, uterus. Usually the resulting amplicons were gel purified, cloned and sequenced to high redundancy. The PCR product derived from exon linking was cloned into the pCR2.1 vector from Invitrogen. The resulting bacterial clone has an insert covering the entire open reading frame cloned into the pCR2.1 vector. The resulting sequences from all clones were assembled with themselves, with other fragments in CuraGen Corporation's database and with public ESTs. Fragments and ESTs were included as components for an assembly when the extent of their identity with another component of the assembly was at least 95% over 50 bp. In addition, sequence traces were evaluated manually and edited for corrections if appropriate. These procedures provide the sequence reported herein.

[0408] 6. Physical Clone: Exons were predicted by homology and the intron/exon boundaries were determined using standard genetic rules. Exons were further selected and refined by means of similarity determination using multiple BLAST (for example, tBlastN, BlastX, and BlastN) searches, and, in some instances, GeneScan and Grail. Expressed sequences from both public and proprietary databases were also added when available to further define and complete the gene sequence. The DNA sequence was then manually corrected for apparent inconsistencies thereby obtaining the sequences encoding the full-length protein.

[0409] The PCR product derived by exon linking, covering the entire open reading frame, was cloned into the pCR2.1 vector from Invitrogen to provide clones used for expression and screening purposes.

Example C Quantitative Expression Analysis of Clones in Various Cells and Tissues

[0410] The quantitative expression of various clones was assessed using microtiter plates containing RNA samples from a variety of normal and pathology-derived cells, cell lines and tissues using real time quantitative PCR (RTQ PCR). RTQ PCR was performed on an Applied Biosystems ABI PRISM® 7700 or an ABI PRISM® 7900 HT Sequence Detection System. Various collections of samples are assembled on the plates, and referred to as Panel 1 (containing normal tissues and cancer cell lines), Panel 2 (containing samples derived from tissues from normal and cancer sources), Panel 3 (containing cancer cell lines), Panel 4 (containing cells and cell lines from normal tissues and cells related to inflammatory conditions), Panel 5D/5I (containing human tissues and cell lines with an emphasis on metabolic diseases), AI_comprehensive_panel (containing normal tissue and samples from autoinflammatory diseases), Panel CNSD.01 (containing samples from normal and diseased brains) and CNS_neurodegeneration_panel (containing samples from normal and Alzheimer's diseased brains).

[0411] RNA integrity from all samples is controlled for quality by visual assessment of agarose gel electropherograms using 28S and 18S ribosomal RNA staining intensity ratio as a guide (2:1 to 2.5:1 28s:18s) and the absence of low molecular weight RNAs that would be indicative of degradation products. Samples are controlled against genomic DNA contamination by RTQ PCR reactions run in the absence of reverse transcriptase using probe and primer sets designed to amplify across the span of a single exon.

[0412] First, the RNA samples were normalized to reference nucleic acids such as constitutively expressed genes (for example, &bgr;-actin and GAPDH). Normalized RNA (5 ul) was converted to cDNA and analyzed by RTQ-PCR using One Step RT-PCR Master Mix Reagents (Applied Biosystems; Catalog No. 4309169) and gene-specific primers according to the manufacturer's instructions.

[0413] In other cases, non-normalized RNA samples were converted to single strand cDNA (sscDNA) using Superscript II (Invitrogen Corporation; Catalog No. 18064-147) and random hexamers according to the manufacturer's instructions. Reactions containing up to 10 &mgr;g of total RNA were performed in a volume of 20 &mgr;l and incubated for 60 minutes at 42° C. This reaction can be scaled up to 50 &mgr;g of total RNA in a final volume of 100 &mgr;l. sscDNA samples are then normalized to reference nucleic acids as described previously, using 1× TaqMan® Universal Master mix (Applied Biosystems; catalog No. 4324020), following the manufacturer's instructions.

[0414] Probes and primers were designed for each assay according to Applied Biosystems Primer Express Software package (version I for Apple Computer's Macintosh Power PC) or a similar algorithm using the target sequence as input. Default settings were used for reaction conditions and the following parameters were set before selecting primers: primer concentration=250 nM, primer melting temperature (Tm) range=58°-60° C., primer optimal Tm=59° C., maximum primer difference=2° C., probe does not have 5′G, probe Tm must be 10° C. greater than primer Tm, amplicon size 75 bp to 100 bp. The probes and primers selected (see below) were synthesized by Synthegen (Houston, Tex., USA). Probes were double purified by HPLC to remove uncoupled dye and evaluated by mass spectroscopy to verify coupling of reporter and quencher dyes to the 5′ and 3′ ends of the probe, respectively. Their final concentrations were: forward and reverse primers, 900 nM each, and probe, 200 nM.

[0415] PCR conditions: When working with RNA samples, normalized RNA from each tissue and each cell line was spotted in each well of either a 96 well or a 384-well PCR plate (Applied Biosystems). PCR cocktails included either a single gene specific probe and primers set, or two multiplexed probe and primers sets (a set specific for the target clone and another gene-specific set multiplexed with the target probe). PCR reactions were set up using TaqMan® One-Step RT-PCR Master Mix (Applied Biosystems, Catalog No. 4313803) following manufacturer's instructions. Reverse transcription was performed at 48° C. for 30 minutes followed by amplification/PCR cycles as follows: 95° C. 10 min, then 40 cycles of 95° C. for 15 seconds, 60° C. for 1 minute. Results were recorded as CT values (cycle at which a given sample crosses a threshold level of fluorescence) using a log scale, with the difference in RNA concentration between a given sample and the sample with the lowest CT value being represented as 2 to the power of delta CT. The percent relative expression is then obtained by taking the reciprocal of this RNA difference and multiplying by 100. Expression with CT values below 28 is considered as high expression, CT values between 28 and 32 is considered moderate and CT value between 32 to 35 is considered as low expression. All the relative expression with CT values above 35 is not considered as significant expression.

[0416] When working with sscDNA samples, normalized sscDNA was used as described previously for RNA samples. PCR reactions containing one or two sets of probe and primers were set up as described previously, using 1× TaqMan® Universal Master mix (Applied Biosystems; catalog No. 4324020), following the manufacturer's instructions. PCR amplification was performed as follows: 95° C. 10 min, then 40 cycles of 95° C. for 15 seconds, 60° C. for 1 minute. Results were analyzed and processed as described previously.

[0417] Panels 1, 1.1, 1.2, and 1.3D

[0418] The plates for Panels 1, 1.1, 1.2 and 1.3D include 2 control wells (genomic DNA control and chemistry control) and 94 wells containing cDNA from various samples. The samples in these panels are broken into 2 classes: samples derived from cultured cell lines and samples derived from primary normal tissues. The cell lines are derived from cancers of the following types: lung cancer, breast cancer, melanoma, colon cancer, prostate cancer, CNS cancer, squamous cell carcinoma, ovarian cancer, liver cancer, renal cancer, gastric cancer and pancreatic cancer. Cell lines used in these panels are widely available through the American Type Culture Collection (ATCC), a repository for cultured cell lines, and were cultured using the conditions recommended by the ATCC. The normal tissues found on these panels are comprised of samples derived from all major organ systems from single adult individuals or fetuses. These samples are derived from the following organs: adult skeletal muscle, fetal skeletal muscle, adult heart, fetal heart, adult kidney, fetal kidney, adult liver, fetal liver, adult lung, fetal lung, various regions of the brain, the spleen, bone marrow, lymph node, pancreas, salivary gland, pituitary gland, adrenal gland, spinal cord, thymus, stomach, small intestine, colon, bladder, trachea, breast, ovary, uterus, placenta, prostate, testis and adipose.

[0419] In the results for Panels 1, 1.1, 1.2 and 1.3D, the following abbreviations are used:

[0420] ca.=carcinoma,

[0421] *=established from metastasis,

[0422] met=metastasis,

[0423] s cell var=small cell variant,

[0424] non-s=non-sm=non-small,

[0425] squam=squamous,

[0426] pl. eff=pl effusion=pleural effusion,

[0427] glio=glioma,

[0428] astro=astrocytoma, and

[0429] neuro=neuroblastoma.

[0430] General_Screening_Panel_v1.4, v1.5, v1.6 and 1.7

[0431] The plates for Panels 1.4, 1.5, 1.6 and 1.7 include 2 control wells (genomic DNA control and chemistry control) and 88 to 94 wells containing cDNA from various samples. The samples in Panels 1.4, 1.5, 1.6 and 1.7 are broken into 2 classes: samples derived from cultured cell lines and samples derived from primary normal tissues. The cell lines are derived from cancers of the following types: lung cancer, breast cancer, melanoma, colon cancer, prostate cancer, CNS cancer, squamous cell carcinoma, ovarian cancer, liver cancer, renal cancer, gastric cancer and pancreatic cancer. Cell lines used in Panels 1.4, 1.5, 1.6 and 1.7 are widely available through the American Type Culture Collection (ATCC), a repository for cultured cell lines, and were cultured using the conditions recommended by the ATCC. The normal tissues found on Panels 1.4, 1.5, 1.6 and 1.7 are comprised of pools of samples derived from all major organ systems from 2 to 5 different adult individuals or fetuses. These samples are derived from the following organs: adult skeletal muscle, fetal skeletal muscle, adult heart, fetal heart, adult kidney, fetal kidney, adult liver, fetal liver, adult lung, fetal lung, various regions of the brain, the spleen, bone marrow, lymph node, pancreas, salivary gland, pituitary gland, adrenal gland, spinal cord, thymus, stomach, small intestine, colon, bladder, trachea, breast, ovary, uterus, placenta, prostate, testis and adipose. Abbreviations are as described for Panels 1, 1.1, 1.2, and 1.3D.

[0432] Panels 2D, 2.2, 2.3 and 2.4

[0433] The plates for Panels 2D, 2.2, 2.3 and 2.4 generally include 2 control wells and 94 test samples composed of RNA or cDNA isolated from human tissue procured by surgeons working in close cooperation with the National Cancer Institute's Cooperative Human Tissue Network (CHTN) or the National Disease Research Initiative (NDRI) or from Ardais or Clinomics). The tissues are derived from human malignancies and in cases where indicated many malignant tissues have “matched margins” obtained from noncancerous tissue just adjacent to the tumor. These are termed normal adjacent tissues and are denoted “NAT” in the results below. The tumor tissue and the “matched margins” are evaluated by two independent pathologists (the surgical pathologists and again by a pathologist at NDRI/CHTN/Ardais/Clinomics). Unmatched RNA samples from tissues without malignancy (normal tissues) were also obtained from Ardais or Clinomics. This analysis provides a gross histopathological assessment of tumor differentiation grade. Moreover, most samples include the original surgical pathology report that provides information regarding the clinical stage of the patient. These matched margins are taken from the tissue surrounding (i.e. immediately proximal) to the zone of surgery (designated “NAT”, for normal adjacent tissue, in Table RR). In addition, RNA and cDNA samples were obtained from various human tissues derived from autopsies performed on elderly people or sudden death victims (accidents, etc.). These tissues were ascertained to be free of disease and were purchased from various commercial sources such as Clontech (Palo Alto, Calif.), Research Genetics, and Invitrogen.

[0434] HASS Panel v 1.0

[0435] The HASS panel v 1.0 plates are comprised of 93 cDNA samples and two controls. Specifically, 81 of these samples are derived from cultured human cancer cell lines that had been subjected to serum starvation, acidosis and anoxia for different time periods as well as controls for these treatments, 3 samples of human primary cells, 9 samples of malignant brain cancer (4 medulloblastomas and 5 glioblastomas) and 2 controls. The human cancer cell lines are obtained from ATCC (American Type Culture Collection) and fall into the following tissue groups: breast cancer, prostate cancer, bladder carcinomas, pancreatic cancers and CNS cancer cell lines. These cancer cells are all cultured under standard recommended conditions. The treatments used (serum starvation, acidosis and anoxia) have been previously published in the scientific literature. The primary human cells were obtained from Clonetics (Walkersville, Md.) and were grown in the media and conditions recommended by Clonetics. The malignant brain cancer samples are obtained as part of a collaboration (Henry Ford Cancer Center) and are evaluated by a pathologist prior to CuraGen receiving the samples. RNA was prepared from these samples using the standard procedures. The genomic and chemistry control wells have been described previously.

[0436] ARDAIS Panel v 1.0

[0437] The plates for ARDAIS panel v 1.0 generally include 2 control wells and 22 test samples composed of RNA isolated from human tissue procured by surgeons working in close cooperation with Ardais Corporation. The tissues are derived from human lung malignancies (lung adenocarcinoma or lung squamous cell carcinoma) and in cases where indicated many malignant samples have “matched margins” obtained from noncancerous lung tissue just adjacent to the tumor. These matched margins are taken from the tissue surrounding (i.e. immediately proximal) to the zone of surgery (designated “NAT”, for normal adjacent tissue) in the results below. The tumor tissue and the “matched margins” are evaluated by independent pathologists (the surgical pathologists and again by a pathologist at Ardais). Unmatched malignant and non-malignant RNA samples from lungs were also obtained from Ardais. Additional information from Ardais provides a gross histopathological assessment of tumor differentiation grade and stage. Moreover, most samples include the original surgical pathology report that provides information regarding the clinical state of the patient.

[0438] ARDAIS Prostate v 1.0

[0439] The plates for ARDAIS prostate 1.0 generally include 2 control wells and 68 test samples composed of RNA isolated from human tissue procured by surgeons working in close cooperation with Ardais Corporation. The tissues are derived from human prostate malignancies and in cases where indicated malignant samples have “matched margins” obtained from noncancerous prostate tissue just adjacent to the tumor. These matched margins are taken from the tissue surrounding (i.e. immediately proximal) to the zone of surgery (designated “NAT”, for normal adjacent tissue) in the results below. The tumor tissue and the “matched margins” are evaluated by independent pathologists (the surgical pathologists and again by a pathologist at Ardais). RNA from unmatched malignant and non-malignant prostate samples were also obtained from Ardais. Additional information from Ardais provides a gross histopathological assessment of tumor differentiation grade and stage. Moreover, most samples include the original surgical pathology report that provides information regarding the clinical state of the patient.

[0440] Panel 3D, 3.1 and 3.2

[0441] The plates of Panel 3D, 3.1, and 3.2 are comprised of 94 cDNA samples and two control samples. Specifically, 92 of these samples are derived from cultured human cancer cell lines, 2 samples of human primary cerebellar tissue and 2 controls. The human cell lines are generally obtained from ATCC (American Type Culture Collection), NCI or the German tumor cell bank and fall into the following tissue groups: Squamous cell carcinoma of the tongue, breast cancer, prostate cancer, melanoma, epidermoid carcinoma, sarcomas, bladder carcinomas, pancreatic cancers, kidney cancers, leukemias/lymphomas, ovarian/uterine/cervical, gastric, colon, lung and CNS cancer cell lines. In addition, there are two independent samples of cerebellum. These cells are all cultured under standard recommended conditions and RNA extracted using the standard procedures. The cell lines in panel 3D, 3.1, 3.2, 1, 1.1., 1.2, 1.3D, 1.4, 1.5, and 1.6 are of the most common cell lines used in the scientific literature.

[0442] Panels 4D, 4R, and 4.1D

[0443] Panel 4 includes samples on a 96 well plate (2 control wells, 94 test samples) composed of RNA (Panel 4R) or cDNA (Panels 4D/4.1D) isolated from various human cell lines or tissues related to inflammatory conditions. Total RNA from control normal tissues such as colon and lung (Stratagene, La Jolla, Calif.) and thymus and kidney (Clontech) was employed. Total RNA from liver tissue from cirrhosis patients and kidney from lupus patients was obtained from BioChain (Biochain Institute, Inc., Hayward, Calif.). Intestinal tissue for RNA preparation from patients diagnosed as having Crohn's disease and ulcerative colitis was obtained from the National Disease Research Interchange (NDRI) (Philadelphia, Pa.).

[0444] Astrocytes, lung fibroblasts, dermal fibroblasts, coronary artery smooth muscle cells, small airway epithelium, bronchial epithelium, microvascular dermal endothelial cells, microvascular lung endothelial cells, human pulmonary aortic endothelial cells, human umbilical vein endothelial cells were all purchased from Clonetics (Walkersville, Md.) and grown in the media supplied for these cell types by Clonetics. These primary cell types were activated with various cytokines or combinations of cytokines for 6 and/or 12-14 hours, as indicated. The following cytokines were used; IL-1 beta at approximately 1-5 ng/ml, TNF alpha at approximately 5-10 ng/ml, IFN gamma at approximately 20-50 ng/ml, IL-4 at approximately 5-10 ng/ml, IL-9 at approximately 5-10 ng/ml, IL-13 at approximately 5-10 ng/ml. Endothelial cells were sometimes starved for various times by culture in the basal media from Clonetics with 0.1% serum.

[0445] Mononuclear cells were prepared from blood of employees at CuraGen Corporation, using Ficoll. LAK cells were prepared from these cells by culture in DMEM 5% FCS (Hyclone), 100 &mgr;M non essential amino acids (Gibco/Life Technologies, Rockville, Md.), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10−5M (Gibco), and 10 mM Hepes (Gibco) and Interleukin 2 for 4-6 days. Cells were then either activated with 10-20 ng/ml PMA and 1-2 &mgr;g/ml ionomycin, IL-12 at 5-10 ng/ml, IFN gamma at 20-50 ng/ml and IL-18 at 5-10 ng/ml for 6 hours. In some cases, mononuclear cells were cultured for 4-5 days in DMEM 5% FCS (Hyclone), 100 &mgr;M non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10−5M (Gibco), and 10 mM Hepes (Gibco) with PHA (phytohemagglutinin) or PWM (pokeweed mitogen) at approximately 5 &mgr;g/ml. Samples were taken at 24, 48 and 72 hours for RNA preparation. MLR (mixed lymphocyte reaction) samples were obtained by taking blood from two donors, isolating the mononuclear cells using Ficoll and mixing the isolated mononuclear cells 1:1 at a final concentration of approximately 2×106 cells/ml in DMEM 5% FCS (Hyclone), 100 &mgr;M non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol (5.5×10−5M) (Gibco), and 10 mM Hepes (Gibco). The MLR was cultured and samples taken at various time points ranging from 1-7 days for RNA preparation.

[0446] Monocytes were isolated from mononuclear cells using CD14 Miltenyi Beads, +ve VS selection columns and a Vario Magnet according to the manufacturer's instructions. Monocytes were differentiated into dendritic cells by culture in DMEM 5% fetal calf serum (FCS) (Hyclone, Logan, Utah), 100 &mgr;M non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10−5M (Gibco), and 10 mM Hepes (Gibco), 50 ng/ml GMCSF and 5 ng/ml IL-4 for 5-7 days. Macrophages were prepared by culture of monocytes for 5-7 days in DMEM 5% FCS (Hyclone), 100 &mgr;M non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10−5M (Gibco), 10 mM Hepes (Gibco) and 10% AB Human Serum or MCSF at approximately 50 ng/ml. Monocytes, macrophages and dendritic cells were stimulated for 6 and 12-14 hours with lipopolysaccharide (LPS) at 100 ng/ml. Dendritic cells were also stimulated with anti-CD40 monoclonal antibody (Pharmingen) at 10 &mgr;g/ml for 6 and 12-14 hours.

[0447] CD4 lymphocytes, CD8 lymphocytes and NK cells were also isolated from mononuclear cells using CD4, CD8 and CD56 Miltenyi beads, positive VS selection columns and a Vario Magnet according to the manufacturer's instructions. CD45RA and CD45RO CD4 lymphocytes were isolated by depleting mononuclear cells of CD8, CD56, CD14 and CD19 cells using CD8, CD56, CD14 and CD19 Miltenyi beads and positive selection. CD45RO beads were then used to isolate the CD45RO CD4 lymphocytes with the remaining cells being CD45RA CD4 lymphocytes. CD45RA CD4, CD45RO CD4 and CD8 lymphocytes were placed in DMEM 5% FCS (Hyclone), 100 &mgr;M non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10−5M (Gibco), and 10 mM Hepes (Gibco) and plated at 106 cells/ml onto Falcon 6 well tissue culture plates that had been coated overnight with 0.5 &mgr;g/ml anti-CD28 (Pharmingen) and 3 ug/ml anti-CD3 (OKT3, ATCC) in PBS. After 6 and 24 hours, the cells were harvested for RNA preparation. To prepare chronically activated CD8 lymphocytes, we activated the isolated CD8 lymphocytes for 4 days on anti-CD28 and anti-CD3 coated plates and then harvested the cells and expanded them in DMEM 5% FCS (Hyclone), 100 &mgr;M non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10−5M (Gibco), and 10 mM Hepes (Gibco) and IL-2. The expanded CD8 cells were then activated again with plate bound anti-CD3 and anti-CD28 for 4 days and expanded as before. RNA was isolated 6 and 24 hours after the second activation and after 4 days of the second expansion culture. The isolated NK cells were cultured in DMEM 5% FCS (Hyclone), 100 &mgr;M non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10−5M (Gibco), and 10 mM Hepes (Gibco) and IL-2 for 4-6 days before RNA was prepared.

[0448] To obtain B cells, tonsils were procured from NDRI. The tonsil was cut up with sterile dissecting scissors and then passed through a sieve. Tonsil cells were then spun down and resupended at 106 cells/ml in DMEM 5% FCS (Hyclone), 100 &mgr;M non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10−5M (Gibco), and 10 mM Hepes (Gibco). To activate the cells, we used PWM at 5 &mgr;g/ml or anti-CD40 (Pharmingen) at approximately 10 &mgr;g/ml and IL-4 at 5-10 ng/ml. Cells were harvested for RNA preparation at 24, 48 and 72 hours.

[0449] To prepare the primary and secondary Th1/Th2 and Tr1 cells, six-well Falcon plates were coated overnight with 10 &mgr;g/ml anti-CD28 (Pharmingen) and 2 &mgr;g/ml OKT3 (ATCC), and then washed twice with PBS. Umbilical cord blood CD4 lymphocytes (Poietic Systems, German Town, Md.) were cultured at 105-106 cells/ml in DMEM 5% FCS (Hyclone), 100 &mgr;M non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10−5M (Gibco), 10 mM Hepes (Gibco) and IL-2 (4 ng/ml). IL-12 (5 ng/ml) and anti-IL4 (1 &mgr;g/ml) were used to direct to Th1, while IL-4 (5 ng/ml) and anti-IFN gamma (1 &mgr;g/ml) were used to direct to Th2 and IL-10 at 5 ng/ml was used to direct to Tr1. After 4-5 days, the activated Th1, Th2 and Tr1 lymphocytes were washed once in DMEM and expanded for 4-7 days in DMEM 5% FCS (Hyclone), 100 &mgr;M non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10−5M (Gibco), 10 mM Hepes (Gibco) and IL-2 (1 ng/ml). Following this, the activated Th1, Th2 and Tr1 lymphocytes were re-stimulated for 5 days with anti-CD28/OKT3 and cytokines as described above, but with the addition of anti-CD95L (1 &mgr;g/ml) to prevent apoptosis. After 4-5 days, the Th1, Th2 and Tr1 lymphocytes were washed and then expanded again with IL-2 for 4-7 days. Activated Th1 and Th2 lymphocytes were maintained in this way for a maximum of three cycles. RNA was prepared from primary and secondary Th1, Th2 and Tr1 after 6 and 24 hours following the second and third activations with plate bound anti-CD3 and anti-CD28 mAbs and 4 days into the second and third expansion cultures in Interleukin 2.

[0450] The following leukocyte cells lines were obtained from the ATCC: Ramos, EOL-1, KU-812. EOL cells were further differentiated by culture in 0.1 mM dbcAMP at 5×105 cells/ml for 8 days, changing the media every 3 days and adjusting the cell concentration to 5×105 cells/ml. For the culture of these cells, we used DMEM or RPMI (as recommended by the ATCC), with the addition of 5% FCS (Hyclone), 100 &mgr;M non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10−5M (Gibco), 10 mM Hepes (Gibco). RNA was either prepared from resting cells or cells activated with PMA at 10 ng/ml and ionomycin at 1 &mgr;g/ml for 6 and 14 hours. Keratinocyte line CCD106 and an airway epithelial tumor line NCI-H292 were also obtained from the ATCC. Both were cultured in DMEM 5% FCS (Hyclone), 100 &mgr;M non essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), mercaptoethanol 5.5×10−5M (Gibco), and 10 mM Hepes (Gibco). CCD1106 cells were activated for 6 and 14 hours with approximately 5 ng/ml TNF alpha and 1 ng/ml IL-1 beta, while NCI-H292 cells were activated for 6 and 14 hours with the following cytokines: 5 ng/ml IL-4, 5 ng/ml IL-9, 5 ng/ml IL-13 and 25 ng/ml IFN gamma.

[0451] For these cell lines and blood cells, RNA was prepared by lysing approximately 107 cells/ml using Trizol (Gibco BRL). Briefly, {fraction (1/10)} volume of bromochloropropane (Molecular Research Corporation) was added to the RNA sample, vortexed and after 10 minutes at room temperature, the tubes were spun at 14,000 rpm in a Sorvall SS34 rotor. The aqueous phase was removed and placed in a 15 ml Falcon Tube. An equal volume of isopropanol was added and left at −20° C. overnight. The precipitated RNA was spun down at 9,000 rpm for 15 min in a Sorvall SS34 rotor and washed in 70% ethanol. The pellet was redissolved in 300 &mgr;l of RNAse-free water and 35 &mgr;l buffer (Promega) 5 &mgr;l DTT, 7 &mgr;l RNAsin and 8 &mgr;l DNAse were added. The tube was incubated at 37° C. for 30 minutes to remove contaminating genomic DNA, extracted once with phenol chloroform and re-precipitated with {fraction (1/10)} volume of 3M sodium acetate and 2 volumes of 100% ethanol. The RNA was spun down and placed in RNAse free water. RNA was stored at −80° C.

[0452] AI_Comprehensive Panel_v1.0

[0453] The plates for AI_comprehensive panel_v1.0 include two control wells and 89 test samples comprised of cDNA isolated from surgical and postmortem human tissues obtained from the Backus Hospital and Clinomics (Frederick, Md.). Total RNA was extracted from tissue samples from the Backus Hospital in the Facility at CuraGen. Total RNA from other tissues was obtained from Clinomics.

[0454] Joint tissues including synovial fluid, synovium, bone and cartilage were obtained from patients undergoing total knee or hip replacement surgery at the Backus Hospital. Tissue samples were immediately snap frozen in liquid nitrogen to ensure that isolated RNA was of optimal quality and not degraded. Additional samples of osteoarthritis and rheumatoid arthritis joint tissues were obtained from Clinomics. Normal control tissues were supplied by Clinomics and were obtained during autopsy of trauma victims.

[0455] Surgical specimens of psoriatic tissues and adjacent matched tissues were provided as total RNA by Clinomics. Two male and two female patients were selected between the ages of 25 and 47. None of the patients were taking prescription drugs at the time samples were isolated.

[0456] Surgical specimens of diseased colon from patients with ulcerative colitis and Crohns disease and adjacent matched tissues were obtained from Clinomics. Bowel tissue from three female and three male Crohn's patients between the ages of 41-69 were used. Two patients were not on prescription medication while the others were taking dexamethasone, phenobarbital, or tylenol. Ulcerative colitis tissue was from three male and four female patients. Four of the patients were taking lebvid and two were on phenobarbital.

[0457] Total RNA from post mortem lung tissue from trauma victims with no disease or with emphysema, asthma or COPD was purchased from Clinomics. Emphysema patients ranged in age from 40-70 and all were smokers, this age range was chosen to focus on patients with cigarette-linked emphysema and to avoid those patients with alpha-lanti-trypsin deficiencies. Asthma patients ranged in age from 36-75, and excluded smokers to prevent those patients that could also have COPD. COPD patients ranged in age from 35-80 and included both smokers and non-smokers. Most patients were taking corticosteroids, and bronchodilators.

[0458] In the labels employed to identify tissues in the AI_comprehensive panel_v1.0 panel, the following abbreviations are used:

[0459] AI=Autoimmunity

[0460] Syn=Synovial

[0461] Normal=No apparent disease

[0462] Rep22/Rep20=individual patients

[0463] RA=Rheumatoid arthritis

[0464] Backus=From Backus Hospital

[0465] OA=Osteoarthritis

[0466] (SS) (BA) (MF)=Individual patients

[0467] Adj=Adjacent tissue

[0468] Match control=adjacent tissues

[0469] -M=Male

[0470] -F=Female

[0471] COPD=Chronic obstructive pulmonary disease

[0472] AI.05 Chondrosarcoma

[0473] The AI.05 chondrosarcoma plates are comprised of SW1353 cells that had been subjected to serum starvation and treatment with cytokines that are known to induce MMP (1, 3 and 13) synthesis (eg. IL1beta). These treatments include: IL-1beta (10 ng/ml), IL-1beta+TNF-alpha (50 ng/ml), IL-1beta+Oncostatin (50 ng/ml) and PMA (100 ng/ml). The SW1353 cells were obtained from the ATCC (American Type Culture Collection) and were all cultured under standard recommended conditions. The SW1353 cells were plated at 3×105 cells/ml (in DMEM medium-10% FBS) in 6-well plates. The treatment was done in triplicate, for 6 and 18 h. The supernatants were collected for analysis of MMP 1, 3 and 13 production and for RNA extraction. RNA was prepared from these samples using the standard procedures.

[0474] Panels 5D and 5I

[0475] The plates for Panel 5D and 5I include two control wells and a variety of cDNAs isolated from human tissues and cell lines with an emphasis on metabolic diseases. Metabolic tissues were obtained from patients enrolled in the Gestational Diabetes study. Cells were obtained during different stages in the differentiation of adipocytes from human mesenchymal stem cells. Human pancreatic islets were also obtained.

[0476] In the Gestational Diabetes study subjects are young (18-40 years), otherwise healthy women with and without gestational diabetes undergoing routine (elective) Caesarean section. After delivery of the infant, when the surgical incisions were being repaired/closed, the obstetrician removed a small sample (less than 1 cc) of the exposed metabolic tissues during the closure of each surgical level. The biopsy material was rinsed in sterile saline, blotted and fast frozen within 5 minutes from the time of removal. The tissue was then flash frozen in liquid nitrogen and stored, individually, in sterile screw-top tubes and kept on dry ice for shipment to or to be picked up by CuraGen. The metabolic tissues of interest include uterine wall (smooth muscle), visceral adipose, skeletal muscle (rectus) and subcutaneous adipose. Patient descriptions are as follows:

[0477] Patient 2: Diabetic Hispanic, overweight, not on insulin

[0478] Patient 7-9: Nondiabetic Caucasian and obese (BMI>30)

[0479] Patient 10: Diabetic Hispanic, overweight, on insulin

[0480] Patient 11: Nondiabetic African American and overweight

[0481] Patient 12: Diabetic Hispanic on insulin

[0482] Adiocyte differentiation was induced in donor progenitor cells obtained from Osirus (a division of Clonetics/BioWhittaker) in triplicate, except for Donor 3U which had only two replicates. Scientists at Clonetics isolated, grew and differentiated human mesenchymal stem cells (HuMSCs) for CuraGen based on the published protocol found in Mark F. Pittenger, et al., Multilineage Potential of Adult Human Mesenchymal Stem Cells Science Apr. 2, 1999: 143-147. Clonetics provided Trizol lysates or frozen pellets suitable for mRNA isolation and ds cDNA production. A general description of each donor is as follows:

[0483] Donor 2 and 3 U: Mesenchymal Stem cells, Undifferentiated Adipose

[0484] Donor 2 and 3 AM: Adipose, AdiposeMidway Differentiated

[0485] Donor 2 and 3 AD: Adipose, Adipose Differentiated

[0486] Human cell lines were generally obtained from ATCC (American Type Culture Collection), NCI or the German tumor cell bank and fall into the following tissue groups: kidney proximal convoluted tubule, uterine smooth muscle cells, small intestine, liver HepG2 cancer cells, heart primary stromal cells, and adrenal cortical adenoma cells. These cells are all cultured under standard recommended conditions and RNA extracted using the standard procedures. All samples were processed at CuraGen to produce single stranded cDNA.

[0487] Panel 5I contains all samples previously described with the addition of pancreatic islets from a 58 year old female patient obtained from the Diabetes Research Institute at the University of Miami School of Medicine. Islet tissue was processed to total RNA at an outside source and delivered to CuraGen for addition to panel 5I.

[0488] In the labels employed to identify tissues in the 5D and 5I panels, the following abbreviations are used:

[0489] GO Adipose=Greater Omentum Adipose

[0490] SK=Skeletal Muscle

[0491] UT=Uterus

[0492] PL=Placenta

[0493] AD=Adipose Differentiated

[0494] AM=Adipose Midway Differentiated

[0495] U=Undifferentiated Stem Cells

[0496] Human Metabolic RTQ-PCR Panel

[0497] The plates for the Human Metabolic RTQ-PCR Panel include two control wells (genomic DNA control and chemistry control) and 211 cDNAs isolated from human tissues and cell lines with an emphasis on metabolic diseases. This panel is useful for establishing the tissue and cellular expression profiles for genes believed to play a role in the etiology and pathogenesis of obesity and/or diabetes and to confirm differential expression of such genes derived from other methods. Metabolic tissues were obtained from patients enrolled in the CuraGen Gestational Diabetes study and from autopsy tissues from Type II diabetics and age, sex and race-matched control patients. One or more of the following were used to characterize the patients: body mass index [BMI=wt (kg)/ht (m2)], serum glucose, HgbA1c. Cell lines used in this panel are widely available through the American Type Culture Collection (ATCC), a repository for cultured cell lines. RNA from human Pancreatic Islets was also obtained.

[0498] In the Gestational Diabetes study, subjects are young (18-40 years), otherwise healthy women with and without gestational diabetes undergoing routine (elective) Caesarian section. After delivery of the infant, when the surgical incisions were being repaired/closed, the obstetrician removed a small sample (less than 1 cc) of the exposed metabolic tissues during the closure of each surgical level. The biopsy material was rinsed in sterile saline, blotted, and then flash frozen in liquid nitrogen and stored, individually, in sterile screw-top tubes and kept on dry ice for shipment to or to be picked up by CuraGen. The metabolic tissues of interest include uterine wall (smooth muscle), visceral adipose, skeletal muscle (rectus), and subcutaneous adipose. Patient descriptions are as follows:

[0499] Patient 7—Non-diabetic Caucasian and obese

[0500] Patient 8—Non-diabetic Caucasian and obese

[0501] Patient 12—Diabetic Caucasian with unknown BMI and on insulin

[0502] Patient 13—Diabetic Caucasian, overweight, not on insulin

[0503] Patient 15—Diabetic Caucasian, obese, not on insulin

[0504] Patient 17—Diabetic Caucasian, normal weight, not on insulin

[0505] Patient 18—Diabetic Hispanic, obese, not on insulin

[0506] Patient 19—Non-diabetic Caucasian and normal weight

[0507] Patient 20—Diabetic Caucasian, overweight, and on insulin

[0508] Patient 21—Non-diabetic Caucasian and overweight

[0509] Patient 22—Diabetic Caucasian, normal weight, on insulin

[0510] Patient 23—Non-diabetic Caucasian and overweight

[0511] Patient 25—Diabetic Caucasian, normal weight, not on insulin

[0512] Patient 26—Diabetic Caucasian, obese, on insulin

[0513] Patient 27—Diabetic Caucasian, obese, on insulin

[0514] Total RNA was isolated from metabolic tissues of 12 Type II diabetic patients and 12 matched control patients included hypothalamus, liver, pancreas, small intestine, psoas muscle, diaphragm muscle, visceral adipose, and subcutaneous adipose. The diabetics and non-diabetics were matched for age, sex, ethnicity, and BMI where possible.

[0515] The panel also contains pancreatic islets from a 22 year old male patient (with a BMI of 35) obtained from the Diabetes Research Institute at the University of Miami School of Medicine. Islet tissue was processed to total RNA at CuraGen.

[0516] Cell lines used in this panel are widely available through the American Type Culture Collection (ATCC), a repository for cultured cell lines, and were cultured at an outside facility. The RNA was extracted at CuraGen according to CuraGen protocols. All samples were then processed at CuraGen to produce single stranded cDNA.

[0517] In the labels used to identify tissues in the Human Metabolic panel, the following abbreviations are used:

[0518] Pl=placenta

[0519] Go=greater omentum

[0520] Sk=skeletal muscle

[0521] Ut=uterus

[0522] CC=Caucasian

[0523] HI=Hispanic

[0524] AA=African American

[0525] AS=Asian

[0526] Diab=Type II diabetic

[0527] Norm=Non-diabetic

[0528] Overwt=Overweight; med BMI

[0529] Obese=Hi BMI

[0530] Low BM=20-25

[0531] Med BM=26-30

[0532] Hi BMI=Greater than 30

[0533] M=Male

[0534] #=Patient identifier

[0535] Vis.=Visceral

[0536] SubQ=Subcutaneous

[0537] Panel CNSD.01

[0538] The plates for Panel CNSD.01 include two control wells and 94 test samples comprised of cDNA isolated from postmortem human brain tissue obtained from the Harvard Brain Tissue Resource Center. Brains are removed from calvaria of donors between 4 and 24 hours after death, sectioned by neuroanatomists, and frozen at −80° C. in liquid nitrogen vapor. All brains are sectioned and examined by neuropathologists to confirm diagnoses with clear associated neuropathology.

[0539] Disease diagnoses are taken from patient records. The panel contains two brains from each of the following diagnoses: Alzheimer's disease, Parkinson's disease, Huntington's disease, Progressive Supernuclear Palsy, Depression, and “Normal controls”. Within each of these brains, the following regions are represented: cingulate gyrus, temporal pole, globus palladus, substantia nigra, Brodman Area 4 (primary motor strip), Brodman Area 7 (parietal cortex), Brodman Area 9 (prefrontal cortex), and Brodman area 17 (occipital cortex). Not all brain regions are represented in all cases; e.g., Huntington's disease is characterized in part by neurodegeneration in the globus palladus, thus this region is impossible to obtain from confirmed Huntington's cases. Likewise Parkinson's disease is characterized by degeneration of the substantia nigra making this region more difficult to obtain. Normal control brains were examined for neuropathology and found to be free of any pathology consistent with neurodegeneration.

[0540] In the labels employed to identify tissues in the CNS panel, the following abbreviations are used:

[0541] PSP=Progressive supranuclear palsy

[0542] Sub Nigra=Substantia nigra

[0543] Glob Palladus=Globus palladus

[0544] Temp Pole=Temporal pole

[0545] Cing Gyr=Cingulate gyrus

[0546] BA 4=Brodman Area 4

[0547] Panel CNS_Neurodegeneration_V1.0

[0548] The plates for Panel CNS_Neurodegeneration_V1.0 include two control wells and 47 test samples comprised of cDNA isolated from postmortem human brain tissue obtained from the Harvard Brain Tissue Resource Center (McLean Hospital) and the Human Brain and Spinal Fluid Resource Center (VA Greater Los Angeles Healthcare System). Brains are removed from calvaria of donors between 4 and 24 hours after death, sectioned by neuroanatomists, and frozen at −80° C. in liquid nitrogen vapor. All brains are sectioned and examined by neuropathologists to confirm diagnoses with clear associated neuropathology.

[0549] Disease diagnoses are taken from patient records. The panel contains six brains from Alzheimer's disease (AD) patients, and eight brains from “Normal controls” who showed no evidence of dementia prior to death. The eight normal control brains are divided into two categories: Controls with no dementia and no Alzheimer's like pathology (Controls) and controls with no dementia but evidence of severe Alzheimer's like pathology, (specifically senile plaque load rated as level 3 on a scale of 0-3; 0=no evidence of plaques, 3=severe AD senile plaque load). Within each of these brains, the following regions are represented: hippocampus, temporal cortex (Brodman Area 21), parietal cortex (Brodman area 7), and occipital cortex (Brodman area 17). These regions were chosen to encompass all levels of neurodegeneration in AD. The hippocampus is a region of early and severe neuronal loss in AD; the temporal cortex is known to show neurodegeneration in AD after the hippocampus; the parietal cortex shows moderate neuronal death in the late stages of the disease; the occipital cortex is spared in AD and therefore acts as a “control” region within AD patients. Not all brain regions are represented in all cases.

[0550] In the labels employed to identify tissues in the CNS_Neurodegeneration_V1.0 panel, the following abbreviations are used:

[0551] AD=Alzheimer's disease brain; patient was demented and showed AD-like pathology upon autopsy

[0552] Control=Control brains; patient not demented, showing no neuropathology

[0553] Control (Path)=Control brains; pateint not demented but showing sever AD-like pathology

[0554] SupTemporal Ctx=Superior Temporal Cortex

[0555] Inf Temporal Ctx=Inferior Temporal Cortex

[0556] Panel CNS_Neurodegeneration_V2.0

[0557] The plates for Panel CNS_Neurodegeneration_V2.0 include two control wells and 47 test samples comprised of cDNA isolated from postmortem human brain tissue obtained from the Harvard Brain Tissue Resource Center (McLean Hospital) and the Human Brain and Spinal Fluid Resource Center (VA Greater Los Angeles Healthcare System). Brains are removed from calvaria of donors between 4 and 24 hours after death, sectioned by neuroanatomists, and frozen at −80° C. in liquid nitrogen vapor. All brains are sectioned and examined by neuropathologists to confirm diagnoses with clear associated neuropathology.

[0558] Disease diagnoses are taken from patient records. The panel contains sixteen brains from Alzheimer's disease (AD) patients, and twenty-nine brains from “Normal controls” who showed no evidence of dementia prior to death. The twenty-nine normal control brains are divided into two categories: Fourteen controls with no dementia and no Alzheimer's like pathology (Controls) and fifteen controls with no dementia but evidence of severe Alzheimer's like pathology, (specifically senile plaque load rated as level 3 on a scale of 0-3; 0=no evidence of plaques, 3=severe AD senile plaque load). Tissue from the temporal cotex (Broddmann Area 21) was selected for all samples from the Harvard Brain Tissue Resource Center; from the two sample from the Human Brain and Spinal Fluid Resource Center (samples 1 and 2) tissue from the inferior and superior temporal cortex was used; each sample on the panel represents a pool of inferior and superior temporal cortex from an individual patient. The temporal cortex was chosen as it shows a loss of neurons in the intermediate stages of the disease. Selection of a region which is affected in the early stages of Alzheimer's disease (e.g., hippocampus or entorhinal cortex) could potentially result in the examination of gene expression after vulnerable neurons are lost, and missing genes involved in the actual neurodegeneration process.

[0559] In the labels employed to identify tissues in the CNS_Neurodegeneration_V2.0 panel, the following abbreviations are used:

[0560] AD=Alzheimer's disease brain; patient was demented and showed AD-like pathology upon autopsy

[0561] Control=Control brains; patient not demented, showing no neuropathology

[0562] AH3=Control brains; pateint not demented but showing sever AD-like pathology

[0563] Inf & Sup Temp Ctx Pool=Pool of inferior and superior temporal cortex for a given individual

[0564] A. CG50907-03 and CG50907-04: Sema4C.

[0565] Expression of gene CG50907-03 and CG50907-04 was assessed using the primer-probe sets Ag1215, Ag1382, Ag37 and Ag7452, described in Tables AA, AB, AC, and AD a. Results of the RTQ-PCR runs are shown in Tables AE, AF, AG, AH, AI, AJ, AK, AL, AM, AN, AO, AP, AQ, and AR. Please note that CG50907-03 is a physical clone for the extracellular domain of this gene. Also, probe-primer set Ag7452 specifically recognizes the splice variant, CG50907-04. 44 TABLE AA Probe Name Ag1215 Start SEQ ID Primers Sequences Length Position No Forward 5′-aacccattatcctgcgtaacat-3′ 22 569 129 Probe TET-5′ccccaccactccatgaagacagagta-3′-TAMRA 26 595 130 Reverse 5′-cctacaaagtgaggttcgttga-3′ 22 635 131

[0566] 45 TABLE AB Probe Name Ag1382 Start SEQ ID Primers Sequences Length Position No Forward 5′-aacccattatcctgcgtaacat-3′ 22 569 132 Probe TET-5′-ccccaccactccatgaagacagagta-3′-TAMRA 26 595 133 Reverse 5′-cctacaaagtgaggttcgttga-3′ 22 635 134

[0567] 46 TABLE AC Probe Name Ag37 Start SEQ ID Primers Sequences Length Position No Forward 5′-ggcttcctcatggtactcctta-3′ 22 1041 135 Probe TET-5′-ccgctggatctcttccaactggtact-3′-TAMRA 26 998 136 Reverse 5′-acagtggggtgacatgtacct-3′ 21 963 137

[0568] 47 TABLE AD Probe Name Ag7452 Start SEQ ID Primers Sequences Length Position No Forward 5′-atgagaagcctggtgctatctc-3′ 22 1420 138 Probe TET-5′-agagcaagaccctccaagctgtgct-3′-TAMRA 25 1442 139 Reverse 5′-gcatggtcagggaagag-3′ 18 1484 140

[0569] 48 TABLE AE Ardais Panel v.1.0 Tissue Name A Tissue Name A 136799_Lung cancer(362) 100.0 136787_lung cancer(356) 51.4 136800_Lung NAT(363) 44.4 136788_lung NAT(357) 42.9 136813_Lung cancer(372) 72.2 136804_Lung cancer(369) 82.4 136814_Lung NAT(373) 13.6 136805_Lung NAT(36A) 25.5 136815_Lung cancer(374) 35.8 136806_Lung cancer(36B) 98.6 136816_Lung NAT(375) 77.4 136807_Lung NAT(36C) 16.3 136791_Lung cancer(35A) 42.9 136789_lung cancer(358) 85.9 136795_Lung cancer(35E) 91.4 136802_Lung cancer(365) 49.7 136797_Lung cancer(360) 19.6 136803_Lung cancer(368) 69.3 136794_lung NAT(35D) 34.6 136811_Lung cancer(370) 25.0 136818_Lung NAT(377) 20.7 136810_Lung NAT(36F) 63.7 Column A - Rel. Exp.(%) Ag1215, Run 67680187

[0570] 49 TABLE AF CNS_neurodegeneration_v1.0 Tissue Name A B Tissue Name A B AD 1 Hippo 12.2 0.0 Control (Path) 3 Temporal Ctx 5.1 13.8 AD 2 Hippo 23.7 27.4 Control (Path) 4 Temporal Ctx 24.3 29.9 AD 3 Hippo 6.0 0.0 AD 1 Occipital Ctx 15.8 10.7 AD 4 Hippo 8.3 9.0 AD 2 Occipital Ctx (Missing) 0.0 0.0 AD 5 Hippo 97.9 26.2 AD 3 Occipital Ctx 5.6 0.0 AD 6 Hippo 48.0 54.0 AD 4 Occipital Ctx 16.6 32.5 Control 2 Hippo 24.1 60.7 AD 5 Occipital Ctx 44.8 40.3 Control 4 Hippo 11.4 13.8 AD 6 Occipital Ctx 33.0 36.3 Control (Path) 3 Hippo 5.4 16.4 Control 1 Occipital Ctx 7.5 19.2 AD 1 Temporal Ctx 20.7 17.0 Control 2 Occipital Ctx 66.4 54.7 AD 2 Temporal Ctx 29.7 9.9 Control 3 Occipital Ctx 16.8 20.4 AD 3 Temporal Ctx 12.9 0.0 Control 4 Occipital Ctx 12.2 14.7 AD 4 Temporal Ctx 23.2 34.6 Control (Path) 1 Occipital Ctx 81.8 55.1 AD 5 Inf Temporal Ctx 100.0 76.3 Control (Path) 2 Occipital Ctx 10.7 7.9 AD 5 Sup Temporal Ctx 35.8 46.0 Control (Path) 3 Occipital Ctx 6.6 0.0 AD 6 Inf Temporal Ctx 65.5 100.0 Control (Path) 4 Occipital Ctx 16.6 17.1 AD 6 Sup Temporal Ctx 52.1 55.5 Control 1 Parietal Ctx 8.7 21.0 Control 1 Temporal Ctx 6.4 5.4 Control 2 Parietal Ctx 49.3 42.0 Control 2 Temporal Ctx 34.9 40.1 Control 3 Parietal Ctx 14.9 12.8 Control 3 Temporal Ctx 14.3 17.3 Control (Path) 1 Parietal Ctx 56.3 43.2 Control 3 Temporal Ctx 8.0 0.0 Control (Path) 2 Parietal Ctx 19.9 20.7 Control (Path) 1 Temporal Ctx 39.2 40.6 Control (Path) 3 Parietal Ctx 4.1 5.1 Control (Path) 2 Temporal Ctx 19.8 35.6 Control (Path) 4 Parietal Ctx 28.7 28.3 Column A - Rel. Exp.(% Ag1215, Run 206228023 Column B - Rel. Exp.(%) Ag7452, Run 306518756

[0571] 50 TABLE AG General_screening_panel_v1.4 Tissue Name A B Tissue Name A B Adipose 4.1 15.3 Renal ca. TK-10 10.0 20.0 Melanoma* Hs688(A).T 8.1 13.6 Bladder 9.5 19.9 Melanoma* Hs688(B).T 6.1 14.7 Gastric ca. (liver met.) NCI-N87 11.7 19.8 Melanoma* M14 40.3 52.1 Gastric ca. KATO III 0.0 0.3 Melanoma* LOXIMVI 12.0 25.2 Colon ca. SW-948 2.4 8.7 Melanoma* SK-MEL-5 22.4 41.5 Colon ca. SW480 13.7 25.9 Squamous Cell carcinoma SCC-4 6.1 30.6 Colon ca.* (SW480 met) SW620 7.9 17.1 Testis Pool 3.1 3.5 Colon ca. HT29 1.6 3.6 Prostate ca.* (bone met) PC-3 12.7 21.3 Colon ca. HCT-116 11.6 20.2 Prostate Pool 4.6 11.8 Colon ca. CaCo-2 10.6 29.3 Placenta 26.2 19.8 Colon cancer tissue 7.1 31.6 Uterus Pool 3.8 13.2 Colon ca. SW1116 2.5 5.4 Ovarian ca. OVCAR-3 20.2 27.5 Colon ca. Colo-205 0.0 0.1 Ovarian ca. SK-OV-3 8.8 23.8 Colon ca. SW-48 0.4 0.9 Ovarian ca. OVCAR-4 3.9 11.5 Colon Pool 9.9 36.6 Ovarian ca. OVCAR-5 21.3 37.6 Small Intestine Pool 20.2 33.9 Ovarian ca. IGROV-1 9.7 30.4 Stomach Pool 7.6 13.1 Ovarian ca. OVCAR-8 8.2 23.3 Bone Marrow Pool 5.2 12.9 Ovary 7.2 2.1 Fetal Heart 6.7 12.7 Breast ca. MCF-7 100.0 100.0 Heart Pool 4.2 11.4 Breast ca. MDA-MB-231 11.0 17.6 Lymph Node Pool 14.3 32.3 Breast ca. BT 549 17.2 23.2 Fetal Skeletal Muscle 5.6 6.4 Breast ca. T47D 33.2 62.9 Skeletal Muscle Pool 3.4 5.3 Breast ca. MDA-N 8.0 10.9 Spleen Pool 10.4 20.6 Breast Pool 13.2 43.5 Thymus pool 6.5 15.8 Trachea 9.0 18.4 CNS cancer (glio/astro) U87-MG 9.2 14.6 Lung 1.4 2.2 CNS cancer (glio/astro) U-118-MG 12.4 21.3 Fetal Lung 21.0 34.9 CNS cancer (neuro; met) SK-N-AS 18.8 33.4 Lung ca. NCI-N417 0.9 2.6 CNS cancer (astro) SF-539 17.9 35.4 Lung ca. LX-1 12.9 21.8 CNS cancer (astro) SNB-75 42.9 74.2 Lung ca. NCI-H146 4.4 6.1 CNS cancer (glio) SNB-19 7.2 16.6 Lung ca. SHP-77 8.2 11.8 CNS cancer (glio) SF-295 14.9 33.7 Lung ca. A549 9.4 11.3 Brain (Amygdala) Pool 11.0 21.2 Lung ca. NCI-H526 3.0 6.5 Brain (cerebellum) 47.0 65.1 Lung ca. NCI-H23 33.9 50.0 Brain (fetal) 33.2 43.8 Lung ca. NCI-H460 8.8 16.6 Brain (Hippocampus) Pool 9.4 14.2 Lung ca. HOP-62 11.3 21.6 Cerebral Cortex Pool 7.5 23.8 Lung ca. NCI-H522 18.3 30.6 Brain (Substantia nigra) Pool 9.4 26.2 Liver 0.5 1.7 Brain (Thalamus) Pool 11.7 18.6 Fetal Liver 6.8 5.1 Brain (whole) 16.2 27.9 Liver ca. HepG2 9.5 12.8 Spinal Cord Pool 12.6 20.9 Kidney Pool 18.8 62.0 Adrenal Gland 8.6 14.4 Fetal Kidney 5.0 12.8 Pituitary gland Pool 1.0 3.1 Renal ca. 786-0 8.0 15.8 Salivary Gland 5.2 4.7 Renal ca. A498 6.8 8.2 Thyroid (female) 3.5 6.7 Renal ca. ACHN 7.8 14.2 Pancreatic ca. CAPAN2 5.0 14.3 Renal ca. UO-31 8.7 14.8 Pancreas Pool 18.2 26.4 Column A - Rel. Exp.(%) Ag1215, Run 212696257 Column B - Rel. Exp.(%) Ag37, Run 216861491

[0572] 51 TABLE AH General_screening_panel_v1.7 Tissue Name A Tissue Name A Adipose 17.8 Gastric ca. (liver met.) NCI-N87 0.7 HUVEC 6.6 Stomach 0.8 Melanoma* Hs688(A).T 0.0 Colon ca. SW-948 5.4 Melanoma* Hs688(B).T 10.2 Colon ca. SW480 5.2 Melanoma (met) SK-MEL-5 33.7 Colon ca. (SW480 met) SW620 25.2 Testis 2.0 Colon ca. HT29 6.7 Prostate ca. (bone met) PC-3 0.0 Colon ca. HCT-116 9.0 Prostate ca. DU145 9.2 Colon cancer tissue 0.6 Prostate pool 2.4 Colon ca. SW1116 2.3 Uterus pool 2.2 Colon ca. Colo-205 0.0 Ovarian ca. OVCAR-3 11.8 Colon ca. SW-48 0.0 Ovarian ca. (ascites) SK-OV-3 0.1 Colon 10.5 Ovarian ca. OVCAR-4 13.4 Small Intestine 3.9 Ovarian ca. OVCAR-5 17.3 Fetal Heart 1.4 Ovarian ca. IGROV-1 12.2 Heart 2.5 Ovarian ca. OVCAR-8 11.9 Lymph Node pool 1 0.8 Ovary 4.1 Lymph Node pool 2 12.9 Breast ca. MCF-7 100.0 Fetal Skeletal Muscle 0.4 Breast ca. MDA-MB-231 21.0 Skeletal Muscle pool 0.3 Breast ca. BT-549 4.5 Skeletal Muscle 3.3 Breast ca. T47D 5.6 Spleen 3.5 Breast pool 3.5 Thymus 2.1 Trachea 17.1 CNS cancer (glio/astro) SF-268 2.4 Lung 20.9 CNS cancer (glio/astro) T98G 6.7 Fetal Lung 16.2 CNS cancer (neuro; met) SK-N-AS 5.3 Lung ca. NCI-N417 0.7 CNS cancer (astro) SF-539 58.2 Lung ca. LX-1 6.7 CNS cancer (astro) SNB-75 17.6 Lung ca. NCI-H146 18.7 CNS cancer (glio) SNB-19 5.8 Lung ca. SHP-77 14.0 CNS cancer (glio) SF-295 1.5 Lung ca. NCI-H23 46.7 Brain (Amygdala) 4.5 Lung ca. NCI-H460 5.0 Brain (Cerebellum) 8.6 Lung ca. HOP-62 31.4 Brain (Fetal) 11.3 Lung ca. NCI-H522 16.8 Brain (Hippocampus) 4.6 Lung ca. DMS-114 9.3 Cerebral Cortex pool 2.6 Liver 0.0 Brain (Substantia nigra) 1.6 Fetal Liver 3.8 Brain (Thalamus) 4.8 Kidney pool 4.8 Brain (Whole) 29.3 Fetal Kidney 0.5 Spinal Cord 2.3 Renal ca. 786-0 14.0 Adrenal Gland 8.4 Renal ca. A498 6.2 Pituitary Gland 2.6 Renal ca. ACHN 5.0 Salivary Gland 3.0 Renal ca. UO-31 5.0 Thyroid 7.0 Renal ca. TK-10 7.5 Pancreatic ca. PANC-1 5.4 Bladder 9.5 Pancreas pool 2.3 Column A - Rel. Exp.(%) Ag7452, Run 318350229

[0573] 52 TABLE AI HASS Panel v1.0 Tissue Name A Tissue Name A MCF-7 C1 50.3 U87-MG F1 (B) 3.9 MCF-7 C2 58.2 U87-MG F2 1.8 MCF-7 C3 42.0 U87-MG F3 2.9 MCF-7 C4 59.5 U87-MG F4 4.2 MCF-7 C5 57.0 U87-MG F5 7.9 MCF-7 C6 73.2 U87-MG F6 8.5 MCF-7 C7 29.7 U87-MG F7 3.5 MCF-7 C9 32.3 U87-MG F8 5.1 MCF-7 C10 73.7 U87-MG F9 2.6 MCF-7 C11 12.8 U87-MG F10 5.2 MCF-7 C12 46.7 U87-MG F11 5.6 MCF-7 C13 35.6 U87-MG F12 5.2 MCF-7 C15 18.4 U87-MG F13 3.5 MCF-7 C16 100.0 U87-MG F14 5.9 MCF-7 C17 60.7 U87-MG F15 3.8 T24 D1 10.4 U87-MG F16 6.6 T24 D2 5.8 U87-MG F17 5.7 T24 D3 9.4 LnCAP A1 3.6 T24 D4 11.9 LnCAP A2 3.1 T24 D5 8.5 LnCAP A3 3.5 T24 D6 11.7 LnCAP A4 3.4 T24 D7 3.1 LnCAP A5 2.7 T24 D9 3.2 LnCAP A6 2.6 T24 D10 4.9 LnCAP A7 4.3 T24 D11 4.8 LnCAP A8 3.5 T24 D12 6.6 LnCAP A9 3.4 T24 D13 2.5 LnCAP A10 3.5 T24 D15 3.2 LnCAP A11 7.5 T24 D16 3.2 LnCAP A12 0.7 T24 D17 4.6 LnCAP A13 0.8 CAPaN B1 6.3 LnCAP A14 0.5 CAPaN B2 4.0 LnCAP A15 0.3 CAPaN B3 1.4 LnCAP A16 5.9 CAPaN B4 6.9 LnCAP A17 3.9 CAPaN B5 4.7 Primary Astrocytes 6.0 CAPaN B6 6.1 Primary Renal Proximal Tubule Epithelial 3.2 cell A2 CAPaN B7 3.7 Primary melanocytes A5 4.8 CAPaN B8 5.3 126443 - 341 medullo 0.8 CAPaN B9 5.0 126444 - 487 medullo 19.3 CAPaN B10 8.1 126445 - 425 medullo 1.8 CAPaN B11 5.6 126446 - 690 medullo 9.0 CAPaN B12 4.3 126447 - 54 adult glioma 3.8 CAPaN B13 6.6 126448 - 245 adult glioma 7.7 CAPaN B14 5.6 126449 - 317 adult glioma 8.3 CAPaN B15 3.3 126450 - 212 glioma 7.4 CAPaN B16 7.0 126451 - 456 glioma 8.4 CAPaN B17 7.4 Column A - Rel. Exp.(%) Ag1215, Run 267674603

[0574] 53 TABLE AJ Oncology_cell_line_screening_panel_v3.2 Tissue Name A Tissue Name A 94905_Daoy_Medulloblastoma/Cerebellum_ssc 2.5 94954_Ca Ski_Cervical epidermoid 14.9 DNA carcinoma (metastasis)_sscDNA 94906_TE671_Medulloblastom/Cerebellum_ssc 7.2 94955_ES-2_Ovarian clear cell 6.6 DNA carcinoma_sscDNA 94907_D283 8.8 94957_Ramos/6 h stim_Stimulated with 0.0 Med_Medulloblastoma/Cerebellum_sscDNA PMA/ionomycin 6 h_sscDNA 94908_PFSK-1_Primitive 9.3 94958_Ramos/14 h stim_Stimulated 0.0 Neuroectodermal/Cerebellum_sscDNA with PMA/ionomycin 14 h_sscDNA 94909_XF-498_CNS_sscDNA 18.8 94962_MEG-01_Chronic myelogenous 12.5 leukemia (megokaryoblast)_sscDNA 94910_SNB-78_CNS/glioma_sscDNA 7.4 94963_Raji_Burkitt's 0.0 lymphoma_sscDNA 94911_SF-268_CNS/glioblastoma_sscDNA 7.4 94964_Daudi_Burkitt's 0.0 lymphoma_sscDNA 94912_T98G_Glioblastoma_sscDNA 11.7 94965_U266_B-cell 0.3 plasmacytoma/myeloma_sscDNA 96776_SK-N-SH_Neuroblastoma 8.5 94968_CA46_Burkitt's 0.0 (metastasis)_sscDNA lymphoma_sscDNA 94913_SF-295_CNS/glioblastoma_sscDNA 6.4 94970_RL_non-Hodgkin's B-cell 0.0 lymphoma_sscDNA 132565_NT2 pool_sscDNA 22.8 94972_JM1_pre-B-cell 0.0 lymphoma/leukemia_sscDNA 94914_Cerebellum_sscDNA 20.9 94973_Jurkat_T cell leukemia_sscDNA 1.2 96777_Cerebellum_sscDNA 20.2 94974_TF-1_Erythroleukemia_sscDNA 16.5 94916_NCI-H292_Mucoepidermoid lung 7.2 94975_HUT 78_T-cell 4.3 carcinoma_sscDNA lymphoma_sscDNA 94917_DMS-114_Small cell lung 13.6 94977_U937_Histiocytic 10.8 cancer_sscDNA lymphoma_sscDNA 94918_DMS-79_Small cell lung 100.0 94980_KU-812_Myelogenous 14.0 cancer/neuroendocrine_sscDNA leukemia_sscDNA 94919_NCI-H146_Small cell lung 11.0 94981_769-P_Clear cell renal 6.3 cancer/neuroendocrine_sscDNA carcinoma_sscDNA 94920_NCI-H526_Small cell lung 14.8 94983_Caki-2_Clear cell renal 6.3 cancer/neuroendocrine_sscDNA carcinoma_sscDNA 94921_NCI-N417_Small cell lung 2.5 94984_SW 839_Clear cell renal 5.7 cancer/neuroendocrine_sscDNA carcinoma_sscDNA 94923_NCI-H82_Small cell lung 6.3 94986_G401_Wilms' tumor_sscDNA 3.4 cancer/neuroendocrine_sscDNA 94924_NCI-H157_Squamous cell lung cancer 8.9 126768_293 cells_sscDNA 2.9 (metastasis)_sscDNA 94925_NCI-H1155_Large cell lung 10.1 94987_Hs766T_Pancreatic carcinoma 7.1 cancer/neuroendocrine_sscDNA (LN metastasis)_sscDNA 94926_NCI-H1299_Large cell lung 14.8 94988_CAPAN-1_Pancreatic 5.4 cancer/neuroendocrine_sscDNA adenocarcinoma (liver metastasis)_sscDNA 94927_NCI-H727_Lung carcinoid_sscDNA 22.5 94989_SU86.86_Pancreatic carcinoma 13.6 (liver metastasis)_sscDNA 94928_NCI-UMC-11_Lung carcinoid_sscDNA 11.3 94990_BxPC-3_Pancreatic 6.3 adenocarcinoma_sscDNA 94929_LX-1_Small cell lung cancer_sscDNA 7.1 94991_HPAC_Pancreatic 18.4 adenocarcinoma_sscDNA 94930_Colo-205_Colon cancer_sscDNA 0.0 94992_MIA PaCa-2_Pancreatic 2.1 carcinoma_sscDNA 94931_KM12_Colon cancer_sscDNA 3.1 94993_CFPAC-1_Pancreatic ductal 16.6 adenocarcinoma_sscDNA 94932_KM20L2_Colon cancer_sscDNA 1.0 94994_PANC-1_Pancreatic epithelioid 9.5 ductal carcinoma_sscDNA 94933_NCI-H716_Colon cancer_sscDNA 4.0 94996_T24_Bladder carcinma 5.0 (transitional cell)_sscDNA 94935_SW-48_Colon adenocarcinoma_sscDNA 0.6 94997_5637_Bladder 9.0 carcinoma_sscDNA 94936_SW1116_Colon 3.7 94998_HT-1197_Bladder 11.0 adenocarcinoma_sscDNA carcinoma_sscDNA 94937_LS 174T_Colon 5.4 94999_UM-UC-3_Bladder carcinma 3.5 adenocarcinoma_sscDNA (transitional cell)_sscDNA 94938_SW-948_Colon 0.8 95000_A204_Rhabdomyosarcoma_ssc 6.3 adenocarcinoma_sscDNA DNA 94939_SW-480_Colon 5.9 95001_HT-1080_Fibrosarcoma_sscDNA 7.7 adenocarcinoma_sscDNA 94940_NCI-SNU-5_Gastric carcinoma_sscDNA 7.3 95002_MG-63_Osteosarcoma 5.6 (bone)_sscDNA 112197_KATO III_Stomach_sscDNA 0.0 95003_SK-LMS-1_Leiomyosarcoma 9.7 (vulva)_sscDNA 94943_NCI-SNU-16_Gastric 2.9 95004_SJRH30_Rhabdomyosarcoma 11.0 carcinoma_sscDNA (met to bone marrow)_sscDNA 94944_NCI-SNU-1_Gastric carcinoma_sscDNA 2.4 95005_A431_Epidermoid 3.1 carcinoma_sscDNA 94946_RF-1_Gastric adenocarcinoma_sscDNA 3.3 95007_WM266-4_Melanoma_sscDNA 5.3 94947_RF-48_Gastric 3.6 112195_DU 145_Prostate_sscDNA 6.8 adenocarcinoma_sscDNA 96778_MKN-45_Gastric carcinoma_sscDNA 10.4 95012_MDA-MB-468_Breast 1.9 adenocarcinoma_sscDNA 94949_NCI-N87_Gastric carcinoma_sscDNA 10.4 112196_SSC-4_Tongue_sscDNA 5.1 94951_OVCAR-5_Ovarian carcinoma_sscDNA 2.7 112194_SSC-9_Tongue_sscDNA 2.6 94952_RL95-2_Uterine carcinoma_sscDNA 3.9 112191_SSC-15_Tongue_sscDNA 4.1 94953_HelaS3_Cervical 4.4 95017_CAL 27_Squamous cell 7.8 adenocarcinoma_sscDNA carcinoma of tongue_sscDNA Column A - Rel. Exp.(%) Ag121, Run 267673682

[0575] 54 TABLE AK Panel 1 Tissue Name A Tissue Name A Endothelial cells 1.1 Renal ca. 786-0 4.6 Endothelial cells (treated) 2.2 Renal ca. A498 2.7 Pancreas 4.9 Renal ca. RXF 393 3.2 Pancreatic ca. CAPAN 2 2.0 Renal ca. ACHN 2.4 Adrenal gland 9.2 Renal ca. UO-31 1.7 Thyroid 6.3 Renal ca.TK-10 4.3 Salivary gland 4.6 Liver 8.5 Pituitary gland 9.1 Liver (fetal) 4.5 Brain (fetal) 12.1 Liver ca. (hepatoblast) HepG2 7.1 Brain (whole) 24.0 Lung 4.5 Brain (amygdala) 6.4 Lung (fetal) 15.1 Brain (cerebellum) 37.9 Lung ca. (small cell) LX-1 3.7 Brain (hippocampus) 28.7 Lung ca. (small cell) NCI-H69 2.1 Brain (substantia nigra) 15.1 Lung ca. (s.cell var.) SHP-77 0.0 Brain (thalamus) 14.5 Lung ca. (large cell)NCI-H460 0.0 Brain (hypothalamus) 4.0 Lung ca. (non-sm. cell) A549 3.0 Spinal cord 32.3 Lung ca. (non-s.cell) NCI-H23 12.1 glio/astro U87-MG 1.9 Lung ca. (non-s.cell) HOP-62 4.7 glio/astro U-118-MG 2.4 Lung ca. (non-s.cl) NCI-H522 14.1 astrocytoma SW1783 0.7 Lung ca. (squam.) SW 900 13.9 neuro*; met SK-N-AS 11.0 Lung ca. (squam.) NCI-H596 2.0 astrocytoma SF-539 9.3 Mammary gland 16.4 astrocytoma SNB-75 10.5 Breast ca.* (pl.ef) MCF-7 100.0 glioma SNB-19 5.3 Breast ca.* (pl.ef) MDA-MB-231 1.4 glioma U251 1.6 Breast ca.* (pl.ef) T47D 2.6 glioma SF-295 3.7 Breast ca. BT-549 0.0 Heart 8.3 Breast ca. MDA-N 7.3 Skeletal muscle 2.9 Ovary 18.8 Bone marrow 1.9 Ovarian ca. OVCAR-3 6.1 Thymus 5.8 Ovarian ca. OVCAR-4 1.5 Spleen 18.8 Ovarian ca. OVCAR-5 5.5 Lymph node 13.0 Ovarian ca. OVCAR-8 6.9 Colon (ascending) 2.0 Ovarian ca. IGROV-1 2.6 Stomach 7.2 Ovarian ca. (ascites) SK-OV-3 2.5 Small intestine 6.5 Uterus 6.2 Colon ca. SW480 1.3 Placenta 45.4 Colon ca.* SW620 (SW480 met) 2.9 Prostate 12.3 Colon ca. HT29 0.9 Prostate ca.* (bone met) PC-3 0.0 Colon ca. HCT-116 0.0 Testis 8.9 Colon ca. CaCo-2 5.9 Melanoma Hs688(A).T 1.0 Colon ca. HCT-15 4.9 Melanoma* (met) Hs688(B).T 1.2 Colon ca. HCC-2998 1.5 Melanoma UACC-62 1.6 Gastric ca.* (liver met) NCI-N87 6.3 Melanoma M14 9.7 Bladder 5.4 Melanoma LOX IMVI 9.8 Trachea 8.5 Melanoma* (met) SK-MEL-5 5.8 Kidney 4.5 Melanoma SK-MEL-28 9.2 Kidney (fetal) 11.8 Column A - Rel. Exp.(%) Ag37, Run 87355114

[0576] 55 TABLE AL Panel 1.2 Tissue Name A B Tissue Name A B Endothelial cells 21.9 17.3 Renal ca. 786-0 6.1 6.7 Heart (Fetal) 100.0 40.9 Renal ca. A498 13.0 9.3 Pancreas 14.7 0.4 Renal ca. RXF 393 8.4 6.0 Pancreatic ca. CAPAN 2 3.4 0.7 Renal ca. ACHN 10.7 4.9 Adrenal Gland 26.4 10.4 Renal ca. UO-31 8.8 3.6 Thyroid 18.8 0.3 Renal ca. TK-10 15.4 6.3 Salivary gland 21.5 5.8 Liver 15.2 3.2 Pituitary gland 23.8 1.4 Liver (fetal) 13.3 5.9 Brain (fetal) 33.9 1.4 Liver ca. (hepatoblast) HepG2 21.8 12.1 Brain (whole) 69.3 3.8 Lung 19.3 0.7 Brain (amygdala) 13.9 3.6 Lung (fetal) 28.1 4.5 Brain (cerebellum) 67.4 3.0 Lung ca. (small cell) LX-1 24.5 24.0 Brain (hippocampus) 45.1 12.6 Lung ca. (small cell) NCI-H69 8.1 12.7 Brain (thalamus) 19.1 26.4 Lung ca. (s. cell var.) SHP-77 3.8 1.8 Cerebral Cortex 53.2 30.1 Lung ca. (large cell)NCI-H460 40.3 19.5 Spinal cord 45.4 7.2 Lung ca. (non-sm. cell) A549 13.1 13.9 glio/astro U87-MG 7.8 21.3 Lung ca. (non-s. cell) NCI-H23 28.1 24.5 glio/astro U-118-MG 6.8 13.5 Lung ca. (non-s. cell) HOP-62 42.3 9.7 astrocytoma SW1783 2.0 1.8 Lung ca. (non-s. cl) NCI-H522 90.1 44.1 neuro*; met SK-N-AS 50.3 27.5 Lung ca. (squam.) SW 900 37.4 57.8 astrocytoma SF-539 20.3 21.2 Lung ca. (squam.) NCI-H596 9.8 4.2 astrocytoma SNB-75 13.7 2.8 Mammary gland 42.6 9.0 glioma SNB-19 19.5 28.9 Breast ca.* (pl. ef) MCF-7 85.3 56.6 glioma U251 15.2 0.1 Breast ca.* (pl. ef) MDA-MB-231 5.3 1.4 glioma SF-295 15.0 5.1 Breast ca.* (pl. ef) T47D 5.6 16.6 Heart 63.3 12.2 Breast ca. BT-549 5.0 2.6 Skeletal Muscle 27.7 0.8 Breast ca. MDA-N 16.7 3.7 Bone marrow 2.9 0.9 Ovary 49.0 23.0 Thymus 4.3 2.8 Ovarian ca. OVCAR-3 46.3 50.7 Spleen 33.4 15.6 Ovarian ca. OVCAR-4 11.3 10.6 Lymph node 23.7 5.4 Ovarian ca. OVCAR-5 28.5 66.9 Colorectal Tissue 8.4 2.4 Ovarian ca. OVCAR-8 19.8 100.0 Stomach 36.3 9.6 Ovarian ca. IGROV-1 18.2 13.3 Small intestine 27.9 11.7 Ovarian ca. (ascites) SK-OV-3 25.7 10.3 Colon ca. SW480 6.1 1.8 Uterus 24.5 3.5 Colon ca.* SW620 (SW480 met) 10.4 40.3 Placenta 90.1 82.9 Colon ca. HT29 3.0 2.5 Prostate 28.5 15.0 Colon ca. HCT-116 6.9 11.0 Prostate ca.* (bone met) PC-3 39.0 15.4 Colon ca. CaCo-2 13.1 28.9 Testis 8.4 0.6 Colon ca. Tissue (ODO3866) 3.1 1.8 Melanoma Hs688(A).T 3.8 1.2 Colon ca. HCC-2998 12.6 9.5 Melanoma* (met) Hs688(B).T 2.9 0.8 Gastric ca.* (liver met) NCI-N87 18.4 17.6 Melanoma UACC-62 23.2 11.4 Bladder 40.1 15.5 Melanoma M14 13.7 6.7 Trachea 13.8 6.0 Melanoma LOX IMVI 9.6 1.8 Kidney 19.5 42.9 Melanoma* (met) SK-MEL-5 27.4 8.9 Kidney (fetal) 30.4 61.6 Coumn A - Rel. Exp.(%) Ag1215, Run 129140825 Column B - Rel. Exp.(%) Ag1382, Run 134498635

[0577] 56 TABLE AM Panel 2.2 Tissue Name A Tissue Name A Normal Colon 31.4 Kidney Margin (OD04348) 39.8 Colon cancer (OD06064) 34.4 Kidney malignant cancer (OD06204B) 15.4 Colon Margin (OD06064) 18.7 Kidney normal adjacent tissue 10.4 (OD06204E) Colon cancer (OD06159) 2.7 Kidney Cancer (OD04450-01) 15.3 Colon Margin (OD06159) 22.5 Kidney Margin (OD04450-03) 20.3 Colon cancer (OD06297-04) 3.2 Kidney Cancer 8120613 1.4 Colon Margin (OD06297-05) 30.8 Kidney Margin 8120614 20.4 CC Gr.2 ascend colon (ODO3921) 11.7 Kidney Cancer 9010320 10.5 CC Margin (ODO3921) 8.4 Kidney Margin 9010321 9.0 Colon cancer metastasis (OD06104) 5.1 Kidney Cancer 8120607 32.3 Lung Margin (OD06104) 8.3 Kidney Margin 8120608 12.2 Colon mets to lung (OD04451-01) 15.3 Normal Uterus 31.9 Lung Margin (OD04451-02) 4.3 Uterine Cancer 064011 31.4 Normal Prostate 11.2 Normal Thyroid 3.0 Prostate Cancer (OD04410) 10.0 Thyroid Cancer 064010 14.9 Prostate Margin (OD04410) 14.3 Thyroid Cancer A302152 37.9 Normal Ovary 74.7 Thyroid Margin A302153 7.0 Ovarian cancer (OD06283-03) 27.5 Normal Breast 35.4 Ovarian Margin (OD06283-07) 6.4 Breast Cancer (OD04566) 15.7 Ovarian Cancer 064008 16.3 Breast Cancer 1024 51.4 Ovarian cancer (OD06145) 8.8 Breast Cancer (OD04590-01) 36.9 Ovarian Margin (OD06145) 24.7 Breast Cancer Mets (OD04590-03) 21.0 Ovarian cancer (OD06455-03) 9.9 Breast Cancer Metastasis (OD04655-05) 66.9 Ovarian Margin (OD06455-07) 12.9 Breast Cancer 064006 18.9 Normal Lung 18.0 Breast Cancer 9100266 27.7 Invasive poor diff. lung adeno 11.8 Breast Margin 9100265 21.6 (ODO4945-01 Lung Margin (ODO4945-03) 13.8 Breast Cancer A209073 15.1 Lung Malignant Cancer (OD03126) 31.6 Breast Margin A2090734 28.5 Lung Margin (OD03126) 5.6 Breast cancer (OD06083) 100.0 Lung Cancer (OD05014A) 17.8 Breast cancer node metastasis (OD06083) 65.1 Lung Margin (OD05014B) 13.8 Normal Liver 17.2 Lung cancer (OD06081) 10.2 Liver Cancer 1026 15.1 Lung Margin (OD06081) 8.2 Liver Cancer 1025 36.3 Lung Cancer (OD04237-01) 15.1 Liver Cancer 6004-T 18.0 Lung Margin (OD04237-02) 24.1 Liver Tissue 6004-N 6.5 Ocular Melanoma Metastasis 25.5 Liver Cancer 6005-T 33.4 Ocular Melanoma Margin (Liver) 18.0 Liver Tissue 6005-N 31.6 Melanoma Metastasis 41.5 Liver Cancer 064003 9.0 Melanoma Margin (Lung) 9.1 Normal Bladder 14.7 Normal Kidney 7.5 Bladder Cancer 1023 6.0 Kidney Ca, Nuclear grade 2 (OD04338) 34.6 Bladder Cancer A302173 28.9 Kidney Margin (OD04338) 7.6 Normal Stomach 33.7 Kidney Ca Nuclear grade 1/2 (OD04339) 38.4 Gastric Cancer 9060397 3.6 Kidney Margin (OD04339) 6.8 Stomach Margin 9060396 12.2 Kidney Ca, Clear cell type (OD04340) 19.2 Gastric Cancer 9060395 15.1 Kidney Margin (OD04340) 18.8 Stomach Margin 9060394 21.2 Kidney Ca, Nuclear grade 3 (OD04348) 10.4 Gastric Cancer 064005 17.4 Colmn A - Rel. Exp. (%) Ag1215, Run 175165684

[0578] 57 TABLE AN Panel 4.1D Tissue Name A Tissue Name A Secondary Th1 act 10.0 HUVEC IL-1beta 19.8 Secondary Th2 act 27.4 HUVEC IFN gamma 5.4 Secondary Tr1 act 15.8 HUVEC TNF alpha + IFN gamma 0.0 Secondary Th1 rest 8.8 HUVEC TNF alpha + IL4 5.6 Secondary Th2 rest 9.9 HUVEC IL-11 0.0 Secondary Tr1 rest 0.0 Lung Microvascular EC none 8.1 Primary Th1 act 1.5 Lung Microvascular EC TNF alpha + IL-1beta 13.7 Primary Th2 act 18.7 Microvascular Dermal EC none 0.0 Primary Tr1 act 5.1 Microsvasular Dermal EC TNF alpha + IL-1beta 18.2 Primary Th1 rest 9.3 Bronchial epithelium TNF alpha + IL1beta 13.2 Primary Th2 rest 13.9 Small airway epithelium none 0.0 Primary Tr1 rest 0.0 Small airway epithelium TNF alpha + IL-1beta 47.3 CD45RA CD4 lymphocyte act 4.5 Coronery artery SMC rest 1.7 CD45RO CD4 lymphocyte act 6.9 Coronery artery SMC TNF alpha + IL-1beta 6.4 CD8 lymphocyte act 14.4 Astrocytes rest 0.0 Secondary CD8 lymphocyte rest 0.0 Astrocytes TNF alpha + IL-1beta 9.3 Secondary CD8 lymphocyte act 0.0 KU-812 (Basophil) rest 33.7 CD4 lymphocyte none 22.5 KU-812 (Basophil) PMA/ionomycin 3.2 2ry Th1/Th2/Tr1_anti-CD95 CH11 31.4 CCD1106 (Keratinocytes) none 3.8 LAK cells rest 6.6 CCD1106 (Keratinocytes) TNF alpha + IL-1beta 2.1 LAK cells IL-2 7.6 Liver cirrhosis 17.9 LAK cells IL-2 + IL-12 0.0 NCI-H292 29.9 LAK cells IL-2 + IFN gamma 7.7 NCI-H292 IL-4 43.8 LAK cells IL-2 + IL-18 6.4 NCI-H292 IL-9 40.6 LAK cells PMA/ionomycin 0.0 NCI-H292 IL-13 84.1 NK Cells IL-2 rest 39.2 NCI-H292 IFN gamma 29.7 Two Way MLR 3 day 3.5 HPAEC none 6.4 Two Way MLR 5 day 0.0 HPAEC TNF alpha + IL-1beta 0.0 Two Way MLR 7 day 0.0 Lung fibroblast none 13.0 PBMC rest 0.0 Lung fibroblast TNF alpha + IL-1beta 26.1 PBMC PWM 4.9 Lung fibroblast IL-4 0.0 PBMC PHA-L 0.0 Lung fibroblast IL-9 10.9 Ramos (B cell) none 0.0 Lung fibroblast IL-13 0.0 Ramos (B cell) ionomycin 0.0 Lung fibroblast IFN gamma 12.5 B lymphocytes PWM 10.6 Dermal fibroblast CCD1070 rest 14.6 B lymphocytes CD40L and IL-4 14.3 Dermal fibroblast CCD1070 TNF alpha 30.8 EOL-1 dbcAMP 100.0 Dermal fibroblast CCD1070 IL-1beta 4.8 EOL-1 dbcAMP PMA/ionomycin 39.2 Dermal fibroblast IFN gamma 0.0 Dendritic cells none 0.0 Dermal fibroblast IL-4 15.9 Dendritic cells LPS 0.0 Dermal Fibroblasts rest 6.7 Dendritic cells anti-CD40 4.6 Neutrophils TNFa + LPS 0.0 Monocytes rest 0.0 Neutrophils rest 0.0 Monocytes LPS 2.9 Colon 3.6 Macrophages rest 3.6 Lung 6.1 Macrophages LPS 0.0 Thymus 0.0 HUVEC none 0.0 Kidney 6.7 HUVEC starved 3.7 Colun A - Rel. Exp.(%) Ag7452, Run 306288903

[0579] 58 TABLE AO Panel 4D Tissue Name A B Tissue Name A B Secondary Th1 act 27.9 19.6 HUVEC IL-1beta 3.9 2.6 Secondary Th2 act 35.4 25.5 HUVEC IFN gamma 19.2 17.1 Secondary Tr1 act 42.0 37.6 HUVEC TNF alpha + IFN gamma 2.1 2.4 Secondary Th1 rest 29.5 18.8 HUVEC TNF alpha + IL4 15.3 12.2 Secondary Th2 rest 27.5 21.9 HUVEC IL-11 13.6 15.3 Secondary Tr1 rest 33.7 23.2 Lung Microvascular EC none 19.9 20.4 Primary Th1 act 35.1 28.1 Lung Microvascular EC TNF alpha + IL-1beta 18.0 14.9 Primary Th2 act 31.4 25.7 Microvascular Dermal EC none 29.7 26.8 Primary Tr1 act 55.9 42.6 Microsvasular Dermal EC TNF alpha + IL-1beta 36.9 33.4 Primary Th1 rest 91.4 100.0 Bronchial epithelium TNF alpha + IL1beta 41.5 25.7 Primary Th2 rest 68.8 64.6 Small airway epithelium none 13.3 8.8 Primary Tr1 rest 55.5 52.1 Small airway epithelium TNF alpha + IL-1beta 56.6 45.4 CD45RA CD4 lymphocyte act 21.6 17.8 Coronery artery SMC rest 22.2 19.8 CD45RO CD4 lymphocyte act 24.5 17.2 Coronery artery SMC TNF alpha + IL-1beta 28.1 19.9 CD8 lymphocyte act 22.1 15.5 Astrocytes rest 13.0 20.2 Secondary CD8 lymphocyte rest 17.1 12.4 Astrocytes TNF alpha + IL-1beta 23.7 18.6 Secondary CD8 lymphocyte act 29.7 18.2 KU-812 (Basophil) rest 97.3 75.3 CD4 lymphocyte none 17.9 15.4 KU-812 (Basophil) PMA/ionomycin 100.0 90.1 2ry Th1/Th2/Trl_anti-CD95 71.7 67.4 CCD1106 (Keratinocytes) none 16.6 13.8 CH11 LAK cells rest 17.1 10.3 CCD1106 (Keratinocytes) TNF alpha + IL-1beta 67.8 11.3 LAK cells IL-2 21.5 15.7 Liver cirrhosis 14.3 12.3 LAK cells IL-2 + IL-12 18.4 17.1 Lupus kidney 28.7 18.8 LAK cells IL-2 + IFN gamma 29.5 22.2 NCI-H292 none 27.4 28.3 LAK cells IL-2 + IL-18 18.0 22.1 NCI-H292 IL-4 61.1 55.1 LAK cells PMA/ionomycin 10.7 7.3 NCI-H292 IL-9 37.6 31.6 NK Cells IL-2 rest 31.9 17.2 NCI-H292 IL-13 44.4 42.9 Two Way MLR 3 day 9.5 7.6 NCI-H292 IFN gamma 21.0 20.3 Two Way MLR 5 day 6.3 6.8 HPAEC none 21.5 17.2 Two Way MLR 7 day 10.5 8.5 HPAEC TNF alpha + IL-1beta 11.0 9.5 PBMC rest 10.7 10.3 Lung fibroblast none 31.0 20.6 PBMC PWM 50.7 38.4 Lung fibroblast TNF alpha + IL-1beta 26.1 23.5 PBMC PHA-L 32.5 31.2 Lung fibroblast IL-4 40.6 37.1 Ramos (B cell) none 0.0 0.0 Lung fibroblast IL-9 21.3 17.7 Ramos (B cell) ionomycin 0.0 0.0 Lung fibroblast IL-13 56.3 53.2 B lymphocytes PWM 36.1 34.2 Lung fibroblast IFN gamma 59.5 45.4 B lymphocytes CD40L and IL-4 18.3 17.2 Dermal fibroblast CCD1070 rest 47.0 33.4 EOL-1 dbcAMP 43.8 30.1 Dermal fibroblast CCD1070 TNF alpha 73.7 55.1 EOL-1 dbcAMP PMA/ionomycin 73.2 63.7 Dermal fibroblast CCD1070 IL-1beta 36.6 37.4 Dendritic cells none 1.6 0.6 Dermal fibroblast IFN gamma 8.8 9.7 Dendritic cells LPS 1.2 5.0 Dermal fibroblast IL-4 20.2 19.6 Dendritic cells anti-CD40 0.9 0.9 IBD Colitis 2 4.1 2.0 Monocytes rest 2.9 1.8 IBD Crohn's 3.1 3.1 Monocytes LPS 29.7 19.2 Colon 29.9 24.3 Macrophages rest 4.9 2.3 Lung 46.0 38.4 Macrophages LPS 7.2 4.4 Thymus 60.3 54.0 HUVEC none 9.2 6.5 Kidney 32.1 26.4 HUVEC starved 18.6 14.7 Column A - Rel. Exp.(%) Ag1215, Run 140416188 Column B - Rel. Exp.(%) Ag1382, Run 145608863

[0580] 59 TABLE AP Panel 5 Islet Tissue Name A Tissue Name A 97457_Patient-02go_adipose 20.7 94709_Donor 2 AM - A_adipose 28.5 97476_Patient-07sk_skeletal muscle 16.5 94710_Donor 2 AM - B_adipose 15.3 97477_Patient-07ut_uterus 28.7 94711_Donor 2 AM - C_adipose 10.9 97478_Patient-07pl_placenta 47.3 94712_Donor 2 AD - A_adipose 14.0 99167_Bayer Patient 1 82.4 94713_Donor 2 AD - B_adipose 17.9 97482_Patient-08ut_uterus 26.8 94714_Donor 2 AD - C_adipose 28.3 97483_Patient-08pl_placenta 25.3 94742_Donor 3 U - A_Mesenchymal Stem 12.0 Cells 97486_Patient-09sk_skeletal muscle 3.3 94743_Donor 3 U - B_Mesenchymal Stem 17.2 Cells 97487_Patient-09ut_uterus 15.7 94730_Donor 3 AM - A_adipose 21.2 97488_Patient-09pl_placenta 21.5 94731_Donor 3 AM - B_adipose 16.2 97492_Patient-10ut_uterus 26.8 94732_Donor 3 AM - C_adipose 21.0 97493_Patient-10pl_placenta 100.0 94733_Donor 3 AD - A_adipose 18.2 97495_Patient-11go_adipose 19.8 94734_Donor 3 AD - B_adipose 12.1 97496_Patient-11sk_skeletal muscle 12.9 94735_Donor 3 AD - C_adipose 19.9 97497_Patient-11ut_uterus 38.7 77138_Liver_HepG2untreated 68.8 97498_Patient-11pl_placenta 31.9 73556_Heart_Cardiac stromal cells 9.4 (primary) 97500_Patient-12go_adipose 39.2 81735_Small Intestine 27.4 97501_Patient-12sk_skeletal muscle 43.2 72409_Kidney Proximal Convoluted 1.6 Tubule 97502_Patient-12ut_uterus 52.1 82685_Small intestine_Duodenum 8.3 97503_Patient-12pl_placenta 31.2 90650_Adrenal_Adrenocortical adenoma 5.7 94721_Donor 2 U - A_Mesenchymal 17.6 72410_Kidney_HRCE 24.3 Stem Cells 94722_Donor 2 U - B_Mesenchymal Stem 16.3 72411_Kidney_HRE 21.0 Cells 94723_Donor 2 U - C_Mesenchymal Stem 22.1 73139_Uterus_Uterine smooth muscle cells 7.5 Cells Colum A - Rel. Exp.(%) Ag1215, Run 258292593

[0581] 60 TABLE AQ Panel CNS 1 Tissue Name A Tissue Name A BA4 Control 20.3 BA17 PSP 31.2 BA4 Control2 34.6 BA17 PSP2 9.9 BA4 Alzheimer's2 9.0 Sub Nigra Control 54.7 BA4 Parkinson's 33.0 Sub Nigra Control2 31.9 BA4 Parkinson's2 47.0 Sub Nigra Alzheimer's2 24.3 BA4 Huntington's 36.3 Sub Nigra Parkinson's2 92.0 BA4 Huntingson's2 11.1 Sub Nigra Huntington's 80.7 BA4 PSP 15.8 Sub Nigra Huntington's2 43.2 BA4 PSP2 46.0 Sub Nigra PSP2 24.8 BA4 Depression 19.8 Sub Nigra Depression 18.6 BA4 Depression2 7.8 Sub Nigra Depression2 12.1 BA7 Control 26.2 Glob Palladus Control 20.3 BA7 Control2 33.0 Glob Palladus Control2 10.7 BA7 Alzheimer's2 4.5 Glob Palladus Alzheimer's 21.6 BA7 Parkinson's 23.0 Glob Palladus Alzheimer's2 5.0 BA7 Parkinson's2 35.6 Glob Palladus Parkinson's 100.0 BA7 Huntington's 39.2 Glob Palladus Parkinson's2 23.0 BA7 Huntington's2 40.6 Glob Palladus PSP 10.2 BA7 PSP 31.2 Glob Palladus PSP2 11.8 BA7 PSP2 32.3 Glob Palladus Depression 23.5 BA7 Depression 6.3 Temp Pole Control 7.7 BA9 Control 12.5 Temp Pole Control2 29.3 BA9 Control2 48.6 Temp Pole Alzheimer's 4.0 BA9 Alzheimer's 6.9 Temp Pole Alzheimer's2 3.6 BA9 Alzheimer's2 5.4 Temp Pole Parkinson's 22.5 BA9 Parkinson's 25.3 Temp Pole Parkinson's2 22.2 BA9 Parkinson's2 33.4 Temp Pole Huntington's 30.6 BA9 Huntington's 45.1 Temp Pole PSP 3.8 BA9 Huntington's2 13.8 Temp Pole PSP2 2.3 BA9 PSP 23.5 Temp Pole Depression2 7.1 BA9 PSP2 5.0 Cing Gyr Control 59.0 BA9 Depression 10.8 Cing Gyr Control2 40.3 BA9 Depression2 11.8 Cing Gyr Alzheimer's 19.3 BA17 Control 39.8 Cing Gyr Alzheimer's2 11.8 BA17 Control2 40.1 Cing Gyr Parkinson's 42.3 BA17Alzheimer's2 7.6 Cing Gyr Parkinson's2 35.8 BA17 Parkinson's 31.2 Cing Gyr Huntington's 62.4 BA17 Parkinson's2 35.4 Cing Gyr Huntington's2 28.7 BA17 Huntington's 47.3 Cing Gyr PSP 66.9 BA17 Huntington's2 25.0 Cing Gyr PSP2 5.2 BA17 Depression 22.2 Cing Gyr Depression 14.8 BA17 Depression2 41.8 Cing Gyr Depression2 32.1 Colum A - Rel. Exp.(%) Ag1215, Run 171629509

[0582] 61 TABLE AR general oncology screening panel_v_2.4 Tissue Name A Tissue Name A Colon cancer 1 18.0 Bladder cancer NAT2 0.4 Colon cancer NAT 1 21.0 Bladder cancer NAT 3 0.9 Colon cancer 2 33.4 Bladder cancer NAT 4 9.0 Colon cancer NAT 2 3.6 Prostate adenocarcinoma 1 46.3 Colon cancer 3 26.8 Prostate adenocarcinoma 2 3.5 Colon cancer NAT 3 19.2 Prostate adenocarcinoma 3 11.9 Colon malignant cancer 4 27.5 Prostate adenocarcinoma 4 16.8 Colon normal adjacent tissue 4.2 Prostate cancer NAT 5 4.9 4 Lung cancer 1 11.4 Prostate adenocarcinoma 6 6.4 Lung NAT 1 1.3 Prostate adenocarcinoma 7 6.6 Lung cancer 2 100.0 Prostate adenocarcinoma 8 3.3 Lung NAT 2 2.2 Prostate adenocarcinoma 9 33.9 Squamous cell carcinoma 3 30.4 Prostate cancer NAT 10 2.5 Lung NAT 3 0.3 Kidney cancer 1 44.1 metastatic melanoma 1 24.5 KidneyNAT 1 15.2 Melanoma 2 3.2 Kidney cancer 2 68.8 Melanoma 3 2.8 Kidney NAT 2 18.4 metastatic melanoma 4 62.9 Kidney cancer 3 29.9 metastatic melanoma 5 42.9 Kidney NAT 3 6.1 Bladder cancer 1 2.3 Kidney cancer 4 18.9 Bladder cancer NAT 1 0.0 Kidney NAT 4 7.4 Bladder cancer 2 5.8 Column A - Rel. Exp.(%) Ag1215, Run 267211472

[0583] Ardais Panel v.1.0 Summary: Ag1215 Expression of this gene is higher in lung cancer samples compared to adjacent normal tissue. Therefore, therapeutic modulation of this gene or its protein product through the use of small molecule or antibodies may be useful in the treatment of lung cancer.

[0584] CNS_neurodegeneration_v1.0 Summary: Ag1215/Ag7452 This panel confirms the expression of this gene at low levels in the brains of an independent group of individuals.

[0585] General_screening_panel_v1.4 Summary: Ag1215/Ag37 Two experiments with two different primer-probe sets are in agreement. Highest expression of this gene is seen in a breast cancer MCF-7 cell line (CTs=24-24.8). High expression of this gene is also seen in cluster of cancer cell lines derived from pancreatic, gastric, colon, lung, liver, renal, breast, ovarian, prostate, squamous cell carcinoma, melanoma and brain cancers. Thus, expression of this gene could be used as a marker to detect the presence of these cancers. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of pancreatic, gastric, colon, lung, liver, renal, breast, ovarian, prostate, squamous cell carcinoma, melanoma type and brain cancers.

[0586] Among tissues with metabolic or endocrine function, this gene is expressed at moderate to high levels in pancreas, adipose, adrenal gland, thyroid, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

[0587] In addition, this gene is expressed at high levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, therapeutic modulation of this gene product may be useful in the treatment of central nervous system In addition, this gene is expressed at high levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, therapeutic modulation of this gene product may be useful in the treatment of central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

[0588] This gene is expressed at much higher levels in fetal (CTs=25-28) when compared to adult lung and liver (CTs=29-32). This suggests that expression of this gene can be used to distinguish fetal from adult lung and liver. In addition, the relative overexpression of this gene in fetal tissue suggests that the protein product may enhance lung and liver growth or development in the fetus and may also act in a regenerative capacity in the adult. Therefore, therapeutic modulation of the protein encoded by this gene could be useful in treatment of liver related diseases.

[0589] General_screening_panel_v1.7 Summary: Ag7452 Highest expression of this gene is seen in a breast cancer MCF7 cell line (CT=27.4). This gene shows wide spread expression in this panel and this pattern of expression is in agreement with panel 1.4 discussed above.

[0590] HASS Panel v1.0 Summary: Ag1215 This gene shows widespread expression in all the samples in this panel with high expression in MCF7 cell lines (CTs=24-25) and thus could be potentially used as a diagnostic and/therapeutic for breast cancer.

[0591] Oncology_cell_line_screening_panel_v3.2 Summary: Ag1215 Highest expression of this gene is seen in a lung cancer DMS-79 cell line (CT=27.9). Moderate to low expression of this gene is seen in number of cancer cell lines derived from tongue, breast, bone, bladder, fibrosarcoma, pancreatic, renal, T cell and erythroleukemia, colon, gastric, lung and brain cancers. Therefore, therapeutic modulation of this gene or its protein product may be used for the treatment of these cancers.

[0592] Panel 1 Summary: Ag37 This gene is expressed at high to moderate levels in the majority of the samples on this panel. Expression of this gene is highest in a breast cancer cell line (CT=22). In addition there is substantial expression in placental tissue and in a number of brain regions. Moreover, therapeutic modulation of this gene or its protein product, through the use of small molecule drugs, antibodies or protein therapeutics, might be of benefit in the treatment of breast cancer. In general, however, expression appears to be higher in normal cells than in the cancer cell lines.

[0593] Among tissues with endocrine or metabolic activity, this gene is expressed at high levels in pancreas, adrenal gland, thyroid, pituitary gland, hypothalamus, heart, skeletal muscle, and liver. This observation indicates an importance for this gene in endocrine and metaboic physiology. Therefore, therapeutic modulation of this gene and/or gene product may prove useful in the treatment of diseases associated with these physiological systems, including diabetes and obesity.

[0594] Expression of the gene is very high throughout the central nervous system including in the spinal cord, amygdala, cerebellum, hippocampus, thalamus, and substantia nigra. This gene encodes a protein with homology to sempaphorins. Semaphorins can act as axon guidance proteins, specifically as chemorepellents which inhibit CNS regenerative capacity. Therefore, therapeutic modulation of the activity and or amount of this protein may be of use in inducing a compensatory synaptogenic response to neuronal death in Alzheimer's disease, Parkinson's disease, Huntington's disease, spinocerebellar ataxia, progressive supranuclear palsy, multiple sclerosis, ALS, head trauma, stroke, or any other disease/condition associated with neuronal loss.

[0595] Panel 1.2 Summary: Ag1215/Ag1382 This gene is expressed at high levels across most of the tissues on this panel with highest expression in ovarian cancer cell line (CTs=22-23). Furthermore, the expression of this gene seems to be associated with reproductive tissues and cancer cell lines which is in agreement with expression seen in panels 1 and 1.4.

[0596] Panel 2.2 Summary: Ag1215 This gene shows a widespread expression. Specifically, highest expression is seen in breast cancer cells. This is reasonably consistent with the results obtained from Panel 1.2. In addition, there is also some correlation with expression in normal kidney tissue when compared to kidney cancers, also consistent with the observations in Panel 1.2. Thus, therapeutic modulation of this gene or gene product may be useful in the treatment of breast cancer, ovarian cancer or kidney cancer.

[0597] Panel 4.1D Summary: Ag7452 Highest expression of this gene is seen in eosinophils (CT=33.3). Low but significant expression of this gene is also seen in resting IL-2 treated NK cells, activated eosinophils, activated NCI-H292 cells, activated small airway epithelium and activated lung fibroblasts. Therefore, therapeutic modulation of this gene through the use of small molecule drug or antibodies may be useful in the treatment of inflammation in lung especially chronic obstructive pulmonary disease, asthma, allergy, and emphysema. In addition, regulating the expression of this gene or the encoded protein may be useful in the treatment of hematopoietic disorders involving eosinphils, parasitic infections and asthma.

[0598] Panel 4D Summary: Ag1215/Ag1382 Results from two replicate experiments performed using probe and primer sets of identical sequences are in reasonable agreement. This gene is widely expressed in cell lines from this panel (CTs=25-30), including thymus, lung, muco-epidermoid cell lines, fibroblasts from diverse origin, and activated T cells. In addition, this gene is expressed in normal colon but not in colons from patients with Crohn's disease or colitis. Thus, protein therapeutics designed with the putative semaphorin encoded by this protein could reduce or eliminate inflammation and tissue destruction due to IBD. High expression of this gene was found on primary resting Th1 T cells, and also primary resting Th2 and Tr1 T cells. The high expression in secondary T cells treated with CD95 suggests that protein encoded by this gene is involved in activation of cell death. Furthermore, high expression of this gene is also found in activated basophils and eosinophils, suggesting a role for this protein in allergic disorder such as asthma, contact hypersensitivity, and hypersensitive immediate reactions. Antibody or protein therapeutics designed against the protein encoded for by this gene could therefore reduce or inhibit inflammation in allergy, asthma, emphysema, psoriasis and/or autoimmunity.

[0599] Panel 5 Islet Summary: Ag1215 Highest expression of this gene is detected in placenta of a diabetic patient (CT=29.8). This gene shows a widespread expression in this panel. This pattern is in agreement with the expression profile in panel 1.4.

[0600] Panel CNS—1 Summary: Ag1215 This gene shows wide spread expression in this panel. This gene codes for semaphorin 4C. Semaphorins can act as axon guidance proteins, specifically through their ability to act as chemorepellents that inhibit CNS regenerative capacity. Therefore therapeutic modulation of levels of this gene or its protein product may therefore be of use in inducing a compensatory synaptogenic response to neuronal death in Alzheimer's disease, Parkinson's disease, Huntington's disease, spinocerebellar ataxia, progressive supranuclear palsy, multiple sclerosis, ALS, head trauma, stroke, or any other disease/condition associated with neuronal loss.

[0601] General oncology screening panel_v—2.4 Summary: Ag1215 Highest expression of this gene is seen in a lung cancer sample (CT=26.6). Interestingly, expression of this gene is upregulated in lung, colon, bladder, metastatic melanoma, prostate and kidney cancers. Therefore, expression of this gene may be used as marker to detect the presence of these cancers and also, therapeutic modulation of this gene or its protein product through the use of small molecule drug or antibodies may be useful in the treatment of these cancers.

[0602] B. CG51896-04: Semaphorin 6A Precursor.

[0603] Expression of gene CG51896-04 was assessed using the primer-probe sets Ag2772, Ag88 and Ag6309, described in Tables BA, BB and BC. Results of the RTQ-PCR runs are shown in Tables BD, BE, BF, BG, BH, BI, BJ, BK and BL. 62 TABLE BA Probe Name Ag2772 Start SEQ ID Primers Sequences Length Position No Forward 5′-actggaagcatctgcttgact-3′ 21 2117 141 Probe TET-5′-cacctgacagcacagaccctttgg-3′-TAMRA 24 2093 142 Reverse 5′-atcactcccttcttgtcttggt-3′ 22 2050 143

[0604] 63 TABLE BB Probe Name Ag88 Start SEQ ID Primers Sequences Length Position No Forward 5′-catcttcaacaggccatggtt-3′ 21 2770 144 Probe TET-5′-tgagaacaatggtcagataccgccttaccaa-3′-TAMRA 31 2737 145 Reverse 5′-agcagctgtgtccactgcaa-3′ 20 2715 146

[0605] 64 TABLE BC Probe Name Ag6309 Start SEQ ID Primers Sequences Length Position No Forward 5′-atacactgtgttgtaagacatttcattatc-3′ 30 2223 147 Probe TET-5′-tggcactgaatgacatttcaactcctc-3′-TAMRA 27 2258 148 Reverse 5′-gggactgtcacaattcctttg-3′ 21 2285 149

[0606] 65 TABLE BD CNS_neurodegeneration_v1.0 Tissue Name A B Tissue Name A B AD 1 Hippo 3.1 8.0 Control (Path) 3 Temporal Ctx 6.0 5.3 AD 2 Hippo 41.8 31.6 Control (Path) 4 Temporal Ctx 4.7 19.6 AD 3 Hippo 12.8 2.3 AD 1 Occipital Ctx 37.6 7.5 AD 4 Hippo 12.3 7.9 AD 2 Occipital Ctx (Missing) 0.0 0.0 AD 5 Hippo 60.7 19.6 AD 3 Occipital Ctx 5.6 4.7 AD 6 Hippo 76.8 72.2 AD 4 Occipital Ctx 43.8 37.6 Control 2 Hippo 67.8 52.9 AD 5 Occipital Ctx 38.2 33.4 Control 4 Hippo 21.9 26.6 AD 6 Occipital Ctx 0.0 14.7 Control (Path) 3 Hippo 0.9 9.7 Control 1 Occipital Ctx 4.5 4.1 AD 1 Temporal Ctx 48.3 11.1 Control 2 Occipital Ctx 77.4 61.6 AD 2 Temporal Ctx 32.1 32.1 Control 3 Occipital Ctx 29.1 24.0 AD 3 Temporal Ctx 8.5 3.4 Control 4 Occipital Ctx 22.8 17.3 AD 4 Temporal Ctx 17.0 35.1 Control (Path) 1 Occipital Ctx 100.0 100.0 AD 5 Inf Temporal Ctx 22.5 48.0 Control (Path) 2 Occipital Ctx 4.1 16.3 AD 5 Sup Temporal Ctx 48.6 41.5 Control (Path) 3 Occipital Ctx 10.4 4.2 AD 6 Inf Temporal Ctx 66.4 45.4 Control (Path) 4 Occipital Ctx 13.4 11.0 AD 6 Sup Temporal Ctx 61.1 18.4 Control 1 Parietal Ctx 22.4 13.1 Control 1 Temporal Ctx 10.3 13.2 Control 2 Parietal Ctx 52.9 33.4 Control 2 Temporal Ctx 39.0 44.4 Control 3 Parietal Ctx 3.1 19.5 Control 3 Temporal Ctx 33.0 27.4 Control (Path) 1 Parietal Ctx 41.2 38.7 Control 3 Temporal Ctx 3.4 12.9 Control (Path) 2 Parietal Ctx 10.2 28.5 Control (Path) 1 Temporal Ctx 47.0 38.2 Control (Path) 3 Parietal Ctx 6.8 5.1 Control (Path) 2 Temporal Ctx 28.9 31.0 Control (Path) 4 Parietal Ctx 42.0 29.3 Column A - Rel. Exp.(% Ag2772, Run 208699007 Column B - Rel. Exp.(%) Ag6309, Run 259476984

[0607] 66 TABLE BE General_screening_panel_v1.5 Tissue Name A Tissue Name A Adipose 2.4 Renal ca. TK-10 1.1 Melanoma* Hs688(A).T 0.0 Bladder 0.5 Melanoma* Hs688(B).T 0.0 Gastric ca. (liver met.) NCI-N87 0.0 Melanoma* M14 1.0 Gastric ca. KATO III 0.0 Melanoma* LOXIMVI 0.0 Colon ca. SW-948 0.0 Melanoma* SK-MEL-5 7.1 Colon ca. SW480 0.0 Squamous Cell carcinoma SCC-4 0.0 Colon ca.* (SW480 met) SW620 0.1 Testis Pool 0.8 Colon ca. HT29 0.0 Prostate ca.* (bone met) PC-3 0.0 Colon ca. HCT-116 0.0 Prostate Pool 0.6 Colon ca. CaCo-2 1.4 Placenta 1.8 Colon cancer tissue 1.0 Uterus Pool 0.5 Colon ca. SW1116 0.0 Ovarian ca. OVCAR-3 0.0 Colon ca. Colo-205 0.3 Ovarian ca. SK-OV-3 0.2 Colon ca. SW-48 0.0 Ovarian ca. OVCAR-4 0.0 Colon Pool 0.3 Ovarian ca. OVCAR-5 0.7 Small Intestine Pool 0.8 Ovarian ca. IGROV-1 5.8 Stomach Pool 0.6 Ovarian ca. OVCAR-8 0.0 Bone Marrow Pool 0.3 Ovary 0.0 Fetal Heart 0.5 Breast ca. MCF-7 0.0 Heart Pool 0.4 Breast ca. MDA-MB-231 0.0 Lymph Node Pool 0.0 Breast ca. BT 549 0.0 Fetal Skeletal Muscle 0.6 Breast ca. T47D 0.8 Skeletal Muscle Pool 0.6 Breast ca. MDA-N 0.0 Spleen Pool 0.2 Breast Pool 0.0 Thymus Pool 0.0 Trachea 0.2 CNS cancer (glio/astro) U87-MG 0.0 Lung 0.4 CNS cancer (glio/astro) U-118-MG 0.0 Fetal Lung 10.4 CNS cancer (neuro; met) SK-N-AS 0.4 Lung ca. NCI-N417 0.6 CNS cancer (astro) SF-539 0.2 Lung ca. LX-1 0.0 CNS cancer (astro) SNB-75 0.0 Lung ca. NCI-H146 0.0 CNS cancer (glio) SNB-19 4.1 Lung ca. SHP-77 0.0 CNS cancer (glio) SF-295 0.0 Lung ca. A549 0.0 Brain (Amygdala) Pool 51.1 Lung ca. NCI-H526 0.0 Brain (cerebellum) 86.5 Lung ca. NCI-H23 0.7 Brain (fetal) 80.7 Lung ca. NCI-H460 0.4 Brain (Hippocampus) Pool 53.6 Lung ca. HOP-62 0.0 Cerebral Cortex Pool 54.3 Lung ca. NCI-H522 0.0 Brain (Substantia nigra) Pool 32.5 Liver 0.0 Brain (Thalamus) Pool 72.2 Fetal Liver 0.0 Brain (whole) 61.1 Liver ca. HepG2 0.0 Spinal Cord Pool 100.0 Kidney Pool 0.5 Adrenal Gland 2.4 Fetal Kidney 2.1 Pituitary gland Pool 0.4 Renal ca. 786-0 4.2 Salivary Gland 0.5 Renal ca. A498 0.0 Thyroid (female) 0.0 Renal ca. ACHN 0.2 Pancreatic ca. CAPAN2 0.0 Renal ca. UO-31 0.0 Pancreas Pool 0.1 Column A - Rel. Exp.(% Ag6309, Run 259428262

[0608] 67 TABLE BF HASS Panel v1.0 Tissue Name A Tissue Name A MCF-7 C1 3.1 U87-MG F1 (B) 0.1 MCF-7 C2 6.0 U87-MG F2 0.0 MCF-7 C3 3.0 U87-MG F3 0.3 MCF-7 C4 6.2 U87-MG F4 0.1 MCF-7 C5 3.8 U87-MG F5 0.2 MCF-7 C6 2.5 U87-MG F6 1.1 MCF-7 C7 5.5 U87-MG F7 0.2 MCF-7 C9 3.2 U87-MG F8 0.6 MCF-7 C10 6.6 U87-MG F9 0.1 MCF-7 C11 1.1 U87-MG F10 0.5 MCF-7 C12 1.7 U87-MG F11 0.7 MCF-7 C13 3.6 U87-MG F12 0.2 MCF-7 C15 2.1 U87-MG F13 0.2 MCF-7 C16 2.7 U87-MG F14 0.7 MCF-7 C17 2.3 U87-MG F15 0.2 T24 D1 0.7 U87-MG F16 0.2 T24 D2 0.0 U87-MG F17 0.3 T24 D3 0.1 LnCAP A1 29.9 T24 D4 0.1 LnCAP A2 26.1 T24 D5 0.0 LnCAP A3 46.7 T24 D6 0.0 LnCAP A4 26.6 T24 D7 0.0 LnCAP A5 39.8 T24 D9 0.0 LnCAP A6 32.8 T24 D10 0.0 LnCAP A7 16.4 T24 D11 0.0 LnCAP A8 42.9 T24 D12 0.0 LnCAP A9 18.9 T24 D13 0.0 LnCAP A10 20.0 T24 D15 0.1 LnCAP A11 45.1 T24 D16 0.0 LnCAP A12 7.9 T24 D17 0.0 LnCAP A13 3.5 CAPaN B1 1.6 LnCAP A14 2.9 CAPaN B2 0.5 LnCAP A15 5.3 CAPaN B3 0.5 LnCAP A16 54.7 CAPaN B4 0.7 LnCAP A17 48.0 CAPaN B5 0.7 Primary Astrocytes 2.3 CAPaN B6 0.8 Primary Renal Proximal Tubule 13.1 Epithelial cell A2 CAPaN B7 0.4 Primary melanocytes A5 31.0 CAPaN B8 0.1 126443 - 341 medullo 1.5 CAPaN B9 0.4 126444 - 487 medullo 100.0 CAPaN B10 0.8 126445 - 425 medullo 1.3 CAPaN B11 1.4 126446 - 690 medullo 46.7 CAPaN B12 1.0 126447 - 54 adult glioma 0.1 CAPaN B13 1.0 126448 - 245 adult glioma 15.1 CAPaN B14 0.1 126449 - 317 adult glioma 20.6 CAPaN B15 0.2 126450 - 212 glioma 48.6 CAPaN B16 1.1 126451 - 456 glioma 84.7 CAPaN B17 1.2 Column A - Rel. Exp.(%) Ag2772, Run 264977485

[0609] 68 TABLE BG Panel 1 Tissue Name A Tissue Name A Endothelial cells 0.4 Renal ca. 786-0 66.9 Endothelical cells (treated) 1.6 Renal ca. A498 0.8 Pancreas 18.2 Renal ca. RXF 393 19.8 Pancreatic ca. CAPAN 2 0.2 Renal ca. ACHN 8.1 Adrenal gland 51.8 Renal ca. UO-31 0.2 Thyroid 4.6 Renal ca. TK-10 18.3 Salivary gland 8.5 Liver 3.7 Pituitary gland 1.8 Liver (fetal) 2.1 Brain (fetal) 8.5 Liver ca. (hepatoblast) HepG2 3.3 Brain (whole) 46.3 Lung 5.7 Brain (amygdala) 9.4 Lung (fetal) 8.0 Brain (cerebellum) 100.0 Lung ca. (small cell) LX-1 0.0 Brain (hippocampus) 34.4 Lung ca. (small cell) NCI-H69 15.7 Brain (substantia nigra) 50.7 Lung ca. (s.cell var.) SHP-77 0.0 Brain (thalamus) 15.4 Lung ca. (large cell)NCI-H460 0.0 Brain (hypothalamus) 2.9 Lung ca. (non-sm. cell) A549 0.0 Spinal cord 22.5 Lung ca. (non-s.cell) NCI-H23 0.5 glio/astro U87-MG 0.1 Lung ca. (non-s.cell) HOP-62 0.4 glio/astro U-118-MG 0.0 Lung ca. (non-s.cl) NCI-H522 0.1 astrocytoma SW1783 0.0 Lung ca. (squam.) SW 900 0.7 neuro*; met SK-N-AS 4.6 Lung ca. (squam.) NCI-H596 30.8 astrocytoma SF-539 0.2 Mammary gland 18.8 astrocytoma SNB-75 1.1 Breast ca.* (pl.ef) MCF-7 1.5 glioma SNB-19 7.1 Breast ca.* (pl.ef) MDA-MB-231 0.0 glioma U251 0.6 Breast ca.* (pl.ef) T47D 30.6 glioma SF-295 0.1 Breast ca. BT-549 0.0 Heart 3.3 Breast ca. MDA-N 0.0 Skeletal muscle 1.1 Ovary 7.0 Bone marrow 0.9 Ovarian ca. OVCAR-3 1.2 Thymus 20.6 Ovarian ca. OVCAR-4 0.0 Spleen 2.5 Ovarian ca. OVCAR-5 11.8 Lymph node 3.2 Ovarian ca. OVCAR-8 0.4 Colon (ascending) 11.5 Ovarian ca. IGROV-1 12.0 Stomach 11.4 Ovarian ca. (ascites) SK-OV-3 0.9 Small intestine 5.5 Uterus 6.4 Colon ca. SW480 0.1 Placenta 43.8 Colon ca.* SW620 (SW480 met) 0.4 Prostate 3.1 Colon ca. HT29 0.0 Prostate ca.* (bone met) PC-3 0.0 Colon ca. HCT-116 0.0 Testis 35.6 Colon ca. CaCo-2 19.6 Melanoma Hs688(A).T 0.0 Colon ca. HCT-15 0.0 Melanoma* (met) Hs688(B).T 0.0 Colon ca. HCC-2998 1.1 Melanoma UACC-62 1.4 Gastric ca.* (liver met) NCI-N87 0.3 Melanoma M14 11.4 Bladder 1.6 Melanoma LOX IMVI 0.8 Trachea 5.0 Melanoma* (met) SK-MEL-5 18.9 Kidney 4.7 Melanoma SK-MEL-28 30.6 Kidney (fetal) 13.7 Column A - Rel. Exp.(%) Ag88, Run 87586103

[0610] 69 TABLE BH Panel 1.3D Tissue Name A Tissue Name A Liver adenocarcinoma 2.4 Kidney (fetal) 13.6 Pancreas 5.3 Renal ca. 786-0 36.6 Pancreatic ca. CAPAN 2 0.2 Renal ca. A498 2.1 Adrenal gland 22.2 Renal ca. RXF 393 27.0 Thyroid 4.4 Renal ca. ACHN 10.0 Salivary gland 5.1 Renal ca. UO-31 0.2 Pituitary gland 2.4 Renal ca. TK-10 6.9 Brain (fetal) 3.3 Liver 1.8 Brain (whole) 15.9 Liver (fetal) 3.1 Brain (amygdala) 14.9 Liver ca. (hepatoblast) HepG2 3.7 Brain (cerebellum) 8.8 Lung 14.9 Brain (hippocampus) 27.0 Lung (fetal) 10.7 Brain (substantia nigra) 11.1 Lung ca. (small cell) LX-1 0.4 Brain (thalamus) 18.2 Lung ca. (small cell) NCI-H69 9.3 Cerebral Cortex 52.1 Lung ca. (s.cell var.) SHP-77 0.4 Spinal cord 66.0 Lung ca. (large cell)NCI-H460 3.0 glio/astro U87-MG 0.5 Lung ca. (non-sm. cell) A549 0.2 glio/astro U-118-MG 0.3 Lung ca. (non-s.cell) NCI-H23 1.6 astrocytoma SW1783 0.0 Lung ca. (non-s.cell) HOP-62 0.8 neuro*; met SK-N-AS 3.2 Lung ca. (non-s.cl) NCI-H522 0.0 astrocytoma SF-539 0.4 Lung ca. (squam.) SW 900 0.8 astrocytoma SNB-75 1.0 Lung ca. (squam.) NCI-H596 19.3 glioma SNB-19 15.1 Mammary gland 6.5 glioma U251 1.0 Breast ca.* (pl.ef) MCF-7 2.5 glioma SF-295 0.2 Breast ca.* (pl.ef) MDA-MB-231 0.1 Heart (fetal) 5.8 Breast ca.* (pl.ef) T47D 16.4 Heart 4.5 Breast ca. BT-549 0.4 Skeletal muscle (fetal) 100.0 Breast ca. MDA-N 0.0 Skeletal muscle 5.5 Ovary 48.0 Bone marrow 0.7 Ovarian ca. OVCAR-3 1.8 Thymus 14.2 Ovarian ca. OVCAR-4 0.0 Spleen 5.9 Ovarian ca. OVCAR-5 7.0 Lymph node 1.2 Ovarian ca. OVCAR-8 0.7 Colorectal 31.9 Ovarian ca. IGROV-1 11.7 Stomach 1.3 Ovarian ca.* (ascites) SK-OV-3 1.9 Small intestine 9.3 Uterus 5.2 Colon ca. SW480 0.4 Placenta 30.6 Colon ca.* SW620(SW480 met) 0.7 Prostate 2.8 Colon ca. HT29 0.2 Prostate ca.* (bone met)PC-3 0.1 Colon ca. HCT-116 1.5 Testis 5.6 Colon ca. CaCo-2 32.1 Melanoma Hs688(A).T 0.2 Colon ca. tissue(ODO3866) 5.7 Melanoma* (met) Hs688(B).T 0.1 Colon ca. HCC-2998 1.8 Melanoma UACC-62 1.7 Gastric ca.* (liver met) NCI-N87 0.1 Melanoma M14 3.4 Bladder 14.1 Melanoma LOX IMVI 0.2 Trachea 5.7 Melanoma* (met) SK-MEL-5 15.4 Kidney 6.1 Adipose 6.6 Colun A - Rel. Exp.(%) Ag2772, Run 164024167

[0611] 70 TABLE BI Panel 2D Tissue Name A B Tissue Name A B Normal Colon 46.7 28.9 Kidney Margin 8120608 2.1 3.1 CC Well to Mod Diff (ODO3866) 2.2 0.8 Kidney Cancer 8120613 0.8 2.0 CC Margin (ODO3866) 9.7 9.7 Kidney Margin 8120614 2.8 1.3 CC Gr.2 rectosigmoid (ODO3868) 2.2 3.0 Kidney Cancer 9010320 8.9 10.3 CC Margin (ODO3868) 2.7 2.1 Kidney Margin 9010321 11.0 10.0 CC Mod Diff (ODO3920) 2.2 1.3 Normal Uterus 1.7 2.0 CC Margin (ODO3920) 13.1 11.5 Uterus Cancer 064011 5.9 5.2 CC Gr.2 ascend colon (ODO3921) 16.5 7.8 Normal Thyroid 3.4 6.2 CC Margin (ODO3921) 10.2 5.8 Thyroid Cancer 064010 1.1 2.3 CC from Partial Hepatectomy 6.7 23.7 Thyroid Cancer A302152 1.1 1.3 (ODO4309) Mets Liver Margin (ODO4309) 9.5 2.7 Thyroid Margin A302153 5.0 4.4 Colon mets to lung (OD04451-01) 4.5 2.6 Normal Breast 12.7 19.2 Lung Margin (OD04451-02) 4.8 4.7 Breast Cancer (OD04566) 1.3 0.8 Normal Prostate 6546-1 27.5 6.8 Breast Cancer (OD04590-01) 3.8 2.3 Prostate Cancer (OD04410) 17.4 14.2 Breast Cancer Mets 5.1 4.8 (OD04590-03) Prostate Margin (OD04410) 10.2 6.7 Breast Cancer Metastasis 22.8 24.1 (OD04655-05) Prostate Cancer (OD04720-01) 6.7 2.8 Breast Cancer 064006 3.0 2.3 Prostate Margin (OD04720-02) 12.8 8.4 Breast Cancer 1024 8.2 4.4 Normal Lung 061010 22.8 15.7 Breast Cancer 9100266 6.1 5.5 Lung Met to Muscle (ODO4286) 0.6 0.8 Breast Margin 9100265 6.9 5.4 Muscle Margin (ODO4286) 1.5 1.6 Breast Cancer A209073 9.0 3.9 Lung Malignant Cancer (OD03126) 3.5 4.8 Breast Margin A209073 9.7 11.4 Lung Margin (OD03126) 36.3 17.7 Normal Liver 3.3 2.6 Lung Cancer (OD04404) 3.3 3.1 Liver Cancer 064003 1.4 0.6 Lung Margin (OD04404) 6.8 8.7 Liver Cancer 1025 3.2 3.4 Lung Cancer (OD04565) 1.2 1.6 Liver Cancer 1026 1.7 1.7 Lung Margin (OD04565) 6.8 6.3 Liver Cancer 6004-T 3.9 5.0 Lung Cancer (OD04237-01) 4.2 4.2 Liver Tissue 6004-N 1.5 0.7 Lung Margin (OD04237-02) 10.8 9.9 Liver Cancer 6005-T 1.6 1.7 Ocular Mel Met to Liver (ODO4310) 100.0 100.0 Liver Tissue 6005-N 1.6 1.3 Liver Margin (ODO4310) 5.4 5.8 Normal Bladder 8.2 6.6 Melanoma Mets to Lung (OD04321) 65.5 55.5 Bladder Cancer 1023 0.5 0.6 Lung Margin (OD04321) 28.9 26.6 Bladder Cancer A302173 6.7 4.4 Normal Kidney 18.4 18.4 Bladder Cancer (OD04718-01) 0.5 0.2 Kidney Ca, Nuclear grade 2 27.7 17.3 Bladder Normal Adjacent 5.0 3.7 (OD04338) (OD04718-03) Kidney Margin (OD04338) 5.9 6.1 Normal Ovary 5.6 3.4 Kidney Ca Nuclear grade 1/2 12.4 9.3 Ovarian Cancer 064008 9.3 6.7 (OD04339) Kidney Margin (OD04339) 10.7 12.6 Ovarian Cancer (OD04768-07) 1.7 0.6 Kidney Ca, Clear cell type (OD04340) 58.2 44.4 Ovary Margin (OD04768-08) 2.8 3.4 Kidney Margin (OD04340) 10.7 15.4 Normal Stomach 12.9 7.0 Kidney Ca, Nuclear grade 3 1.5 1.6 Gastric Cancer 9060358 1.7 2.2 (OD04348) Kidney Margin (OD04348) 6.7 9.5 Stomach Margin 9060359 2.7 1.2 Kidney Cancer (OD04622-01) 12.5 21.3 Gastric Cancer 9060395 3.0 2.8 Kidney Margin (OD04622-03) 2.0 1.9 Stomach Margin 9060394 4.3 2.3 Kidney Cancer (OD04450-01) 34.2 35.4 Gastric Cancer 9060397 27.9 11.0 Kidney Margin (OD04450-03) 5.8 7.2 Stomach Margin 9060396 1.3 0.4 Kidney Cancer 8120607 6.8 5.1 Gastric Cancer 064005 6.7 2.0 Clumn A - Rel. Exp.(%) Ag2772, Run 162440317 Column B - Rel. Exp.(%) Ag88, Run 144771649

[0612] 71 TABLE BJ Panel 3D Tissue Name A Tissue Name A Daoy-Medulloblastoma 1.0 Ca Ski-Cervical epidermoid carcinoma 0.0 (metastasis) TE671-Medulloblastoma 37.4 ES-2-Ovarian clear cell carcinoma 0.0 D283 Med-Medulloblastoma 1.3 Ramos-Stimulated with PMA/ionomycin 6 h 0.0 PFSK-1-Primitive Neuroectodermal 17.8 Ramos-Stimulated with PMA/ionomycin 14 h 0.0 XF-498-CNS 4.0 MEG-01-Chronic myelogenous leukemia 4.9 (megokaryoblast) SNB-78-Glioma 0.0 Raji-Burkitt's lymphoma 0.0 SF-268-Glioblastoma 0.0 Daudi-Burkitt's lymphoma 0.3 T98G-Glioblastoma 1.0 U266-B-cell plasmacytoma 0.0 SK-N-SH-Neuroblastoma (metastasis) 7.2 CA46-Burkitt's lymphoma 0.0 SF-295-Glioblastoma 1.0 RL-non-Hodgkin's B-cell lymphoma 0.0 Cerebellum 58.2 JM1-pre-B-cell lymphoma 0.0 Cerebellum 44.8 Jurkat-T cell leukemia 0.0 NCI-H292-Mucoepidermoid lung 0.0 TF-1-Erythroleukemia 2.2 carcinoma DMS-114-Small cell lung cancer 0.3 HUT 78-T-cell lymphoma 0.1 DMS-79-Small cell lung cancer 49.0 U937-Histiocytic lymphoma 0.7 NCI-H146-Small cell lung cancer 18.0 KU-812-Myelogenous leukemia 0.6 NCI-H526-Small cell lung cancer 0.2 769-P-Clear cell renal carcinoma 100.0 NCI-N417-Small cell lung cancer 50.0 Caki-2-Clear cell renal carcinoma 5.9 NCI-H82-Small cell lung cancer 9.3 SW 839-Clear cell renal carcinoma 79.6 NCI-H157-Squamous cell lung cancer 0.0 Rhabdoid kidney tumor 0.0 (metastasis) NCI-H1155-Large cell lung cancer 0.4 Hs766T-Pancreatic carcinoma (LN 0.0 metastasis) NCI-H1299-Large cell lung cancer 5.7 CAPAN-1-Pancreatic adenocarcinoma (liver 0.0 metastasis) NCI-H727-Lung carcinoid 7.4 SU86.86-Pancreatic carcinoma (liver 1.3 metastasis) NCI-UMC-11-Lung carcinoid 28.1 BxPC-3-Pancreatic adenocarcinoma 0.0 LX-1-Small cell lung cancer 0.3 HPAC-Pancreatic adenocarcinoma 0.1 Colo-205-Colon cancer 6.4 MIA PaCa-2-Pancreatic carcinoma 0.0 KM12-Colon cancer 2.9 CFPAC-1-Pancreatic ductal adenocarcinoma 0.7 KM20L2-Colon cancer 0.0 PANC-1-Pancreatic epithelioid ductal 0.2 carcinoma NCI-H716-Colon cancer 33.9 T24-Bladder carcinma (transitional cell) 0.0 SW-48-Colon adenocarcinoma 2.8 5637-Bladder carcinoma 1.3 SW1116-Colon adenocarcinoma 0.0 HT-1197-Bladder carcinoma 3.0 LS 174T-Colon adenocarcinoma 0.6 UM-UC-3-Bladder carcinma (transitional 0.0 cell) SW-948-Colon adenocarcinoma 0.3 A204-Rhabdomyosarcoma 0.0 SW-480-Colon adenocarcinoma 0.0 HT-1080-Fibrosarcoma 0.7 NCI-SNU-5-Gastric carcinoma 0.3 MG-63-Osteosarcoma 0.0 KATO III-Gastric carcinoma 0.0 SK-LMS-1-Leiomyosarcoma (vulva) 0.0 NCI-SNU-16-Gastric carcinoma 1.0 SJRH30-Rhabdomyosarcoma (met to bone 50.7 marrow) NCI-SNU-1-Gastric carcinoma 14.7 A431-Epidermoid carcinoma 0.0 RF-1-Gastric adenocarcinoma 2.8 WM266-4-Melanoma 2.5 RF-48-Gastric adenocarcinoma 2.4 DU 145-Prostate carcinoma (brain metastasis) 0.0 MKN-45-Gastric carcinoma 0.3 MDA-MB-468-Breast adenocarcinoma 0.0 NCI-N87-Gastric carcinoma 0.0 SCC-4-Squamous cell carcinoma of tongue 0.0 OVCAR-5-Ovarian carcinoma 0.0 SCC-9-Squamous cell carcinoma of tongue 0.0 RL95-2-Uterine carcinoma 0.0 SCC-15-Squamous cell carcinoma of tongue 0.0 HelaS3-Cervical adenocarcinoma 0.0 CAL 27-Squamous cell carcinoma of tongue 0.0 Clumn A - Rel. Exp.(%) Ag88, Run 153109696

[0613] 72 TABLE BK Panel 4D Tissue Name A B Tissue Name A B Secondary Th1 act 0.8 0.0 HUVEC IL-1beta 0.5 1.1 Secondary Th2 act 1.5 0.4 HUVEC IFN gamma 2.5 4.1 Secondary Tr1 act 2.8 0.0 HUVEC TNF alpha + IFN gamma 1.1 0.0 Secondary Th1 rest 0.7 0.0 HUVEC TNF alpha + IL4 2.0 2.4 Secondary Th2 rest 1.7 0.0 HUVEC IL-11 3.0 3.0 Secondary Tr1 rest 1.0 0.0 Lung Microvascular EC none 1.8 0.9 Primary Th1 act 3.2 0.0 Lung Microvascular EC TNF alpha + IL-1beta 1.5 0.3 Primary Th2 act 2.6 0.0 Microvascular Dermal EC none 3.9 3.3 Primary Tr1 act 5.0 0.0 Microsvasular Dermal EC TNF alpha + IL-1beta 2.5 2.4 Primary Th1 rest 7.1 0.0 Bronchial epithelium TNF alpha + IL1beta 18.3 22.5 Primary Th2 rest 2.8 0.0 Small airway epithelium none 1.2 5.1 Primary Tr1 rest 2.5 0.0 Small airway epithelium TNF alpha + IL-1beta 24.0 23.3 CD45RA CD4 lymphocyte act 1.4 0.6 Coronery artery SMC rest 1.1 1.8 CD45RO CD4 lymphocyte act 1.6 0.3 Coronery artery SMC TNF alpha + IL-1beta 0.6 0.9 CD8 lymphocyte act 2.0 0.0 Astrocytes rest 19.8 14.1 Secondary CD8 lymphocyte rest 2.7 0.0 Astrocytes TNF alpha + IL-1beta 3.4 4.4 Secondary CD8 lymphocyte act 0.3 0.2 KU-812 (Basophil) rest 2.4 1.2 CD4 lymphocyte none 0.7 0.0 KU-812 (Basophil) PMA/ionomycin 11.3 11.3 2ry Th1/Th2/Tr1_anti-CD95 1.5 0.0 CCD1106 (Keratinocytes) none 0.1 0.2 CH11 LAK cells rest 2.6 0.4 CCD1106 (Keratinocytes) TNF alpha + IL-1beta 0.0 1.3 LAK cells IL-2 2.6 0.0 Liver cirrhosis 11.9 15.0 LAK cells IL-2 + IL-12 2.5 1.3 Lupus kidney 7.3 23.8 LAK cells IL-2 + IFN gamma 5.6 0.8 NCI-H292 none 1.0 0.0 LAK cells IL-2 + IL-18 4.2 0.9 NCI-H292 IL-4 2.0 0.0 LAK cells PMA/ionomycin 1.8 0.0 NCI-H292 IL-9 1.9 0.0 NK Cells IL-2 rest 2.4 0.0 NCI-H292 IL-13 1.1 0.2 Two Way MLR 3 day 2.7 0.0 NCI-H292 IFN gamma 1.1 0.0 Two Way MLR 5 day 1.7 0.0 HPAEC none 1.2 1.7 Two Way MLR 7 day 0.7 0.4 HPAEC TNF alpha + IL-1beta 2.3 1.3 PBMC rest 1.0 0.0 Lung fibroblast none 0.4 0.4 PBMC PWM 12.9 10.3 Lung fibroblast TNF alpha + IL-1beta 1.9 1.9 PBMC PHA-L 2.1 1.4 Lung fibroblast IL-4 2.4 0.4 Ramos (B cell) none 1.6 0.0 Lung fibroblast IL-9 0.9 1.9 Ramos (B cell) ionomycin 12.7 0.0 Lung fibroblast IL-13 2.0 1.3 B lymphocytes PWM 5.8 3.8 Lung fibroblast IFN gamma 0.9 1.7 B lymphocytes CD40L and IL-4 7.2 0.4 Dermal fibroblast CCD1070 rest 3.8 2.6 EOL-1 dbcAMP 1.3 0.0 Dermal fibroblast CCD1070 TNF alpha 3.1 0.5 EOL-1 dbcAMP PMA/ionomycin 1.9 0.0 Dermal fibroblast CCD1070 IL-1beta 0.2 0.3 Dendritic cells none 0.9 0.4 Dermal fibroblast IFN gamma 2.3 0.9 Dendritic cells LPS 1.5 1.4 Dermal fibroblast IL-4 1.6 1.0 Dendritic cells anti-CD40 2.3 0.3 IBD Colitis 2 1.0 4.1 Monocytes rest 1.4 0.0 IBD Crohn's 4.9 6.9 Monocytes LPS 1.7 0.7 Colon 100.0 87.1 Macrophages rest 2.9 0.5 Lung 18.4 24.3 Macrophages LPS 0.4 0.0 Thymus 34.4 100.0 HUVEC none 2.0 1.0 Kidney 20.9 34.4 HUVEC starved 4.8 0.8 Coumn A - Rel. Exp.(%) Ag2772, Run 161924079 Column B - Rel. Exp.(%) Ag88, Run 139410561

[0614] 73 TABLE BL general oncology screening panel_v_2.4 Tissue Name A B Tissue Name A B Colon cancer 1 5.0 14.4 Bladder NAT 2 0.0 0.3 Colon NAT 1 7.0 9.2 Bladder NAT 3 0.0 0.1 Colon cancer 2 0.0 1.2 Bladder NAT 4 6.5 1.6 Colon NAT 2 18.3 12.3 Prostate adenocarcinoma 1 0.0 7.7 Colon cancer 3 15.9 11.3 Prostate adenocarcinoma 2 0.0 1.0 Colon NAT 3 33.9 25.0 Prostate adenocarcinoma 3 0.0 4.6 Colon malignant cancer 4 0.0 7.7 Prostate adenocarcinoma 4 0.0 2.1 Colon NAT 4 13.9 9.3 Prostate NAT 5 7.5 0.5 Lung cancer 1 8.0 0.9 Prostate adenocarcinoma 6 0.0 2.7 Lung NAT 1 12.5 1.2 Prostate adenocarcinoma 7 0.0 2.8 Lung cancer 2 100.0 100.0 Prostate adenocarcinoma 8 0.0 0.6 Lung NAT 2 31.2 4.3 Prostate adenocarcinoma 9 0.0 6.4 Squamous cell carcinoma 3 20.0 2.5 Prostate NAT 10 0.0 0.3 Lung NAT 3 5.0 0.2 Kidney cancer 1 33.4 12.9 Metastatic melanoma 1 0.0 14.9 Kidney NAT 1 0.0 5.8 Melanoma 2 0.0 1.1 Kidney cancer 2 40.6 80.7 Melanoma 3 0.0 1.9 Kidney NAT 2 0.0 4.6 Metastatic melanoma 4 0.0 18.8 Kidney cancer 3 6.3 49.3 Metastatic melanoma 5 7.5 32.1 Kidney NAT 3 0.0 2.4 Bladder cancer 1 0.0 0.6 Kidney cancer 4 6.8 19.1 Bladder NAT 1 0.0 0.0 Kidney NAT 4 0.0 4.3 Bladder cancer 2 0.0 1.0 Column A - Rel. Exp.(%) Ag6309 Run 259804334 Column B - Rel. Exp.(%) Ag88, Run 262228151

[0615] CNS_neurodegeneration_v1.0 Summary: Ag2772/Ag6309 This panel confirms the expression of this gene at low levels in the brains of an independent group of individuals.

[0616] General_screening_panel_v1.5 Summary: Ag6309 Highest expression of this gene is detected in spinal cord (CT=29.4). Moderate expression of this gene is mainly seen in all the region of central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. This gene codes for semaphorin 6A protein (Sema6A). Sema6A is shown to be expressed in thalamocortical neurons and required for their axons to project properly (Leighton Pa., Mitchell K J, Goodrich L V, Lu X, Pinson K, Scherz P, Skarnes W C, Tessier-Lavigne M. 2001, Nature 410(6825):174-9). Therefore, therapeutic modulation of this gene product may be useful in the treatment of central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

[0617] Low expression of this gene is also seen in number of cancer cell lines derived from brain, ovarian, melanoma and a renal cancer. Therefore, therapeutic modulation of the expression of this gene or Sema6A protien encoded by this gene through the use of small molecules or antibodies may be useful in the treatment of these cancer, especially in inhibiting migration of these cancer cell lines.

[0618] HASS Panel v1.0 Summary: Ag2772 Highest expression of this gene is seen in a brain cancer (487 medullo) sample (CT=27.3). High to moderate expression of this gene is seen in medulloblastoma and glioma brain cancer samples and prostate cancer (LnCAP) cell line. Expression of this gene is downregulated in LnCAP cells under acidic plus hypoxic environment. In addition, low expression of this gene is also seen in MCF7 cells. Therefore, therapeutic modulation of this gene or its protein product may be useful in the treatment of brain, prostate and breast cancers.

[0619] Panel 1 Summary: Ag88 Highest expression of this gene is seen in cerebellum (CT=24.5). High expression of this gene is mainly seen in all the regions of central nervous system examined. Please see panel 1.5 for further discussion of this gene.

[0620] High to moderate expression of this gene is also seen in tissues with metabolic/endocrine functions including, pancreas, thyroid, adrenal gland, pituitary gland, skeletal muscle, heart, liver and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

[0621] High to moderate expression of this gene is also seen in number of cancer cell lines derived from melanoma, ovarian, renal, colon, liver and brain cancers. Therefore therapeutic modulation of this gene or its protein product may be useful in the treatment of these cancers.

[0622] Panel 1.3D Summary: Ag2772 Highest expression of this gene is seen in fetal skeletal muscle (CT=27.4). Interestingly, this gene is expressed at much higher levels in fetal (CT=27.4) when compared to adult skeletal muscle (CT=31.5). This observation suggests that expression of this gene can be used to distinguish fetal from adult skeletal muscle. In addition, the relative overexpression of this gene in fetal tissue suggests that the protein product may enhance muscle growth or development in the fetus and thus may also act in a regenerative capacity in the adult. Therefore, therapeutic modulation of the protein encoded by this gene could be useful in treatment of muscle related diseases.

[0623] Some expression pattern correlates with (ex: cancer cell lines) that seen in panel 1.

[0624] Panel 2D Summary: Ag2772/Ag88 Two experiments with different probe primer sets are in excellent agreement, with highest expression of this gene seen in a liver cancer (ODO4310) sample (CTs=25-28). This gene shows a widespread expression in this panel, with high to moderate expression in normal and cancer samples from stomach, ovary, bladder, colon, liver, lung, metastatic melanoma, kidney, uterus, thyroid and breast. Interestingly, expression of this gene is upregulated in metastatic melanoma, gastric, liver and kidney cancers. Therefore, expression of this gene may be used as marker to detect the presence of metastatic melanoma, gastric, liver and kidney cancers, furthermore, therapeutic modulation of this gene or its protein product may be useful in the treatment of these cancers.

[0625] Panel 3D Summary: Ag88 Highest expression of this gene is detected in a renal cancer cell line (CT=30). Moderate expression of this gene is also seen number of cancer cell lines derived from brain, lung, colon, gastric, renal and bone cancers. Therefore, therapeutic modulation of this gene or its protein product may be useful in the treatment of these cancers.

[0626] Panel 4D Summary: Ag2772/Ag88 Two experiments with different probe-primer sets are in good agreement with highest expression of this gene seen in colon and thymus (CTs 27-30). This gene shows moderate to low expression in most of samples in this panel. Expression of this gene is upregulated in activated bronchial and small airway epithelium, basophils, liver cirrhosis and lupus kidney. Therefore therapeutic modulation of this gene or its protein product may be useful in the treatment of asthma, allergies, chronic obstructive pulmonary disease, Crohn's disease, ulcerative colitis, liver cirrhosis and lupus erythematosus.

[0627] General oncology screening panel_v—2.4 Summary: Ag6309/Ag88 Highest expression of this gene is seen in lung cancer sample (CTs=27-34.7). Moderate to low expression of this gene is seen in normal and cancer samples from lung, colon, metastatic melanoms, prostate, and kidney. Expression of this gene is upregulated in kidney, metastatic melanoma and lung cancers, which is in agreement with expression seen in panel 2D. Please see panel 2D for further discussion of this gene.

[0628] C. CG52324-01: Phosphatidylethanolamine-Binding Protein.

[0629] Expression of gene CG52324-01 was assessed using the primer-probe sets Ag2678 and Ag36, described in Tables CA and CB. Results of the RTQ-PCR runs are shown in Tables CC, CD, CE, CF, CG, CH and CI. 74 TABLE CA Probe Name Ag2678 Start SEQ ID Primers Sequences Length Position No Forward 5′-cgcaacctatatcctggtgat-3′ 21 373 150 Probe TET-5′-atccagatgcccctagcagagcagaa-3′-TAMRA 26 399 151 Reverse 5′-agccaatgtctccagaatctct-3′ 22 432 152

[0630] 75 TABLE CB Probe Name Ag36 Start SEQ ID Primers Sequences Length Position No Forward 5′-caggtggaaacggttcagaaa-3′ 21 650 153 Probe TET-5′-ctgtccattttccaagagcctcgagttttgt-3′-TAMRA 31 618 154 Reverse 5′-catctctctccttcccaaggaa-3′ 22 595 155

[0631] 76 TABLE CC CNS_neurodegeneration_v1.0 Tissue Name A B C Tissue Name A B C AD 1 Hippo 25.0 20.4 21.9 Control (Path) 3 Temporal Ctx 9.3 5.4 3.9 AD 2 Hippo 45.7 37.4 25.9 Control (Path) 4 Temporal Ctx 27.4 20.4 33.9 AD 3 Hippo 7.4 3.1 6.4 AD 1 Occipital Ctx 12.3 14.0 12.1 AD 4 Hippo 12.9 15.3 19.5 AD 2 Occipital Ctx (Missing) 0.0 0.0 0.0 AD 5 hippo 68.3 66.9 73.7 AD 3 Occipital Ctx 10.2 4.2 2.9 AD 6 Hippo 94.6 100.0 100.0 AD 4 Occipital Ctx 28.3 35.8 21.2 Control 2 Hippo 68.3 51.1 62.0 AD 5 Occipital Ctx 22.4 49.7 55.5 Control 4 Hippo 50.7 40.6 40.1 AD 6 Occipital Ctx 58.6 39.5 39.2 Control (Path) 3 Hippo 12.8 4.2 8.3 Control 1 Occipital Ctx 2.6 3.7 6.1 AD 1 Temporal Ctx 23.8 23.3 13.2 Control 2 Occipital Ctx 64.6 73.7 45.1 AD 2 Temporal Ctx 42.6 23.8 29.5 Control 3 Occipital Ctx 29.3 17.3 0.0 AD 3 Temporal Ctx 5.6 3.7 4.3 Control 4 Occipital Ctx 22.4 14.0 15.9 AD 4 Temporal Ctx 23.3 21.9 28.1 Control (Path) 1 Occipital Ctx 84.7 64.2 97.9 AD 5 Inf Temporal Ctx 87.1 81.8 57.8 Control (Path) 2 Occipital Ctx 15.1 14.8 20.2 AD 5 Sup Temporal Ctx 100.0 80.7 90.8 Control (Path) 3 Occipital Ctx 0.7 2.4 2.8 AD 6 Inf Temporal Ctx 57.0 52.5 55.5 Control (Path) 4 Occipital Ctx 8.2 8.3 16.8 AD 6 Sup Temporal Ctx 55.1 43.8 58.2 Control 1 Parietal Ctx 13.4 6.8 6.4 Control 1 Temporal Ctx 4.2 5.0 7.2 Control 2 Parietal Ctx 60.7 48.0 32.8 Control 2 Temporal Ctx 44.1 47.6 34.4 Control 3 Parietal Ctx 27.9 19.8 36.1 Control 3 Temporal Ctx 32.1 33.7 43.2 Control (Path) 1 Parietal Ctx 99.3 71.2 65.1 Control 4 Temporal Ctx 16.3 20.7 12.9 Control (Path) 2 Parietal Ctx 37.1 36.1 32.3 Control (Path) 1 Temporal Ctx 49.0 45.4 51.8 Control (Path) 3 Parietal Ctx 6.6 6.5 2.8 Control (Path) 2 Temporal Ctx 35.1 34.9 52.9 Control (Path) 4 Parietal Ctx 28.1 26.4 42.3 Column A - Rel. Exp.(% Ag2678, Run 206231405 Column B - Rel. Exp.(%) Ag2678, Run 206271178 Column C - Rel. Exp.(%) Ag36, Run 206943639

[0632] 77 TABLE CD Panel 1 Tissue Name A Tissue Name A Endothelial cells 0.0 Renal ca. 786-0 0.0 Endothelial cells (treated) 0.0 Renal ca. A498 0.0 Pancreas 2.0 Renal ca. RXF 393 0.0 Pancreatic ca. CAPAN 2 0.0 Renal ca. ACHN 0.0 Adrenal gland 0.9 Renal ca. UO-31 0.0 Thyroid 21.2 Renal ca. TK-10 0.0 Salivary gland 7.6 Liver 0.1 Pituitary gland 0.1 Liver (fetal) 0.0 Brain (fetal) 0.2 Liver ca. (hepatoblast) HepG2 0.0 Brain (whole) 2.0 Lung 6.2 Brain (amygdala) 1.0 Lung (fetal) 7.1 Brain (cerebellum) 4.6 Lung ca. (small cell) LX-1 0.0 Brain (hippocampus) 3.0 Lung ca. (small cell) NCI-H69 0.0 Brain (substantia nigra) 6.3 Lung ca. (s.cell var.) SHP-77 0.0 Brain (thalamus) 4.8 Lung ca. (large cell) NCI-H460 0.0 Brain (hypothalamus) 10.5 Lung ca. (non-sm. cell) A549 0.0 Spinal cord 1.8 Lung ca. (non-s.cell) NCI-H23 0.0 glio/astro U87-MG 0.0 Lung ca. (non-s.cell) HOP-62 0.0 glio/astro U-118-MG 0.0 Lung ca. (non-s.cl) NCI-H522 0.0 astrocytoma SW1783 0.0 Lung ca. (squam.) SW 900 0.0 neuro*; met SK-N-AS 0.0 Lung ca. (squam.) NCI-H596 0.1 astrocytoma SF-539 0.1 Mammary gland 0.5 astrocytoma SNB-75 0.0 Breast ca.* (pl.ef) MCF-7 0.0 glioma SNB-19 0.0 Breast ca.* (pl.ef) MDA-MB-231 0.0 glioma U251 0.0 Breast ca.* (pl.ef) T47D 0.0 glioma SF-295 0.0 Breast ca. BT-549 0.0 Heart 33.9 Breast ca. MDA-N 0.0 Skeletal muscle 100.0 Ovary 0.1 Bone marrow 1.0 Ovarian ca. OVCAR-3 0.0 Thymus 0.3 Ovarian ca. OVCAR-4 0.0 Spleen 0.1 Ovarian ca. OVCAR-5 0.0 Lymph node 0.3 Ovarian ca. OVCAR-8 0.0 Colon (ascending) 0.0 Ovarian ca. IGROV-1 0.0 Stomach 0.6 Ovarian ca. (ascites) SK-OV-3 0.0 Small intestine 0.1 Uterus 0.5 Colon ca. SW480 0.0 Placenta 0.2 Colon ca.* SW620 (SW480 met) 0.0 Prostate 15.0 Colon ca. HT29 0.0 Prostate ca.* (bone met) PC-3 0.0 Colon ca. HCT-116 0.0 Testis 8.7 Colon ca. CaCo-2 0.0 Melanoma Hs688(A).T 0.0 Colon ca. HCT-15 0.0 Melanoma* (met) Hs688(B).T 0.0 Colon ca. HCC-2998 0.0 Melanoma UACC-62 0.0 Gastric ca. * (liver met) NCI-N87 0.0 Melanoma M14 0.0 Bladder 0.2 Melanoma LOX IMVI 0.0 Trachea 1.2 Melanoma* (met) SK-MEL-5 0.0 Kidney 0.4 Melanoma SK-MEL-28 0.0 Kidney (fetal) 0.3 Column A - Rel. Exp.(%) Ag36, Run 87587974

[0633] 78 TABLE CE Panel 1.3D Tissue Name A B Tissue Name A B Liver adenocarcinoma 0.0 0.0 Kidney (fetal) 0.1 0.0 Pancreas 0.8 0.2 Renal ca. 786-0 0.0 0.0 Pancreatic ca. CAPAN 2 0.0 0.0 Renal ca. A498 0.0 0.0 Adrenal gland 0.2 0.2 Renal ca. RXF 393 0.0 0.0 Thyroid 22.7 6.8 Renal ca. ACHN 0.0 0.0 Salivary gland 3.9 1.0 Renal ca. UO-31 0.0 0.0 Pituitary gland 3.6 0.5 Renal ca. TK-10 0.0 0.0 Brain (fetal) 0.1 0.1 Liver 1.0 0.2 Brain (whole) 1.4 0.5 Liver (fetal) 0.0 0.0 Brain (amygdala) 1.0 0.5 Liver ca. (hepatoblast) HepG2 0.0 0.0 Brain (cerebellum) 0.9 0.6 Lung 59.9 12.8 Brain (hippocampus) 7.9 0.9 Lung (fetal) 11.0 5.8 Brain (substantia nigra) 3.8 1.4 Lung ca. (small cell) LX-1 0.1 0.0 Brain (thalamus) 6.0 2.2 Lung ca. (small cell) NCI-H69 0.0 0.0 Cerebral Cortex 7.2 6.2 Lung ca. (s. cell var.) SHP-77 0.0 0.0 Spinal cord 1.1 1.7 Lung ca. (large cell)NCI-H460 0.0 0.0 glio/astro U87-MG 0.0 0.0 Lung ca. (non-sm. cell) A549 0.0 0.0 glio/astro U-118-MG 0.1 0.0 Lung ca. (non-s. cell) NCI-H23 0.0 0.0 astrocytoma SW1783 0.0 0.0 Lung ca. (non-s. cell) HOP-62 0.0 0.0 neuro*; met SK-N-AS 0.0 0.0 Lung ca. (non-s. cl) NCI-H522 0.0 0.0 astrocytoma SF-539 0.2 0.1 Lung ca. (squam.) SW 900 0.0 0.0 astrocytoma SNB-75 0.1 0.0 Lung ca. (squam.) NCI-H596 0.0 0.0 glioma SNB-19 0.0 0.0 Mammary gland 1.0 0.3 glioma U251 0.0 0.0 Breast ca.* (pl. ef) MCF-7 0.0 0.0 glioma SF-295 0.0 0.0 Breast ca.* (pl. ef) MDA-MB-231 0.0 0.0 Heart (fetal) 8.1 7.4 Breast ca.* (pl. ef) T47D 0.0 0.0 Heart 21.2 27.7 Breast ca. BT-549 0.1 0.0 Skeletal muscle (fetal) 100.0 85.3 Breast ca. MDA-N 0.0 0.0 Skeletal muscle 51.4 100.0 Ovary 0.8 0.6 Bone marrow 0.5 0.1 Ovarian ca. OVCAR-3 0.0 0.0 Thymus 0.2 0.3 Ovarian ca. OVCAR-4 0.0 0.0 Spleen 0.2 0.0 Ovarian ca. OVCAR-5 0.1 0.0 Lymph node 0.3 0.0 Ovarian ca. OVCAR-8 0.0 0.1 Colorectal 0.2 0.1 Ovarian ca. IGROV-1 0.0 0.0 Stomach 1.5 0.3 Ovarian ca.* (ascites) SK-OV-3 0.0 0.0 Small intestine 0.1 0.0 Uterus 0.0 0.0 Colon ca. SW480 0.0 0.0 Placenta 0.4 0.0 Colon ca.* SW620(SW480 met) 0.0 0.0 Prostate 8.2 4.6 Colon ca. HT29 0.0 0.0 Prostate ca.* (bone met)PC-3 0.0 0.0 Colon ca. HCT-116 0.0 0.0 Testis 6.1 2.0 Colon ca. CaCo-2 0.0 0.0 Melanoma Hs688(A).T 0.0 0.0 Colon ca. tissue(ODO3866) 0.1 0.0 Melanoma* (met) Hs688(B).T 0.0 0.0 Colon ca. HCC-2998 0.0 0.0 Melanoma UACC-62 0.0 0.0 Gastric ca.* (liver met) NCI-N87 0.0 0.0 Melanoma M14 0.0 0.0 Bladder 0.0 0.0 Melanoma LOX IMVI 0.0 0.0 Trachea 4.8 1.7 Melanoma* (met) SK-MEL-5 0.0 0.0 Kidney 0.2 0.2 Adipose 1.2 0.6 Colun A - Rel. Exp.(%) Ag2678, Run 158535212 Column B - Rel. Exp.(%) Ag36, Run 161682677

[0634] 79 TABLE CF Panel 2D Tissue Name A B Tissue Name A B Normal Colon 6.5 5.3 Kidney Margin 8120608 0.3 0.4 CC Well to Mod Diff (ODO3866) 0.1 0.0 Kidney Cancer 8120613 0.1 0.0 CC Margin (ODO3866) 0.1 0.1 Kidney Margin 8120614 1.5 1.4 CC Gr.2 rectosigmoid (ODO3868) 0.0 0.0 Kidney Cancer 9010320 0.1 0.1 CC Margin (ODO3868) 0.1 0.1 Kidney Margin 9010321 1.1 0.8 CC Mod Diff (ODO3920) 0.0 0.0 Normal Uterus 0.2 0.1 CC Margin (ODO3920) 0.0 0.1 Uterus Cancer 064011 0.3 0.4 CC Gr.2 ascend colon (ODO3921) 0.0 0.0 Normal Thyroid 22.1 23.5 CC Margin (ODO3921) 0.0 0.0 Thyroid Cancer 064010 6.6 10.3 CC from Partial Hepatectomy 0.1 0.2 Thyroid Cancer A302152 14.1 20.9 (ODO4309) Mets Liver Margin (ODO4309) 0.5 0.3 Thyroid Margin A302153 24.3 18.6 Colon mets to lung (OD04451-01) 10.4 14.0 Normal Breast 1.2 0.3 Lung Margin (OD04451-02) 36.6 50.0 Breast Cancer (OD04566) 0.0 0.1 Normal Prostate 6546-1 13.1 13.6 Breast Cancer (OD04590-01) 3.1 2.5 Prostate Cancer (OD04410) 4.9 6.5 Breast Cancer Mets 0.3 0.3 (OD04590-03) Prostate Margin (OD04410) 13.6 26.8 Breast Cancer Metastasis 0.3 0.2 (OD04655-05) Prostate Cancer (OD04720-01) 11.4 18.9 Breast Cancer 064006 0.2 0.3 Prostate Margin (OD04720-02) 30.4 38.7 Breast Cancer 1024 1.4 0.8 Normal Lung 061010 35.8 46.0 Breast Cancer 9100266 0.2 0.1 Lung Met to Muscle (ODO4286) 0.0 0.0 Breast Margin 9100265 0.7 0.4 Muscle Margin (ODO4286) 54.3 55.5 Breast Cancer A209073 0.3 0.4 Lung Malignant Cancer (OD03126) 11.7 14.9 Breast Margin A209073 0.7 0.9 Lung Margin (OD03126) 92.7 100.0 Normal Liver 0.0 0.0 Lung Cancer (OD04404) 7.7 12.5 Liver Cancer 064003 0.0 0.0 Lung Margin (OD04404) 22.5 29.5 Liver Cancer 1025 0.0 0.2 Lung Cancer (OD04565) 0.1 0.1 Liver Cancer 1026 0.1 0.0 Lung Margin (OD04565) 18.9 29.1 Liver Cancer 6004-T 0.1 0.1 Lung Cancer (OD04237-01) 1.1 1.1 Liver Tissue 6004-N 0.0 0.0 Lung Margin (OD04237-02) 29.9 27.0 Liver Cancer 6005-T 0.1 0.1 Ocular Mel Met to Liver (ODO4310) 0.0 0.1 Liver Tissue 6005-N 0.1 0.0 Liver Margin (ODO4310) 0.2 0.1 Normal Bladder 0.1 0.1 Melanoma Mets to Lung (OD04321) 0.5 0.4 Bladder Cancer 1023 0.1 0.2 Lung Margin (OD04321) 100.0 92.0 Bladder Cancer A302173 0.0 0.1 Normal Kidney 0.7 0.7 Bladder Cancer (OD04718-01) 0.1 0.1 Kidney Ca, Nuclear grade 2 0.7 0.3 Bladder Normal Adjacent 0.0 0.0 (OD04338) (OD04718-03) Kidney Margin (OD04338) 1.4 0.8 Normal Ovary 0.3 0.1 Kidney Ca Nuclear grade 1/2 0.1 0.0 Ovarian Cancer 064008 0.4 0.1 (OD04339) Kidney Margin (OD04339) 0.6 1.4 Ovarian Cancer (OD04768-07) 0.0 0.0 Kidney Ca, Clear cell type (OD04340) 0.3 0.3 Ovary Margin (OD04768-08) 0.1 0.0 Kidney Margin (OD04340) 1.2 0.7 Normal Stomach 0.5 0.7 Kidney Ca, Nuclear grade 3 0.0 0.2 Gastric Cancer 9060358 0.2 0.3 (OD04348) Kidney Margin (OD04348) 0.3 0.4 Stomach Margin 9060359 1.2 1.1 Kidney Cancer (OD04622-01) 0.3 0.1 Gastric Cancer 9060395 0.2 0.2 Kidney Margin (OD04622-03) 0.0 0.2 Stomach Margin 9060394 0.8 0.8 Kidney Cancer (OD04450-01) 0.0 0.0 Gastric Cancer 9060397 0.2 0.1 Kidney Margin (OD04450-03) 1.0 0.6 Stomach Margin 9060396 0.3 0.5 Kidney Cancer 8120607 0.2 0.0 Gastric Cancer 064005 0.0 0.1 Coumn A - Rel. Exp.(%) Ag2678, Run 158536099 Column B - Rel. Exp.(%) Ag36, Run 161680686

[0635] 80 TABLE CG Panel 3D Tissue Name A Tissue Name A Daoy-Medulloblastoma 4.1 Ca Ski-Cervical epidermoid carcinoma 0.0 (metastasis) TE671-Medulloblastoma 0.0 ES-2-Ovarian clear cell carcinoma 0.0 D283 Med-Medulloblastoma 0.0 Ramos-Stimulated with PMA/ionomycin 6 h 0.0 PFSK-1-Primitive Neuroectodermal 2.7 Ramos-Stimulated with PMA/ionomycin 14 h 0.0 XF-498-CNS 0.0 MEG-01-Chronic myelogenous leukemia 0.0 (megokaryoblast) SNB-78-Glioma 0.0 Raji-Burkitt's lymphoma 0.0 SF-268-Glioblastoma 0.0 Daudi-Burkitt's lymphoma 3.4 T98G-Glioblastoma 0.7 U266-B-cell plasmacytoma 0.8 SK-N-SH-Neuroblastoma (metastasis) 0.0 CA46-Burkitt's lymphoma 0.7 SF-295-Glioblastoma 1.4 RL-non-Hodgkin's B-cell lymphoma 0.0 Cerebellum 100.0 JM1-pre-B-cell lymphoma 0.0 Cerebellum 98.6 Jurkat-T cell leukemia 0.0 NCI-H292-Mucoepidermoid lung 1.2 TF-1-Erythroleukemia 0.0 carcinoma DMS-114-Small cell lung cancer 0.6 HUT 78-T-cell lymphoma 0.0 DMS-79-Small cell lung cancer 1.4 U937-Histiocytic lymphoma 1.8 NCI-H146-Small cell lung cancer 0.0 KU-812-Myelogenous leukemia 0.0 NCI-H526-Small cell lung cancer 0.0 769-P-Clear cell renal carcinoma 0.0 NCI-N417-Small cell lung cancer 0.0 Caki-2-Clear cell renal carcinoma 0.0 NCI-H82-Small cell lung cancer 0.0 SW 839-Clear cell renal carcinoma 0.0 NCI-H157-Squamous cell lung cancer 0.0 Rhabdoid kidney tumor 0.0 (metastasis) NCI-H1155-Large cell lung cancer 0.0 Hs766T-Pancreatic carcinoma (LN metastasis) 1.3 NCI-H1299-Large cell lung cancer 0.0 CAPAN-1-Pancreatic adenocarcinoma (liver 0.0 metastasis) NCI-H727-Lung carcinoid 0.6 SU86.86-Pancreatic carcinoma (liver 0.0 metastasis) NCI-UMC-11-Lung carcinoid 0.0 BxPC-3-Pancreatic adenocarcinoma 0.3 LX-1-Small cell lung cancer 0.0 HPAC-Pancreatic adenocarcinoma 0.0 Colo-205-Colon cancer 0.0 MIA PaCa-2-Pancreatic carcinoma 0.0 KM12-Colon cancer 0.8 CFPAC-1-Pancreatic ductal adenocarcinoma 0.8 KM20L2-Colon cancer 0.0 PANC-1-Pancreatic epithelioid ductal 0.0 carcinoma NCI-H716-Colon cancer 0.0 T24-Bladder carcinma (transitional cell) 0.0 SW-48-Colon adenocarcinoma 0.0 5637-Bladder carcinoma 0.0 SW1116-Colon adenocarcinoma 0.0 HT-1197-Bladder carcinoma 2.6 LS 174T-Colon adenocarcinoma 0.0 UM-UC-3-Bladder carcinma (transitional cell) 0.0 SW-948-Colon adenocarcinoma 0.0 A204-Rhabdomyosarcoma 0.0 SW-480-Colon adenocarcinoma 0.0 HT-1080-Fibrosarcoma 0.0 NCI-SNU-5-Gastric carcinoma 0.0 MG-63-Osteosarcoma 1.5 KATO III-Gastric carcinoma 0.0 SK-LMS-1-Leiomyosarcoma (vulva) 0.0 NCI-SNU-16-Gastric carcinoma 0.0 SJRH30-Rhabdomyosarcoma (met to bone 0.0 marrow) NCI-SNU-1-Gastric carcinoma 0.0 A431-Epidermoid carcinoma 0.0 RF-1-Gastric adenocarcinoma 0.6 WM266-4-Melanoma 0.0 RF-48-Gastric adenocarcinoma 0.0 DU 145-Prostate carcinoma (brain metastasis) 0.0 MKN-45-Gastric carcinoma 0.0 MDA-MB-468-Breast adenocarcinoma 0.0 NCI-N87-Gastric carcinoma 0.0 SCC-4-Squamous cell carcinoma of tongue 0.0 OVCAR-5-Ovarian carcinoma 0.0 SCC-9-Squamous cell carcinoma of tongue 0.0 RL95-2-Uterine carcinoma 0.0 SCC-15-Squamous cell carcinoma of tongue 0.0 HelaS3-Cervical adenocarcinoma 0.0 CAL 27-Squamous cell carcinoma of tongue 0.0 Clumn A - Rel. Exp.(%) Ag36, Run 161682678

[0636] 81 TABLE CH Panel 4D Tissue Name A B Tissue Name A B Secondary Th1 act 0.0 0.0 HUVEC IL-1beta 0.0 0.0 Secondary Th2 act 0.0 0.0 HUVEC IFN gamma 0.0 0.0 Secondary Tr1 act 0.0 0.0 HUVEC TNF alpha + IFN gamma 0.0 0.0 Secondary Th1 rest 0.0 0.0 HUVEC TNF alpha + IL4 0.0 0.0 Secondary Th2 rest 0.0 0.0 HUVEC IL-11 0.0 0.0 Secondary Tr1 rest 0.2 0.2 Lung Microvascular EC none 0.0 0.1 Primary Th1 act 0.0 0.0 Lung Microvascular EC TNF alpha + IL-1beta 0.0 0.1 Primary Th2 act 0.0 0.0 Microvascular Dermal EC none 0.0 0.0 Primary Tr1 act 0.0 0.0 Microsvasular Dermal EC TNF alpha + IL-1beta 0.0 0.0 Primary Th1 rest 0.0 0.0 Bronchial epithelium TNF alpha + IL1beta 0.2 0.0 Primary Th2 rest 0.0 0.1 Small airway epithelium none 0.0 0.0 Primary Tr1 rest 0.3 0.1 Small airway epithelium TNF alpha + IL-1beta 0.0 0.1 CD45RA CD4 lymphocyte act 0.2 0.0 Coronery artery SMC rest 0.0 0.0 CD45RO CD4 lymphocyte act 0.0 0.0 Coronery artery SMC TNF alpha + IL-1beta 0.0 0.0 CD8 lymphocyte act 0.0 0.0 Astrocytes rest 0.0 0.0 Secondary CD8 lymphocyte rest 0.0 0.0 Astrocytes TNF alpha + IL-1beta 0.3 0.0 Secondary CD8 lymphocyte act 0.0 0.0 KU-812 (Basophil) rest 0.0 0.0 CD4 lymphocyte none 0.0 0.0 KU-812 (Basophil) PMA/ionomycin 0.0 0.0 2ry Th1/Th2/Tr1_anti-CD95 CH11 0.0 0.0 CCD1106 (Keratinocytes) none 0.0 0.0 LAK cells rest 0.0 0.0 CCD1106 (Keratinocytes) TNF alpha + IL-1beta 0.0 0.0 LAK cells IL-2 0.2 0.0 Liver cirrhosis 1.4 0.0 LAK cells IL-2 + IL-12 0.0 0.0 Lupus kidney 0.0 0.1 LAK cells IL-2 + IFN gamma 0.0 0.0 NCI-H292 none 2.4 1.8 LAK cells IL-2 + IL-18 0.4 0.0 NCI-H292 IL-4 2.2 1.8 LAK cells PMA/ionomycin 0.1 0.0 NCI-H292 IL-9 3.2 0.7 NK Cells IL-2 rest 0.0 0.0 NCI-H292 IL-13 2.4 0.3 Two Way MLR 3 day 0.2 0.0 NCI-H292 IFN gamma 0.8 0.1 Two Way MLR 5 day 0.0 0.0 HPAEC none 0.0 0.0 Two Way MLR 7 day 0.0 0.0 HPAEC TNF alpha + IL-1beta 0.0 0.0 PBMC rest 0.0 0.0 Lung fibroblast none 0.2 0.0 PBMC PWM 0.0 0.0 Lung fibroblast TNF alpha + IL-1beta 0.7 0.0 PBMC PHA-L 0.0 0.0 Lung fibroblast IL-4 1.1 0.3 Ramos (B cell) none 0.0 0.0 Lung fibroblast IL-9 0.4 0.4 Ramos (B cell) ionomycin 0.7 0.1 Lung fibroblast IL-13 0.2 0.3 B lymphocytes PWM 0.0 0.0 Lung fibroblast IFN gamma 0.4 0.1 B lymphocytes CD40L and IL-4 0.9 0.5 Dermal fibroblast CCD1070 rest 0.2 0.2 EOL-1 dbcAMP 0.0 0.0 Dermal fibroblast CCD1070 TNF alpha 0.0 0.0 EOL-1 dbcAMP PMA/ionomycin 0.1 0.0 Dermal fibroblast CCD1070 IL-1beta 0.0 0.6 Dendritic cells none 0.0 0.0 Dermal fibroblast IFN gamma 0.0 0.3 Dendritic cells LPS 0.4 0.3 Dermal fibroblast IL-4 0.2 0.0 Dendritic cells anti-CD40 0.2 0.0 IBD Colitis 2 0.0 0.0 Monocytes rest 0.0 0.0 IBD Crohn's 0.1 0.1 Monocytes LPS 0.0 0.0 Colon 1.5 0.2 Macrophages rest 0.6 0.9 Lung 100.0 100.0 Macrophages LPS 0.0 0.1 Thymus 1.9 3.2 HUVEC none 0.0 0.0 Kidney 2.5 2.1 HUVEC starved 0.0 0.0 Colmn A - Rel. Exp.(%) Ag2678, Run 158536138 Column B - Rel. Exp.(%) Ag36, Run 161681141

[0637] 82 TABLE CI Panel 5D Tissue Name A Tissue Name A 97457_Patient-02go_adipose 0.3 94709_Donor 2 AM - A_adipose 0.3 97476_Patient-07sk_skeletal muscle 5.0 94710_Donor 2 AM - B_adipose 0.4 97477_Patient-07ut_uterus 0.2 94711_Donor 2 AM - C_adipose 0.1 97478_Patient-07pl_placenta 0.4 94712_Donor 2 AD - A_adipose 0.1 97481_Patient-08sk_skeletal muscle 11.1 94713_Donor 2 AD - B_adipose 0.2 97482_Patient-08ut_uterus 0.0 94714_Donor 2 AD - C_adipose 0.2 97483_Patient-08pl_placenta 0.1 94742_Donor 3 U - A_Mesenchymal Stem 0.0 Cells 97486_Patient-09sk_skeletal muscle 14.5 94743_Donor 3 U - B_Mesenchymal Stem 0.0 Cells 97487_Patient-09ut_uterus 0.1 94730_Donor 3 AM - A_adipose 0.1 97488_Patient-09pl_placenta 0.3 94731_Donor 3 AM - B_adipose 0.0 97492_Patient-10ut_uterus 0.3 94732_Donor 3 AM - C_adipose 0.0 97493_Patient-10pl_placenta 0.2 94733_Donor 3 AD - A_adipose 26.8 97495_Patient-11go_adipose 0.1 94734_Donor 3 AD - B_adipose 0.0 97496_Patient-11sk_skeletal muscle 36.9 94735_Donor 3 AD - C_adipose 0.0 97497_Patient-11ut_uterus 0.1 77138_Liver_HepG2untreated 0.0 97498_Patient-11pl_placenta 0.2 73556_Heart_Cardiac stromal cells 0.1 (primary) 97500_Patient-12go_adipose 0.1 81735_Small Intestine 1.1 97501_Patient-12sk_skeletal muscle 100.0 72409_Kidney_Proximal Convoluted 0.1 Tubule 97502_Patient-12ut_uterus 0.1 82685_Small intestine_Duodenum 0.0 97503_Patient-12pl_placenta 0.0 90650_Adrenal_Adrenocortical adenoma 0.0 94721_Donor 2 U - A_Mesenchymal 0.0 72410_Kidney_HRCE 0.1 Stem Cells 94722_Donor 2 U - B_Mesenchymal Stem 0.1 72411_Kidney_HRE 0.0 Cells 94723_Donor 2 U - C_Mesenchymal Stem 0.0 73139_Uterus_Uterine smooth muscle cells 0.0 Cells Column A - Rel. Exp.(%) Ag36, Run 169315041

[0638] CNS_neurodegeneration_v1.0 Summary: Ag2678/Ag36 This panel confirms the expression of this gene at low levels in the brains of an independent group of individuals.

[0639] Panel 1 Summary: Ag36 Highest expression of this gene is seen in skeletal muscle (CT=23.8). The pattern of expression in this panel is in agreement with that seen in panel 1.3D.

[0640] Panel 1.3D Summary: Ag2678/Ag36 Two experiments with different probe-primer sets are in good agreement. Highest expression of this gene is seen in fetal and adult skeletal muscle (CTs=25). Therefore, therapeutic modulation of this gene expression or its protein product may be useful in the treatment of muscle related diseases. In addition, significant expression of this gene is also seen in other tissues with metabolic/endocrine functions including adipose, pancreas, thyroid, adrenal gland, pituitary gland, heart, liver and gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

[0641] Moderate expression of this gene is also seen in all the regions of central nervous system examined including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. Therefore, therapeutic modulation of this gene product may be useful in the treatment of central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

[0642] Panel 2D Summary: Ag2678/Ag36 Two experiments with different probe-primer sets are in good agreement. Highest expression of this gene is seen in normal lung margin samples (CTs=24.8-26). Lung margins show consistently higher expression than the corresponsing lung cancer tissues. Interestingly, expression of this gene is higher in normal tissues compared to the cancer sample. Therefore, therapeutic modulation of the activity of this gene or its protein product, through the use of small molecule drugs, protein therapeutics or antibodies, might be beneficial in the treatment of lung, stomach, breast, prostate, thyroid, kidney, and colon cancers.

[0643] Panel 3D Summary: Ag36 Highest expression of this gene is mainly seen in cerebellum sample (CTs=30). Therefore, therapeutic modulation of this gene or its protein product may be useful in the treatment of cerebellum related diseases such as ataxia and autism.

[0644] Panel 4D Summary: Ag2678/Ag36 Two experiments with different probe-primer sets are in good agreement. Highest expression of this gene is seen in lung (CTs=27). Moderate to low expression of this gene is also seen in resting and activated mucoepidermoid cell line NCI-H292, colon, thymus and kidney. Therefore, therapeutic modulation of this gene may be used for the treatment of inflammatory/autoimmune diseases that affect colon, lung and kidney including asthma, allergies, inflammatory bowel disease, lupus erythematosus, psoriasis, and emphysema.

[0645] Panel 5D Summary: Ag36 Highest expression of this gene is seen in a diabetic patient on insulin (patient 12)(CT=26.6). Significant expression of this gene is also seen in skeletal muscle from non-diabetic but obese patients and also in adipose tissue. Therefore, therapeutic modulation of the activity of this gene or its protein product may be useful in the treatment of metabolic disease such as diabetes and obesity.

[0646] D. CG53054-02: Wnt-14 Protein Precursor.

[0647] Expression of gene CG53054-02 was assessed using the primer-probe sets Ag2261 and Ag3035, described in Tables DA and DB. Results of the RTQ-PCR runs are shown in Tables DC, DD, DE, DF, DG, DH, DI, DJ and DK. 83 TABLE DA Probe Name Ag2261 Start SEQ ID Primers Sequences Length Position No Forward 5′-ggatgactcgcctagcttct-3′ 20 882 156 Probe TET-5′-gccgtaggtgccaccgtgagaag-3′-TAMRA 23 935 157 Reverse 5′-agcagatgctctcgcagtt-3′ 19 958 158

[0648] 84 TABLE DB Probe Name Ag3035 Start SEQ ID Primers Sequences Length Position No Forward 5′-acagcagcaagttcgtcaag-3′ 20 527 159 Probe TET-5′-agacggtcaagcaaggatctgcgag-3′-TAMRA 25 559 160 Reverse 5′-cagaggttgttgtggaagt-3′ 20 593 161

[0649] 85 TABLE DC AI comprehensive panel v1.0 Tissue Name A Tissue Name A 110967 COPD-F 13.1 112427 Match Control Psoriasis-F 84.1 110980 COPD-F 44.1 112418 Psoriasis-M 11.5 110968 COPD-M 32.3 112723 Match Control Psoriasis-M 2.6 110977 COPD-M 100.0 112419 Psoriasis-M 17.3 110989 Emphysema-F 48.0 112424 Match Control Psoriasis-M 9.9 110992 Emphysema-F 28.7 112420 Psoriasis-M 45.1 110993 Emphysema-F 17.9 112425 Match Control Psoriasis-M 36.1 110994 Emphysema-F 7.4 104689 (MF) OA Bone-Backus 16.6 110995 Emphysema-F 50.3 104690 (MF) Adj “Normal” Bone-Backus 10.2 110996 Emphysema-F 17.3 104691 (MF) OA Synovium-Backus 27.9 110997 Asthma-M 1.6 104692 (BA) OA Cartilage-Backus 0.0 111001 Asthma-F 13.1 104694 (BA) OA Bone-Backus 21.3 111002 Asthma-F 46.7 104695 (BA) Adj “Normal” Bone-Backus 8.1 111003 Atopic Asthma-F 25.3 104696 (BA) OA Synovium-Backus 22.1 111004 Atopic Asthma-F 44.4 104700 (SS) OA Bone-Backus 6.0 111005 Atopic Asthma-F 22.4 104701 (SS) Adj “Normal” Bone-Backus 12.4 111006 Atopic Asthma-F 6.9 104702 (SS) OA Synovium-Backus 39.5 111417 Allergy-M 22.1 117093 OA Cartilage Rep7 21.3 112347 Allergy-M 2.2 112672 OA Bone5 17.9 112349 Normal Lung-F 0.9 112673 OA Synovium5 10.1 112357 Normal Lung-F 76.8 112674 OA Synovial Fluid cells5 7.6 112354 Normal Lung-M 11.3 117100 OA Cartilage Rep14 12.8 112374 Crohns-F 30.1 112756 OA Bone9 24.0 112389 Match Control Crohns-F 20.6 112757 OA Synovium9 49.3 112375 Crohns-F 29.9 112758 OA Synovial Fluid Cells9 5.7 112732 Match Control Crohns-F 14.3 117125 RA Cartilage Rep2 17.3 112725 Crohns-M 6.4 113492 Bone2 RA 25.5 112387 Match Control Crohns-M 18.8 113493 Synovium2 RA 6.3 112378 Crohns-M 1.6 113494 Syn Fluid Cells RA 16.8 112390 Match Control Crohns-M 25.9 113499 Cartilage4 RA 13.1 112726 Crohns-M 14.1 113500 Bone4 RA 21.8 112731 Match Control Crohns-M 25.9 113501 Synovium4 RA 13.9 112380 Ulcer Col-F 33.0 113502 Syn Fluid Cells4 RA 6.8 112734 Match Control Ulcer Col-F 19.2 113495 Cartilage3 RA 14.4 112384 Ulcer Col-F 21.8 113496 Bone3 RA 13.9 112737 Match Control Ulcer Col-F 3.6 113497 Synovium3 RA 10.0 112386 Ulcer Col-F 10.8 113498 Syn Fluid Cells3 RA 23.0 112738 Match Control Ulcer Col-F 25.5 117106 Normal Cartilage Rep20 15.5 112381 Ulcer Col-M 0.2 113663 Bone3 Normal 0.0 112735 Match Control Ulcer Col-M 1.9 113664 Synovium3 Normal 0.0 112382 Ulcer Col-M 14.4 113665 Syn Fluid Cells3 Normal 0.1 112394 Match Control Ulcer Col-M 3.1 117107 Normal Cartilage Rep22 3.6 112383 Ulcer Col-M 31.6 113667 Bone4 Normal 18.3 112736 Match Control Ulcer Col-M 11.3 113668 Synovium4 Normal 16.4 112423 Psoriasis-F 7.1 113669 Syn Fluid Cells4 Normal 43.8 Column A - Rel. Exp.(% Ag3035, Run 311087483

[0650] 86 TABLE DD HASS Panel v1.0 Tissue Name A Tissue Name A MCF-7 C1 1.7 U87-MG F1 (B) 0.0 MCF-7 C2 2.6 U87-MG F2 0.0 MCF-7 C3 2.8 U87-MG F3 0.1 MCF-7 C4 2.9 U87-MG F4 0.2 MCF-7 C5 5.6 U87-MG F5 0.5 MCF-7 C6 2.2 U87-MG F6 0.3 MCF-7 C7 6.3 U87-MG F7 0.0 MCF-7 C9 4.4 U87-MG F8 0.0 MCF-7 C10 2.4 U87-MG F9 0.0 MCF-7 C11 0.9 U87-MG F10 0.4 MCF-7 C12 1.6 U87-MG F11 0.2 MCF-7 C13 4.5 U87-MG F12 0.3 MCF-7 C15 3.4 U87-MG F13 0.0 MCF-7 C16 5.7 U87-MG F14 0.0 MCF-7 C17 4.8 U87-MG F15 0.1 T24 D1 1.4 U87-MG F16 0.5 T24 D2 0.2 U87-MG F17 0.7 T24 D3 4.8 LnCAP A1 2.4 T24 D4 0.5 LnCAP A2 1.2 T24 D5 3.1 LnCAP A3 2.6 T24 D6 0.3 LnCAP A4 2.3 T24 D7 2.0 LnCAP A5 6.0 T24 D9 4.5 LnCAP A6 3.8 T24 D10 0.7 LnCAP A7 7.2 T24 D11 1.8 LnCAP A8 10.7 T24 D12 0.3 LnCAP A9 14.6 T24 D13 1.5 LnCAP A10 3.1 T24 D15 2.6 LnCAP A11 7.9 T24 D16 0.5 LnCAP A12 2.9 T24 D17 1.2 LnCAP A13 1.7 CAPaN B1 68.8 LnCAP A14 3.0 CAPaN B2 36.9 LnCAP A15 3.2 CAPaN B3 16.5 LnCAP A16 9.3 CAPaN B4 28.3 LnCAP A17 7.3 CAPaN B5 44.1 Primary Astrocytes 2.3 CAPaN B6 44.4 Primary Renal Proximal Tubule Epithelial 1.9 cell A2 CAPaN B7 34.9 Primary melanocytes A5 0.5 CAPaN B8 34.2 126443 - 341 medullo 0.5 CAPaN B9 45.1 126444 - 487 medullo 9.6 CAPaN B10 47.3 126445 - 425 medullo 0.0 CAPaN B11 51.1 126446 - 690 medullo 2.8 CAPaN B12 64.2 126447 - 54 adult glioma 1.1 CAPaN B13 29.7 126448 - 245 adult glioma 0.1 CAPaN B14 26.4 126449 - 317 adult glioma 0.4 CAPaN B15 16.4 126450 - 212 glioma 0.2 CAPaN B16 77.4 126451 - 456 glioma 0.6 CAPaN B17 100.0 Column A Rel.Exp. (%) Ag3035, Run 259153969

[0651] 87 TABLE DE Oncology_cell_line_screening_panel_v3.2 Tissue Name A Tissue Name A 94905_Daoy_Medulloblastoma/Cerebellum_ssc 0.2 94954_Ca Ski_Cervical epidermoid 8.4 DNA carcinoma (metastasis)_sscDNA 94906_TE671_Medulloblastoma/Cerebellum_ssc 0.5 94955_ES-2_Ovarian clear cell 0.0 DNA carcinoma_sscDNA 94907_D283 0.2 94957_Ramos/6 h stim_Stimulated with 0.0 Med_Medulloblastoma/Cerebellum_sscDNA PMA/ionomycin 6 h_sscDNA 94908_PFSK-1_Primitive 0.0 94958_Ramos/14 h stim_Stimulated 0.0 Neuroectodermal/Cerebellum_sscDNA with PMA/ionomycin 14 h_sscDNA 94909_XF-498_CNS_sscDNA 0.2 94962_MEG-01_Chronic myelogenous 0.0 leukemia (megokaryoblast)_sscDNA 94910_SNB-78_CNS/glioma_sscDNA 0.5 94963_Raji_Burkitt's 0.0 lymphoma_sscDNA 94911_SF-268_CNS/glioblastoma_sscDNA 0.3 94964_Daudi_Burkitt's 0.0 lymphoma_sscDNA 94912_T98G_Glioblastoma_sscDNA 0.5 94965_U266_B-cell 0.0 plasmacytoma/myeloma_sscDNA 96776_SK-N-SH_Neuroblastoma 0.0 94968_CA46_Burkitt's 0.0 (metastasis)_sscDNA lymphoma_sscDNA 94913_SF-295_CNS/glioblastoma_sscDNA 0.6 94970_RL_non-Hodgkin's B-cell 0.0 lymphoma_sscDNA 132565_NT2pool_sscDNA 3.9 94972_JM1_pre-B-cell 1.1 lymphoma/leukemia_sscDNA 94914_Cerebellum_sscDNA 0.7 94973_Jurkat_T cell leukemia_sscDNA 0.0 96777_Cerebellum_sscDNA 0.8 94974_TF-1_Erythroleukemia_sscDNA 0.0 94916_NCI-H292_Mucoepidermoid lung 11.7 94975_HUT 78_T-cell 0.1 carcinoma_sscDNA lymphoma_sscDNA 94917_DMS-114_Small cell lung 0.3 94977_U937_Histocytic 0.0 cancer_sscDNA lymphoma_sscDNA 94918_DMS-79_Small cell lung 100.0 94980_KU-812_Myelogenous 1.3 cancer/neuroendocrine_sscDNA leukemia_sscDNA 94919_NCI-H146_Small cell lung 16.4 94981_769-P_Clear cell renal 1.9 cancer/neuroendocrine_sscDNA carcinoma_sscDNA 94920_NCI-H526_Small cell lung 0.0 94983_Caki-2_Clear cell renal 1.8 cancer/neuroendocrine_sscDNA carcinoma_sscDNA 94921_NCI-N417_Small cell lung 0.0 94984_SW 839_Clear cell renal 0.8 cancer/neuroendocrine_sscDNA carcinoma_sscDNA 94923_NCI-H82_Small cell lung 0.4 94986_G401_Wilms' tumor_sscDNA 0.4 cancer/neuroendocrine_sscDNA 94924_NCI-H157_Squamous cell lung cancer 2.4 126768_293 cells_sscDNA 1.9 (metastasis)_sscDNA 94925_NCI-H1155_Large cell lung 15.5 94987_Hs766T_Pancreatic carcinoma 2.1 cancer/neuroendocrine_sscDNA (LN metastasis)_sscDNA 94926_NCI-H1299_Large cell lung 3.4 94988_CAPAN-1_Pancreatic 3.2 cancer/neuroendocrine_sscDNA adenocarcinoma (liver metastasis)_sscDNA 94927_NCI-H727_Lung carcinoid_sscDNA 9.5 94989_SU86.86_Pancreatic carcinoma 1.6 (liver metastasis)_sscDNA 94928_NCI-UMC-11_Lung carcinoid_sscDNA 20.2 94990_BxPC-3_Pancreatic 3.0 adenocarcinoma_sscDNA 94929_LX-1_Small cell lung cancer_sscDNA 0.0 94991_HPAC_Pancreatic 0.9 adenocarcinoma_sscDNA 94930_Colo-205_Colon cancer_sscDNA 0.0 94992_MIA PaCa-2_Pancreatic 1.1 carcinoma_sscDNA 94931_KM12_Colon cancer_sscDNA 0.0 94993_CFPAC-1_Pancreatic ductal 0.2 adenocarcinoma_sscDNA 94932_KM20L2_Colon cancer_sscDNA 0.0 94994_PANC-1_Pancreatic epithelioid 22.8 ductal carcinoma_sscDNA 94933_NCI-H716_Colon cancer_sscDNA 4.3 94996_T24_Bladder carcinma 0.2 (transitional cell)_sscDNA 94935_SW-48_Colon adenocarcinoma_sscDNA 0.0 94997_5637_Bladder 0.5 carcinoma_sscDNA 94936_SW1116_Colon 1.2 94998_HT-1197_Bladder 12.5 adenocarcinoma_sscDNA carcinoma_sscDNA 94937_LS 174T_Colon 0.6 94999_UM-UC-3_Bladder carcinma 0.0 adenocarcinoma_sscDNA (transitional cell)_sscDNA 94938_SW-948_Colon 0.0 95000_A204_Rhabdomyosarcoma_ssc 0.0 adenocarcinoma_sscDNA DNA 94939_SW-480_Colon 0.0 95001_HT-1080_Fibrosarcoma_sscDNA 1.6 adenocarcinoma_sscDNA 94940_NCI-SNU-5_Gastric carcinoma_sscDNA 6.9 95002_MG-63_Osteosarcoma 14.7 (bone)_sscDNA 112197_KATO III_Stomach_sscDNA 0.3 95003_SK-LMS-1_Leiomyosarcoma 0.0 (vulva)_sscDNA 94943_NCI-SNU-16_Gastric 0.6 95004_SJRH30_Rhabdomyosarcoma 1.3 carcinoma_sscDNA (met to bone marrow)_sscDNA 94944_NCI-SNU-1_Gastric carcinoma_sscDNA 2.9 95005_A431_Epidermoid 5.9 carcinoma_sscDNA 94946_RF-1_Gastric adenocarcinoma_sscDNA 0.0 95007_WM266-4_Melanoma_sscDNA 0.0 94947_RF-48_Gastric 0.0 112195_DU 145_Prostate_sscDNA 1.1 adenocarcinoma_sscDNA 96778_MKN-45_Gastric carcinoma_sscDNA 0.6 95012_MDA-MB-468_Breast 2.2 adenocarcinoma_sscDNA 94949_NCI-N87_Gastric carcinoma_sscDNA 3.9 112196_SSC-4_Tongue_sscDNA 2.6 94951_OVCAR-5_Ovarian carcinoma_sscDNA 1.3 112194_SSC-9_Tongue_sscDNA 3.3 94952_RL95-2_Uterine carcinoma_sscDNA 3.0 112191_SSC-15_Tongue_sscDNA 1.8 94953_HelaS3_Cervical 1.7 95017_CAL 27_Squamous cell 1.2 adenocarcinoma_sscDNA carcinoma of tongue_sscDNA Column A - Rel. Exp.(%) Ag3035, Run 259180377

[0652] 88 TABLE DF Panel 1.3D Tissue Name A B C Tissue Name A B C Liver adenocarcinoma 22.4 19.6 71.2 Kidney (fetal) 2.1 0.0 2.7 Pancreas 3.9 2.5 2.8 Renal ca. 786-0 0.0 0.0 0.0 Pancreatic ca. CAPAN 2 5.3 3.5 9.5 Renal ca. A498 10.2 5.3 9.2 Adrenal gland 2.1 0.6 2.0 Renal ca. RXF 393 0.0 0.0 0.0 Thyroid 7.0 9.8 3.9 Renal ca. ACHN 0.0 2.2 0.0 Salivary gland 1.9 2.1 4.2 Renal ca. UO-31 0.0 0.0 0.0 Pituitary gland 1.0 2.2 6.7 Renal ca. TK-10 0.0 0.0 0.0 Brain (fetal) 6.8 4.9 10.8 Liver 0.0 0.0 0.0 Brain (whole) 4.8 3.0 1.4 Liver (fetal) 7.6 0.0 0.0 Brain (amygdala) 4.6 5.3 1.5 Liver ca. (hepatoblast) HepG2 0.0 0.0 0.0 Brain (cerebellum) 1.6 1.6 2.0 Lung 14.3 15.8 9.2 Brain (hippocampus) 7.5 11.3 0.6 Lung (fetal) 15.1 15.4 7.4 Brain (substantia nigra) 1.2 2.6 1.3 Lung ca. (small cell) LX-1 1.6 0.0 0.0 Brain (thalamus) 2.5 1.7 2.6 Lung ca. (small cell) NCI-H69 29.5 19.1 31.2 Cerebral Cortex 0.0 0.0 5.0 Lung ca. (s. cell var.) SHP-77 11.0 5.1 37.4 Spinal cord 1.7 2.1 2.7 Lung ca. (large cell)NCI-H460 0.0 0.0 0.0 glio/astro U87-MG 0.0 0.0 0.0 Lung ca. (non-sm. cell) A549 0.0 1.2 1.6 glio/astro U-118-MG 55.1 50.3 42.9 Lung ca. (non-s. cell) NCI-H23 0.0 1.3 0.8 astrocytoma SW1783 0.0 7.5 0.0 Lung ca. (non-s. cell) HOP-62 0.0 1.7 0.0 neuro*; met SK-N-AS 0.0 0.0 0.7 Lung ca. (non-s. cl) NCI-H522 8.0 8.3 7.3 astrocytoma SF-539 1.9 4.7 9.9 Lung ca. (squam.) SW 900 4.0 0.0 1.8 astrocytoma SNB-75 2.0 4.9 6.9 Lung ca. (squam.) NCI-H596 15.8 10.2 58.2 glioma SNB-19 6.7 2.4 3.7 Mammary gland 7.2 4.1 4.4 glioma U251 2.1 4.5 6.8 Breast ca.* (pl. ef) MCF-7 1.7 3.4 7.3 glioma SF-295 10.0 0.6 4.6 Breast ca.* (pl. ef) 23.2 19.6 19.2 MDA-MB-231 Heart (fetal) 11.1 9.9 38.2 Breast ca.* (pl. ef) T47D 4.3 5.8 21.8 Heart 4.9 6.0 15.2 Breast ca. BT-549 0.0 4.2 2.2 Skeletal muscle (fetal) 100.0 100.0 85.3 Breast ca. MDA-N 0.0 0.0 0.0 Skeletal muscle 5.5 8.4 39.8 Ovary 3.6 3.1 8.1 Bone marrow 0.0 0.0 0.7 Ovarian ca. OVCAR-3 1.1 1.0 5.6 Thymus 10.0 3.9 6.4 Ovarian ca. OVCAR-4 0.0 0.0 0.7 Spleen 3.8 4.2 1.6 Ovarian ca. OVCAR-5 0.0 0.0 11.5 Lymph node 5.0 1.1 1.4 Ovarian ca. OVCAR-8 1.3 4.3 4.1 Colorectal 3.4 5.4 6.8 Ovarian ca. IGROV-1 0.0 0.0 8.1 Stomach 6.0 15.4 3.1 Ovarian ca.* (ascites) 7.5 16.0 100.0 SK-OV-3 Small intestine 15.9 18.7 2.3 Uterus 17.8 15.1 9.9 Colon ca. SW480 24.3 15.3 11.6 Placenta 4.6 8.2 2.1 Colon ca.* SW620(SW480 0.0 0.0 2.1 Prostate 3.6 5.3 0.6 met) Colon ca. HT29 0.0 0.0 0.0 Prostate ca.* (bone met)PC-3 1.7 1.5 6.1 Colon ca. HCT-116 3.8 0.6 3.3 Testis 21.9 14.6 1.6 Colon ca. CaCo-2 0.0 0.8 0.3 Melanoma Hs688(A).T 3.1 4.7 1.4 Colon ca. tissue(ODO3866) 2.3 0.0 1.6 Melanoma* (met) Hs688(B).T 0.4 1.3 0.0 Colon ca. HCC-2998 0.0 0.0 1.6 Melanoma UACC-62 0.0 0.0 0.0 Gastric ca.* (liver met) 16.7 14.9 15.3 Melanoma M14 0.0 0.0 0.0 NCI-N87 Bladder 1.6 3.2 3.0 Melanoma LOX IMVI 0.0 0.0 0.0 Trachea 24.3 33.7 5.7 Melanoma* (met) SK-MEL-5 0.0 2.0 0.7 Kidney 0.0 0.0 0.0 Adipose 6.7 7.2 21.2 Colun A - Rel. Exp.(%) Ag2261, Run 150631675 Column B - Rel. Exp.(%) Ag2261, Run 152887692 Column C - Rel. Exp.(%) Ag3035, Run 167597764

[0653] 89 TABLE DG Panel 2D Tissue Name A B Tissue Name A B Normal Colon 19.1 19.8 Kidney Margin 8120608 2.4 0.0 CC Well to Mod Diff (ODO3866) 0.0 5.8 Kidney Cancer 8120613 14.6 7.3 CC Margin (ODO3866) 19.5 12.5 Kidney Margin 8120614 4.8 1.5 CC Gr.2 rectosigmoid (ODO3868) 3.8 1.4 Kidney Cancer 9010320 0.0 0.0 CC Margin (ODO3868) 2.6 5.1 Kidney Margin 9010321 0.0 0.0 CC Mod Diff (ODO3920) 6.0 2.9 Normal Uterus 9.7 2.8 CC Margin (ODO3920) 23.8 6.4 Uterus Cancer 064011 85.9 41.5 CC Gr.2 ascend colon (ODO3921) 9.3 2.2 Normal Thyroid 15.2 7.3 CC Margin (ODO3921) 16.8 11.7 Thyroid Cancer 064010 0.0 3.0 CC from Partial Hepatectomy 2.4 0.0 Thyroid Cancer A302152 1.9 1.2 (ODO4309) Mets Liver Margin (ODO4309) 2.6 0.0 Thyroid Margin A302153 2.6 2.8 Colon mets to lung (OD04451-01) 7.9 4.5 Normal Breast 16.2 2.7 Lung Margin (OD04451-02) 11.3 12.9 Breast Cancer (OD04566) 78.5 29.7 Normal Prostate 6546-1 6.3 2.6 Breast Cancer (OD04590-01) 37.6 23.8 Prostate Cancer (OD04410) 17.8 7.3 Breast Cancer Mets 100.0 24.5 (OD04590-03) Prostate Margin (OD04410) 10.7 7.4 Breast Cancer Metastasis 94.0 45.4 (OD04655-05) Prostate Cancer (OD04720-01) 4.7 4.4 Breast Cancer 064006 25.7 24.8 Prostate Margin (OD04720-02) 13.9 5.6 Breast Cancer 1024 23.2 7.1 Normal Lung 061010 36.6 14.3 Breast Cancer 9100266 33.0 7.5 Lung Met to Muscle (ODO4286) 1.0 0.0 Breast Margin 9100265 7.6 7.6 Muscle Margin (ODO4286) 31.0 38.2 Breast Cancer A209073 13.9 0.9 Lung Malignant Cancer (OD03126) 81.8 100.0 Breast Margin A209073 2.5 0.0 Lung Margin (OD03126) 35.8 18.2 Normal Liver 0.0 0.0 Lung Cancer (OD04404) 57.0 39.5 Liver Cancer 064003 0.0 0.0 Lung Margin (OD04404) 9.4 11.8 Liver Cancer 1025 4.8 1.7 Lung Cancer (OD04565) 37.1 42.0 Liver Cancer 1026 7.1 0.0 Lung Margin (OD04565) 22.7 9.3 Liver Cancer 6004-T 4.8 0.0 Lung Cancer (OD04237-01) 5.3 6.4 Liver Tissue 6004-N 4.4 1.8 Lung Margin (OD04237-02) 78.5 32.8 Liver Cancer 6005-T 0.0 6.0 Ocular Mel Met to Liver (ODO4310) 0.0 0.0 Liver Tissue 6005-N 0.0 1.8 Liver Margin (ODO4310) 2.4 0.0 Normal Bladder 2.4 3.0 Melanoma Mets to Lung (OD04321) 13.0 0.0 Bladder Cancer 1023 8.5 4.9 Lung Margin (OD04321) 96.6 50.0 Bladder Cancer A302173 17.0 11.8 Normal Kidney 0.0 0.0 Bladder Cancer (OD04718-01) 10.0 5.7 Kidney Ca, Nuclear grade 2 0.0 0.0 Bladder Normal Adjacent 19.3 27.5 (OD04338) (OD04718-03) Kidney Margin (OD04338) 4.0 4.6 Normal Ovary 13.6 12.4 Kidney Ca Nuclear grade 1/2 0.0 3.3 Ovarian Cancer 064008 37.9 2.1 (OD04339) Kidney Margin (OD04339) 18.7 0.0 Ovarian Cancer (OD04768-07) 18.4 3.7 Kidney Ca, Clear cell type (OD04340) 8.8 11.7 Ovary Margin (OD04768-08) 28.3 12.2 Kidney Margin (OD04340) 0.0 2.0 Normal Stomach 48.3 17.3 Kidney Ca, Nuclear grade 3 3.5 4.0 Gastric Cancer 9060358 0.0 0.0 (OD04348) Kidney Margin (OD04348) 2.0 1.7 Stomach Margin 9060359 9.9 3.0 Kidney Cancer (OD04622-01) 9.3 0.0 Gastric Cancer 9060395 20.7 10.4 Kidney Margin (OD04622-03) 0.0 6.3 Stomach Margin 9060394 10.0 12.2 Kidney Cancer (OD04450-01) 0.0 0.0 Gastric Cancer 9060397 8.7 1.5 Kidney Margin (OD04450-03) 0.0 0.0 Stomach Margin 9060396 7.5 6.2 Kidney Cancer 8120607 0.0 0.7 Gastric Cancer 064005 10.7 4.8 Colmn A - Rel. Exp.(%) Ag2261, Run 150811744 Column B - Rel. Exp.(%) Ag2261, Run 152887693

[0654] 90 TABLE DH Panel 4.1D Tissue Name A B Tissue Name A B Secondary Th1 act 0.0 0.0 HUVEC IL-1beta 1.7 0.0 Secondary Th2 act 0.0 0.0 HUVEC IFN gamma 0.8 11.8 Secondary Tr1 act 0.0 0.0 HUVEC TNF alpha + IFN gamma 0.2 0.0 Secondary Th1 rest 0.0 0.0 HUVEC TNF alpha + IL4 0.6 4.5 Secondary Th2 rest 0.0 2.0 HUVEC IL-11 1.1 17.2 Secondary Tr1 rest 0.0 0.0 Lung Microvascular EC none 2.7 7.2 Primary Th1 act 0.0 0.0 Lung Microvascular EC TNF alpha + IL-1beta 0.6 0.0 Primary Th2 act 0.0 0.0 Microvascular Dermal EC none 3.8 0.0 Primary Tr1 act 0.0 0.0 Microsvasular Dermal EC TNF alpha + IL-1beta 1.2 0.0 Primary Th1 rest 0.0 0.0 Bronchial epithelium TNF alpha + IL1beta 3.7 5.0 Primary Th2 rest 0.0 0.0 Small airway epithelium none 1.9 10.7 Primary Tr1 rest 0.0 0.0 Small airway epithelium TNF alpha + IL-1beta 4.0 24.5 CD45RA CD4 lymphocyte act 0.0 2.3 Coronery artery SMC rest 0.2 2.2 CD45RO CD4 lymphocyte act 0.0 0.0 Coronery artery SMC TNF alpha + IL-1beta 0.0 0.0 CD8 lymphocyte act 0.0 0.0 Astrocytes rest 2.4 7.9 Secondary CD8 lymphocyte rest 0.0 0.0 Astrocytes TNF alpha + IL-1beta 1.3 0.0 Secondary CD8 lymphocyte act 0.0 0.0 KU-812 (Basophil) rest 0.0 2.3 CD4 lymphocyte none 0.0 0.0 KU-812 (Basophil) PMA/ionomycin 2.1 4.5 2ry Th1/Th2/Tr1_anti-CD95 0.0 0.0 CCD1106 (Keratinocytes) none 22.2 100.0 CH11 LAK cells rest 0.0 4.7 CCD1106 (Keratinocytes) TNF alpha + IL-1beta 18.8 52.5 LAK cells IL-2 0.0 0.0 Liver cirrhosis 0.7 4.2 LAK cells IL-2 + IL-12 0.0 0.0 NCI-H292 none 0.4 0.0 LAK cells IL-2 + IFN gamma 0.0 0.0 NCI-H292 IL-4 1.5 0.0 LAK cells IL-2 + IL-18 0.0 3.0 NCI-H292 IL-9 2.0 8.8 LAK cells PMA/ionomycin 11.0 42.0 NCI-H292 IL-13 1.4 17.8 NK Cells IL-2 rest 0.0 5.2 NCI-H292 IFN gamma 1.5 6.9 Two Way MLR 3 day 0.0 0.0 HPAEC none 3.1 18.7 Two Way MLR 5 day 0.0 0.0 HPAEC TNF alpha + IL-1beta 0.5 0.0 Two Way MLR 7 day 0.0 0.0 Lung fibroblast none 6.2 29.9 PBMC rest 0.0 0.0 Lung fibroblast TNF alpha + IL-1beta 2.1 0.0 PBMC PWM 0.5 0.0 Lung fibroblast IL-4 4.2 9.8 PBMC PHA-L 0.4 0.0 Lung fibroblast IL-9 8.3 25.3 Ramos (B cell) none 0.0 0.0 Lung fibroblast IL-13 4.0 3.9 Ramos (B cell) ionomycin 0.0 0.0 Lung fibroblast IFN gamma 8.1 59.5 B lymphocytes PWM 0.0 0.0 Dermal fibroblast CCD1070 rest 0.4 0.0 B lymphocytes CD40L and IL-4 0.0 0.0 Dermal fibroblast CCD1070 TNF alpha 0.9 4.1 EOL-1 dbcAMP 0.0 2.7 Dermal fibroblast CCD1070 IL-1beta 2.9 0.0 EOL-1 dbcAMP PMA/ionomycin 1.0 1.7 Dermal fibroblast IFN gamma 5.8 41.8 Dendritic cells none 0.0 0.0 Dermal fibroblast IL-4 17.2 62.4 Dendritic cells LPS 0.0 0.0 Dermal Fibroblast rest 4.8 12.9 Dendritic cells anti-CD40 0.0 0.0 Neutrophils TNFa + LPS 1.0 0.0 Monocytes rest 0.0 0.0 Neutrophils rest 2.2 2.3 Monocytes LPS 0.6 0.0 Colon 2.6 0.0 Macrophages rest 0.0 0.0 Lung 8.8 0.0 Macrophages LPS 0.0 0.0 Thymus 17.1 1.8 HUVEC none 2.4 7.6 Kidney 100.0 0.0 HUVEC starved 8.8 22.1 Colun A - Rel. Exp.(%) Ag3035, Run 190944495 Column B - Rel. Exp.(%) Ag3035, Run 259180379

[0655] 91 TABLE DI Panel 4D Tissue Name A B Tissue Name A B Secondary Th1 act 0.0 2.1 HUVEC IL-1beta 0.0 1.7 Secondary Th2 act 0.0 0.0 HUVEC IFN gamma 3.7 11.5 Secondary Tr1 act 0.0 4.2 HUVEC TNF alpha + IFN gamma 0.0 3.1 Secondary Th1 rest 0.0 0.0 HUVEC TNF alpha + IL4 4.3 5.1 Secondary Th2 rest 0.0 2.3 HUVEC IL-11 4.0 11.2 Secondary Tr1 rest 0.0 0.0 Lung Microvascular EC none 7.2 8.1 Primary Th1 act 0.0 0.0 Lung Microvascular EC TNF alpha + IL-1beta 0.0 0.0 Primary Th2 act 0.0 0.0 Microvascular Dermal EC none 8.4 14.5 Primary Tr1 act 0.0 0.0 Microvasular Dermal EC TNF alpha + IL-1beta 0.0 2.2 Primary Th1 rest 0.0 0.0 Bronchial epithelium TNF alpha + IL1beta 0.0 16.3 Primary Th2 rest 0.0 0.0 Small airway epithelium none 5.9 18.8 Primary Tr1 rest 0.0 0.0 Small airway epithelium TNF alpha + IL-1beta 24.3 58.6 CD45RA CD4 lymphocyte act 0.0 0.0 Coronery artery SMC rest 0.0 2.0 CD45RO CD4 lymphocyte act 0.0 0.0 Coronery artery SMC TNF alpha + IL-1beta 0.0 0.0 CD8 lymphocyte act 0.0 0.0 Astrocytes rest 3.3 13.5 Secondary CD8 lymphocyte rest 0.0 0.7 Astrocytes TNF alpha + IL-1beta 0.0 8.6 Secondary CD8 lymphocyte act 1.6 0.0 KU-812 (Basophil) rest 0.0 0.0 CD4 lymphocyte none 0.0 0.0 KU-812 (Basophil) PMA/ionomycin 0.0 9.7 2ry Th1/Th2/Tr1_anti-CD95 0.0 1.4 CCD1106 (Keratinocytes) none 47.3 100.0 CH11 LAK cells rest 3.5 0.0 CCD1106 (Keratinocytes) TNF alpha + IL-1beta 9.0 53.6 LAK cells IL-2 0.0 0.0 Liver cirrhosis 32.8 9.4 LAK cells IL-2 + IL-12 0.0 0.0 Lupus kidney 0.0 1.6 LAK cells IL-2 + IFN gamma 0.0 4.0 NCI-H292 none 3.8 3.4 LAK cells IL-2 + IL-18 0.0 0.0 NCI-H292 IL-4 8.0 19.5 LAK cells PMA/ionomycin 26.1 50.7 NCI-H292 IL-9 0.0 4.2 NK Cells IL-2 rest 0.0 0.0 NCI-H292 IL-13 13.8 7.0 Two Way MLR 3 day 0.0 0.0 NCI-H292 IFN gamma 16.2 5.7 Two Way MLR 5 day 0.0 0.0 HPAEC none 6.7 30.1 Two Way MLR 7 day 0.0 0.0 HPAEC TNF alpha + IL-1beta 0.0 0.0 PBMC rest 0.0 0.0 Lung fibroblast none 7.6 42.0 PBMC PWM 0.0 0.0 Lung fibroblast TNF alpha + IL-1beta 3.1 6.3 PBMC PHA-L 0.0 0.0 Lung fibroblast IL-4 4.3 34.2 Ramos (B cell) none 0.0 0.0 Lung fibroblast IL-9 12.7 27.5 Ramos (B cell) ionomycin 0.0 0.0 Lung fibroblast IL-13 6.8 19.9 B lymphocytes PWM 0.0 0.0 Lung fibroblast IFN gamma 30.4 51.1 B lymphocytes CD40L and IL-4 3.1 0.0 Dermal fibroblast CCD1070 rest 0.0 2.8 EOL-1 dbcAMP 0.0 0.0 Dermal fibroblast CCD1070 TNF alpha 5.2 19.6 EOL-1 dbcAMP PMA/ionomycin 3.5 2.7 Dermal fibroblast CCD1070 IL-1beta 0.0 2.0 Dendritic cells none 0.0 0.0 Dermal fibroblast IFN gamma 28.5 32.1 Dendritic cells LPS 0.0 0.0 Dermal fibroblast IL-4 42.9 91.4 Dendritic cells anti-CD40 0.0 0.0 IBD Colitis 2 2.2 5.5 Monocytes rest 0.0 0.0 IBD Crohn's 3.1 9.6 Monocytes LPS 0.0 0.0 Colon 100.0 58.6 Macrophages rest 0.0 0.0 Lung 36.3 26.1 Macrophages LPS 0.0 0.0 Thymus 0.0 0.0 HUVEC none 0.0 17.7 Kidney 4.0 33.0 HUVEC starved 17.4 51.1 Column A - Rel. Exp. (%) Ag2261, Run 152887762 Column B - Rel. Exp. (%) Ag3035, Run 165242424

[0656] 92 TABLE DJ Panel 5 Islet Tissue Name A Tissue Name A 97457_Patient-02go_adipose 19.3 94709_Donor 2 AM - A_adipose 0.8 97476_Patient-07sk_skeletal muscle 13.0 94710_Donor 2 AM - B_adipose 0.0 97477_Patient-07ut_uterus 5.3 94711_Donor 2 AM - C_adipose 1.8 97478_Patient-07pl_placenta 1.4 94712_Donor 2 AD - A_adipose 5.3 99167_Bayer Patient 1 89.5 94713_Donor 2 AD - B_adipose 3.2 97482_Patient-08ut_uterus 9.6 94714_Donor 2 AD - C_adipose 0.0 97483_Patient-08pl_placenta 7.4 94742_Donor 3 U - A_Mesenchymal Stem 2.6 Cells 97486_Patient-09sk_skeletal muscle 10.7 94743_Donor 3 U - B_Mesenchymal Stem 2.6 Cells 97487_Patient-09ut_uterus 4.7 94730_Donor 3 AM - A_adipose 0.8 97488_Patient-09pl_placenta 3.6 94731_Donor 3 AM - B_adipose 1.7 97492_Patient-10ut_uterus 6.1 94732_Donor 3 AM - C_adipose 1.5 97493_Patient-10pl_placenta 6.8 94733_Donor 3 AD - A_adipose 4.8 97495_Patient-11go_adipose 1.6 94734_Donor 3 AD - B_adipose 2.0 97496_Patient-11sk_skeletal muscle 20.7 94735_Donor 3 AD - C_adipose 2.5 97497_Patient-11ut_uterus 3.2 77138_Liver_HepG2untreated 0.0 97498_Patient-11pl_placenta 1.8 73556_Heart_Cardiac stromal cells 0.0 (primary) 97500_Patient-12go_adipose 8.5 81735_Small Intestine 15.6 97501_Patient-12sk_skeletal muscle 100.0 72409_Kidney_Proximal Convoluted 0.0 Tubule 97502_Patient-12ut_uterus 2.2 82685_Small intestine_Duodenum 5.9 97503_Patient-12pl_placenta 0.0 90650_Adrenal_Adrenocortical adenoma 2.9 94721_Donor 2 U - A_Mesenchymal 0.0 72410_Kidney_HRCE 7.5 Stem Cells 94722_Donor 2 U - B_Mesenchymal Stem 1.5 72411_Kidney_HRE 3.3 Cells 94723_Donor 2 U - C_Mesenchymal Stem 1.5 73139_Uterus_Uterine smooth muscle cells 0.0 Cells Colun A - Rel. Exp.(%) Ag3035, Run 259234350

[0657] 93 TABLE DK general oncology screening panel_v_2.4 Tissue Name A Tissue Name A Colon cancer 1 7.6 Bladder cancer NAT 2 0.0 Colon cancer NAT 1 14.7 Bladder cancer NAT 3 0.0 Colon cancer 2 3.7 Bladder cancer NAT 4 25.7 Colon cancer NAT 2 10.0 Prostate adenocarcinoma 1 8.3 Colon cancer 3 7.3 Prostate adenocarcinoma 2 1.6 Colon cancer NAT 3 25.9 Prostate adenocarcinoma 3 3.4 Colon malignant cancer 4 1.7 Prostate adenocarcinoma 4 9.5 Colon normal adjacent tissue 1.6 Prostate cancer NAT 5 2.4 4 Lung cancer 1 9.5 Prostate adenocarcinoma 6 0.0 Lung NAT 1 2.9 Prostate adenocarcinoma 7 4.9 Lung cancer 2 42.3 Prostate adenocarcinoma 8 0.0 Lung NAT 2 23.3 Prostate adenocarcinoma 9 20.6 Squamous cell carcinoma 3 73.7 Prostate cancer NAT 10 0.4 Lung NAT 3 1.3 Kidney cancer 1 1.9 metastatic melanoma 1 37.1 KidneyNAT 1 8.1 Melanoma 2 9.4 Kidney cancer 2 34.4 Melanoma 3 1.4 Kidney NAT 2 7.6 metastatic melanoma 4 100.0 Kidney cancer 3 12.9 metastatic melanoma 5 39.8 Kidney NAT 3 4.5 Bladder cancer 1 2.9 Kidney cancer 4 3.4 Bladder cancer NAT 1 0.0 Kidney NAT 4 5.9 Bladder cancer 2 3.2 Column A - Rel. Exp.(%) Ag3035, Run 259737910

[0658] AI_comprehensive panel_v1.0 Summary: Ag3035 Highest expression of this gene is detected in a COPD sample (CT=30). Moderate levels of expression of this gene are detected in samples derived from normal and orthoarthitis/rheumatoid arthritis bone and adjacent bone, cartilage, synovium and synovial fluid samples, from normal lung, COPD lung, emphysema, atopic asthma, asthma, allergy, Crohn's disease (normal matched control and diseased), ulcerative colitis (normal matched control and diseased), and psoriasis (normal matched control and diseased). Therefore, therapeutic modulation of this gene product may ameliorate symptoms/conditions associated with autoimmune and inflammatory disorders including psoriasis, allergy, asthma, inflammatory bowel disease, rheumatoid arthritis and osteoarthritis.

[0659] HASS Panel v1.0 Summary: Ag3035 Expression is seen at a low level in LnCAP, T24, MCF-7 cell lines and at a moderate level in CaPan cell line. The expression is slightly increased by a decrease in oxygen tension in LnCAP cell line but not in any other cell line suggesting a specific induction inthis prostate cancer cell line. A low level of expression is also seen in 2 of 4 medulloblastomas and primary astrocytes and primary renal proximal tubular epithelial cells.

[0660] Oncology_cell_line_screening_panel_v3.2 Summary: Ag3035 Highest expression of this gene is seen in a lung cancer DMS-79 cell line (28.6). Moderate to low expression of this gene is seen in number of cancer cell lines derived from tongue, bone, bladder, pancreatic, cervical, uterine, gastric, colon and lung cancer. Therefore, expression of this gene may be used as marker to detect the presence of these cancer. Furthermore, therapeutic modulation of the activity of this gene or its protein product may be useful in the treatment of these cancers.

[0661] Panel 1.3D Summary: Ag2261 This gene is expressed at moderate levels in a number of metabolic tissues, with highest overall expression seen in fetal skeletal muscle (CTs=30.4-31.8). The higher levels of expression in fetal skeletal muscle when compared to adult skeletal muscle suggests that the protein product encoded by this gene may be useful in treating muscular dystrophy, Lesch-Nyhan syndrome, myasthenia gravis and other conditions that result in weak or dystrophic muscle. This gene is also expressed in adipose, thyroid and heart. Since biologic cross-talk between adipose and thyroid is a component of some forms of obesity, this gene product may be a protein therapeutic for the treatment of metabolic disease, including obesity and Type 2 diabetes.

[0662] Ag3035 This probe/primer set recognizes a distinct portion of this gene and shows a distinctive expression pattern when compared to Ag2261. This observation may indicate that the probe/primer sets can distinguish splice variants of this gene. Expression of this gene is highest in an ovarian cancer cell line (CT=30.6). As is the case for probe-primer set Ag2261, expression of this gene using probe-primer Ag3035 also shows relatively high levels in fetal skeletal muscle. However, in addition, this gene shows increased levels of this gene in adult skeletal muscle as well as in adult and fetal heart. Most other expression is similar using both probe/primer sets.

[0663] Panel 2D Summary: Ag2261 The expression of this gene was assessed in two independent runs on panel 2D. This gene was found to be consistently expressed in samples of breast cancer, uterine cancer and lung cancer when compared to their respective normal adjacent tissue controls. Thus, the expression of this gene could be used to distinguish breast cancer, lung cancer or uterine cancer from their normal tissues. Moreover, therapeutic modulation of this gene, through the use of small molecule drugs, antibodies or protein therapeutics might be of use in the treatment of breast, lung or uterine cancer.

[0664] Panel 4.1D Summary: Ag3035 This probe/primer set recognizes a distinct portion of this gene and shows a distinctive expression pattern when compared to Ag2261 in Panel 4D. This observation may indicate that the probe/primer sets can distinguish splice variants of this gene. Expression of this gene is highest in kidney (CT=30.6). Expression in other samples in this panel is similar using both probe/primer sets. This gene, a WNT-14 homolog is also expressed at moderate to low levels in several unstimulated or cytokine-activated keratinocyte and lung and dermal fibroblast preparations (CT range 29-34). Thus, WNT-14 encoded by this gene may be useful as a protein therapeutic that reduces or eliminates the symptoms of chronic obstructive pulmonary disease, asthma, emphysema, or psoriasis. In addition, due to its known effects on development of vertebrate joints, the protein encoded by this gene may also reduce or eliminate the symptoms of osetoarthritis (See Hartmann and Tabin, 2001, Wnt-14 Plays a Pivotal Role in Inducing Synovial Joint Formation in the Developing Appendicular Skeleton Cell, Vol 104, 341-351).

[0665] Panel 4D Summary: Ag2261 This gene is expressed at low levels in colon (CT=33.5). Low but significant levels of expression are also found in the lung, keratinocytes and dermal fibroblast. Thus, this transcript could be used as a marker for thymic, lung and skin tissues. The putative Wnt-14 molecule encoded by this gene may play an important role in the normal homeostasis of these tissues. Therapeutics designed with the protein encoded by this gene could be important for maintaining or restoring normal function to these organs during inflammation.

[0666] Panel 5 Islet Summary: Ag3035 Highest expression of this gene is seen in a diabetic patient (CT=31.8). Significant expression of this gene is also seen in islet cells. Therefore, therapeutic modulation of the activity of this gene or its protein product may be useful in the treatment of metabolic related disease such as obesity and diabetes, especially type II diabetes.

[0667] General oncology screening panel_v—2.4 Summary: Ag3035 Highest expression of this gene is detected in metastatic melanoma (CT=31.3). Moderate to low expression of this gene is also seen in cancer and normal adjacent samples from lung, kidney, colon, prostate cancers. Expression of this gene is higher in metastatic melanoma, prostate, lung and kidney cancers. Therefore, expression of this gene may be used as marker to detect the presence of these cancers and also, therapeutic modulation of the activity of this gene or its protein product may be useful in the treatment of these cancers.

[0668] E. CG54818-01: Semaphorin 3E.

[0669] Expression of gene CG54818-01 was assessed using the primer-probe set Ag2060, described in Table EA. Results of the RTQ-PCR runs are shown in Tables EB, EC, ED, EE, EF, EG, EH, EI, EJ, EK, EL and EM. 94 TABLE EA Probe Name Ag2060 Start SEQ ID Primers Sequences Length Position No Forward 5′-atgtttcatgtcccaccattt-3′ 21 5174 162 Probe TET-5′-tttctccctctctctcccaacacaca-3′-TAMRA 26 5201 163 Reverse 5′-agtatgtgaggggtgtgtgtgt-3′ 22 5228 164

[0670] 95 TABLE EB AI comprehensive panel v1.0 Column A-Rel. Exp.(% Ag2060, Run 276596902 Tissue Name A 110967 COPD-F 1.0 110980 COPD-F 3.4 110968 COPD-M 1.3 110977 COPD-M 11.3 110989 Emphysema-F 1.3 110992 Emphysema-F 2.9 110993 Emphysema-F 1.1 110994 Emphysema-F 0.3 110995 Emphysema-F 3.8 110996 Emphysema-F 1.2 110997 Asthma-M 1.2 111001 Asthma-F 1.7 111002 Asthma-F 4.3 111003 Atopic Asthma-F 4.0 111004 Atopic Asthma-F 15.6 111005 Atopic Asthma-F 7.5 111006 Atopic Asthma-F 2.8 111417 Allergy-M 4.6 l12347 Allergy-M 0.1 112349 Normal Lung-F 0.1 112357 Normal Lung-F 0.3 112354 Normal Lung-M 1.3 112374 Crohns-F 0.6 112389 Match Control Crohns-F 1.8 112375 Crohns-F 0.2 112732 Match Control Crohns-F 0.3 112725 Crohns-M 0.9 112378 Match Control Crohns-M 0.2 112387 Crohns-M 0.2 112390 Match Control Crohns-M 7.8 112726 Crohns-M 1.8 112731 Match Control Crohns-M 3.6 112380 Ulcer Col-F 2.9 112734 Match Control Ulcer Col-F 2.2 112384 Ulcer Col-F 1.7 112737 Match Control Ulcer Col-F 0.9 112386 Ulcer Col-F 0.4 112738 Match Control Ulcer Col-F 2.1 112381 Ulcer Col-M 0.1 112735 Match Control Ulcer Col-M 0.3 112382 Ulcer Col-M 6.6 112394 Match Control Ulcer Col-M 0.7 112383 Ulcer Col-M 1.3 112736 Match Control Ulcer Col-M 1.1 112423 Psoriasis-F 1.0 112427 Match Contol Psoriasis-F 10.4 112418 Psoriasis-M 0.9 112723 Match Control Psoriasis-M 0.0 112419 Psoriasis-M 2.4 112424 Match Control Psoriasis-M 2.3 112420 Psoriasis-M 1.6 112425 Match Control Psoriasis-M 18.9 104689 (MF) OA Bone-Backus 10.7 104690 (MF) Adj “Normal” Bone-Backus 16.7 104691 (MF) OA Synovium-Backus 76.3 104692 (BA) OA Cartilage-Backus 100.0 104694 (BA) OA Bone-Backus 14.1 104695 (BA) Adj “Normal” Bone-Backus 24.1 104696 (BA) OA Synovium-Backus 26.1 104700 (55) OA Bone-Backus 6.7 104701 (55) Adj “Normal” Bone-Backus 15.0 104702 (55) OA Synovium-Backus 18.6 117093 OA Cartilage Rep7 0.4 112672 OA Bone5 1.1 112673 OA Synovium5 0.5 112674 OA Synovial Fluid cells5 0.9 117100 OA Cartilage Rep14 0.1 112756 OA Bone9 1.4 112757 OA Synovium9 0.4 112758 OA Synovial Fluid Cells9 0.7 117125 RA Cartilage Rep2 0.6 113492 Bone2 RA 9.0 113493 Synovium2 RA 4.9 113494 Syn Fluid Cells RA 8.8 113499 Cartilage4 RA 9.9 113500 Bone4 RA 13.5 113501 Synovium4 RA 10.5 113502 Syn Fluid Cells4 RA 7.3 113495 Cartilage3 RA 6.0 113496 Bone3 RA 7.9 113497 Synovium3 RA 3.7 113498 Syn Fluid Cells3 RA 6.5 117106 Normal Cartilage Rep20 0.0 113663 Bone3 Normal 0.0 113664 Synovium3 Normal 0.0 113665 Syn Fluid Cells3 Normal 0.1 117107 Normal Cartilage Rep22 0.1 113667 Bone4 Normal 1.1 113668 Synovium4 Normal 0.8 113669 Syn Fluid Cells4 Normal 1.1

[0671] 96 TABLE EC Ardais Panel v.1.0 Tissue Name A Tissue Name A 136799_Lung cancer(362) 2.6 136787_lung cancer(356) 15.4 136800_Lung NAT(363) 47.3 136788_lung NAT(357) 57.8 136813_Lung cancer(372) 8.9 136804_Lung cancer(369) 23.3 136814_Lung NAT(373) 47.3 136805_Lung NAT(36A) 40.6 136815_Lung cancer(374) 20.6 136806_Lung cancer(36B) 6.3 136816_Lung NAT(375) 10.3 136807_Lung NAT(36C) 29.9 136791_Lung cancer(35A) 45.4 136789_lung cancer(358) 4.4 136795_Lung cancer(35E) 97.9 136802_Lung cancer(365) 4.2 136797_Lung cancer(360) 2.0 136803_Lung cancer(368) 100.0 136794_lung NAT(35D) 33.9 136811_Lung cancer(370) 1.1 136818_Lung NAT(377) 39.2 136810_Lung NAT(36F) 60.7 Column A - Rel. Exp.(%) Ag2060, Run 267680190

[0672] 97 TABLE ED CNS neurodegeneration v1.0 Tissue Name A Tissue Name A AD 1 Hippo 9.7 Control (Path) 3 Temporal Ctx 0.7 AD 2 Hippo 32.8 Control (Path) 4 Temporal Ctx 11.6 AD 3 Hippo 3.1 AD 1 Occipital Ctx 24.3 AD 4 Hippo 7.1 AD 2 Occipital Ctx (Missing) 0.0 AD 5 hippo 100.0 AD 3 Occipital Ctx 3.0 AD 6 Hippo 35.1 AD 4 Occipital Ctx 15.0 Control 2 Hippo 49.0 AD 5 Occipital Ctx 17.8 Control 4 Hippo 2.8 AD 6 Occipital Ctx 28.7 Control (Path) 3 Hippo 2.0 Control 1 Occipital Ctx 1.5 AD 1 Temporal Ctx 9.3 Control 2 Occipital Ctx 62.0 AD 2 Temporal Ctx 26.1 Control 3 Occipital Ctx 23.7 AD 3 Temporal Ctx 1.6 Control 4 Occipital Ctx 1.9 AD 4 Temporal Ctx 15.3 Control (Path) 1 Occipital Ctx 97.3 AD 5 Inf Temporal Ctx 57.0 Control (Path) 2 Occipital Ctx 12.7 AD 5 SupTemporal Ctx 19.6 Control (Path) 3 Occipital Ctx 1.4 AD 6 Inf Temporal Ctx 25.5 Control (Path) 4 Occipital Ctx 12.6 AD 6 Sup Temporal Ctx 21.0 Control 1 Parietal Ctx 3.0 Control 1 Temporal Ctx 1.5 Control 2 Parietal Ctx 28.3 Control 2 Temporal Ctx 24.5 Control 3 Parietal Ctx 12.9 Control 3 Temporal Ctx 16.0 Control (Path) 1 Parietal Ctx 52.1 Control 4 Temporal Ctx 1.0 Control (Path) 2 Parietal Ctx 12.6 Control (Path) 1 33.0 Control (Path) 3 Parietal Ctx 1.5 Temporal Ctx Control (Path) 2 29.3 Control (Path) 4 Parietal Ctx 15.5 Temporal Ctx Column A - Rel. Exp.(% Ag2060, Run 206231411

[0673] 98 TABLE EE HASS Panel v1.0 Tissue Name A Tissue Name A MCF-7 C1 0.0 U87-MG F1 (B) 0.0 MCF-7 C2 0.0 U87-MG F2 0.0 MCF-7 C3 0.1 U87-MG F3 0.2 MCF-7 C4 0.1 U87-MG F4 0.3 MCF-7 C5 0.1 U87-MG F5 0.6 MCF-7 C6 0.0 U87-MG F6 0.8 MCF-7 C7 0.1 U87-MG F7 0.2 MCF-7 C9 0.2 U87-MG F8 0.6 MCF-7 C10 0.0 U87-MG F9 0.0 MCF-7 C11 0.0 U87-MG F10 0.2 MCF-7 C12 0.1 U87-MG F11 0.7 MCF-7 C13 0.1 U87-MG F12 0.6 MCF-7 C15 0.0 U87-MG F13 0.1 MCF-7 C16 0.1 U87-MG F14 0.2 MCF-7 C17 0.0 U87-MG F15 0.3 T24 D1 0.0 U87-MG F16 0.7 T24 D2 0.0 U87-MG F17 1.0 T24 D3 0.0 LnCAP A1 0.0 T24 D4 0.2 LnCAP A2 0.0 T24 D5 0.1 LnCAP A3 0.0 T24 D6 0.2 LnCAP A4 0.0 T24 D7 0.0 LnCAP A5 0.0 T24 D9 0.0 LnCAP A6 0.0 T24 D10 0.0 LnCAP A7 0.0 T24 D11 0.0 LnCAP A8 0.0 T24 D12 0.2 LnCAP A9 0.0 T24 D13 0.0 LnCAP A10 0.0 T24 D15 0.0 LnCAP A11 0.0 T24 D16 0.0 LnCAP A12 0.0 T24 D17 0.0 LnCAP A13 0.0 CAPaN B1 0.1 LnCAP A14 0.0 CAPaN B2 0.0 LnCAP A15 0.0 CAPaN B3 0.0 LnCAP A16 0.0 CAPaN B4 0.1 LnCAP A17 0.0 CAPaN B5 0.0 Primary Astrocytes 1.4 CAPaN B6 0.0 Primary Renal Proximal Tubule Epithelial 0.3 cell A2 CAPaN B7 0.1 Primary melanocytes A5 2.8 CAPaN B8 0.1 126443 - 341 medullo 0.0 CAPaN B9 0.0 126444 - 487 medullo 0.0 CAPaN B10 0.1 126445 - 425 medullo 0.0 CAPaN B11 0.0 126446 - 690 medullo 0.0 CAPaN B12 0.0 126447 - 54 adult glioma 1.4 CAPaN B13 0.1 126448 - 245 adult glioma 100.0 CAPaN B14 0.0 126449 - 317 adult glioma 6.7 CAPaN B15 0.0 126450 - 212 glioma 0.0 CAPaN B16 0.0 126451 - 456 glioma 0.0 CAPaN B17 0.0 Column A - Rel. Exp.(%) Ag2060, Run 267674609

[0674] 99 TABLE EF Oncology_cell_line_screening_panel_v3.2 Tissue Name A Tissue Name A 94905_Daoy_Medulloblastoma/Cerebellum_ssc 15.6 94954_Ca Ski_Cervical epidermoid 0.0 DNA carcinoma (metastasis)_sscDNA 94906_TE671_Medulloblastom/Cerebellum_ssc 0.0 94955_ES-2_Ovarian clear cell 0.0 DNA carcinoma_sscDNA 94907_D283 0.2 94957_Ramos/6 h stim_Stimulated with 0.0 Med_Medulloblastoma/Cerebellum_sscDNA PMA/ionomycin 6 h_sscDNA 94908_PFSK-1_Primitive 100.0 94958_Ramos/14 h stim_Stimulated 0.0 Neuroectodermal/Cerebellum_sscDNA with PMA/ionomycin 14 h_sscDNA 94909_XF-498_CNS_sscDNA 51.1 94962_MEG-01_Chronic myelogenous 0.0 leukemia (megokaryoblast)_sscDNA 94910_SNB-78_CNS/glioma_sscDNA 0.0 94963_Raji_Burkitt's 0.0 lymphoma_sscDNA 94911_SF-268_CNS/glioblastoma_sscDNA 0.7 94964_Daudi_Burkitt's 0.0 lymphoma_sscDNA 94912_T98G_Glioblastoma_sscDNA 0.0 94965_U266_B-cell 0.0 plasmacytoma/myeloma_sscDNA 96776_SK-N-SH_Neuroblastoma 0.6 94968_CA46_Burkitt's 0.0 (metastasis)_sscDNA lymphoma_sscDNA 94913_SF-295_CNS/glioblastoma_sscDNA 0.0 94970_RL_non-Hodgkin's B-cell 0.0 lymphoma_sscDNA 132565_NT2 pool_sscDNA 0.0 94972_JM1_pre-B-cell 0.0 lymphoma/leukemia_sscDNA 94914_Cerebellum_sscDNA 20.6 94973_Jurkat_T cell leukemia_sscDNA 0.0 96777_Cerebellum_sscDNA 0.1 94974_TF-1_Erythroleukemia_sscDNA 0.0 94916_NCI-H292_Mucoepidermoid lung 0.2 94975_HUT 78_T-cell 0.0 carcinoma_sscDNA lymphoma_sscDNA 94917_DMS-114_Small cell lung 0.9 94977_U937_Histiocytic 0.0 cancer_sscDNA lymphoma_sscDNA 94918_DMS-79_Small cell lung 3.8 94980_KU-812_Myelogenous 40.9 cancer/neuroendocrine_sscDNA leukemia_sscDNA 94919_NCI-H146_Small cell lung 3.0 94981_769-P_Clear cell renal 0.0 cancer/neuroendocrine_sscDNA carcinoma_sscDNA 94920_NCI-H526_Small cell lung 2.4 94983_Caki-2_Clear cell renal 3.6 cancer/neuroendocrine_sscDNA carcinoma_sscDNA 94921_NCI-N417_Small cell lung 6.4 94984_SW 839_Clear cell renal 0.3 cancer/neuroendocrine_sscDNA carcinoma_sscDNA 94923_NCI-H82_Small cell lung 0.0 94986_G401_Wilms' tumor_sscDNA 0.9 cancer/neuroendocrine_sscDNA 94924_NCI-H157_Squamous cell lung cancer 2.0 126768_293 cells_sscDNA 6.0 (metastasis)_sscDNA 94925_NCI-H1155_Large cell lung 1.4 94987_Hs766T_Pancreatic carcinoma 0.0 cancer/neuroendocrine_sscDNA (LN metastasis)_sscDNA 94926_NCI-H1299_Large cell lung 4.2 94988_CAPAN-1_Pancreatic 4.3 cancer/neuroendocrine_sscDNA adenocarcinoma (liver metastasis)_sscDNA 94927_NCI-H727_Lung carcinoid_sscDNA 0.9 94989_SU86.86_Pancreatic carcinoma 2.8 (liver metastasis)_sscDNA 94928_NCI-UMC-11_Lung carcinoid_sscDNA 0.0 94990_BxPC-3_Pancreatic 1.2 adenocarcinoma_sscDNA 94929_LX-1_Small cell lung cancer_sscDNA 0.3 94991_HPAC_Pancreatic 4.6 adenocarcinoma_sscDNA 94930_Colo-205_Colon cancer_sscDNA 0.0 94992_MIA PaCa-2_Pancreatic 0.3 carcinoma_sscDNA 94931_KM12_Colon cancer_sscDNA 0.0 94993_CFPAC-1_Pancreatic ductal 1.7 adenocarcinoma_sscDNA 94932_KM20L2_Colon cancer_sscDNA 0.9 94994_PANC-1_Pancreatic epithelioid 6.8 ductal carcinoma_sscDNA 94933_NCI-H716_Colon cancer_sscDNA 4.7 94996_T24_Bladder carcinma 0.0 (transitional cell)_sscDNA 94935_SW-48_Colon adenocarcinoma_sscDNA 0.0 94997_5637_Bladder 0.0 carcinoma_sscDNA 94936_SW1116_Colon 0.0 94998_HT-1197_Bladder 0.0 adenocarcinoma_sscDNA carcinoma_sscDNA 94937_LS 174T_Colon 0.0 94999_UM-UC-3_Bladder carcinma 0.1 adenocarcinoma_sscDNA (transitional cell)_sscDNA 94938_SW-948_Colon 0.0 95000_A204_Rhabdomyosarcoma_ssc 0.0 adenocarcinoma_sscDNA DNA 94939_SW-480_Colon 0.0 95001_HT-1080_Fibrosarcoma_sscDNA 0.0 adenocarcinoma_sscDNA 94940_NCI-SNU-5_Gastric carcinoma_sscDNA 0.0 95002_MG-63_Osteosarcoma 0.3 (bone)_sscDNA 112197_KATO III_Stomach_sscDNA 0.0 95003_SK-LMS-1_Leiomyosarcoma 52.9 (vulva)_sscDNA 94943_NCI-SNU-16_Gastric 1.9 95004_SJRH30_Rhabdomyosarcoma 0.2 carcinoma_sscDNA (met to bone marrow)_sscDNA 94944_NCI-SNU-1_Gastric carcinoma_sscDNA 11.4 95005_A431_Epidermoid 0.0 carcinoma_sscDNA 94946_RF-1_Gastric adenocarcinoma_sscDNA 0.0 95007_WM266-4_Melanoma_sscDNA 21.8 94947_RF-48_Gastric 0.0 112195_DU 145_Prostate_sscDNA 0.0 adenocarcinoma_sscDNA 96778_MKN-45_Gastric carcinoma_sscDNA 0.0 95012_MDA-MB-468_Breast 14.3 adenocarcinoma_sscDNA 94949_NCI-N87_Gastric carcinoma_sscDNA 1.0 112196_SSC-4_Tongue_sscDNA 0.0 94951_OVCAR-5_Ovarian carcinoma_sscDNA 0.9 112194_SSC-9_Tongue_sscDNA 0.3 94952_RL95-2_Uterine carcinoma_sscDNA 0.3 112191_SSC-15_Tongue_sscDNA 0.0 94953_HelaS3_Cervical 0.0 95017_CAL 27_Squamous cell 1.7 adenocarcinoma_sscDNA carcinoma of tongue_sscDNA Column A - Rel. Exp.(%) Ag2060, Run 311303311

[0675] 100 TABLE EG Panel 1.3D Tissue Name A Tissue Name A Liver adenocarcinoma 0.2 Kidney (fetal) 0.7 Pancreas 0.8 Renal ca. 786-0 0.8 Pancreatic ca. CAPAN 2 0.5 Renal ca. A498 0.0 Adrenal gland 0.8 Renal ca. RXF 393 0.0 Thyroid 1.5 Renal ca. ACHN 2.9 Salivary gland 0.9 Renal ca. UO-31 41.8 Pituitary gland 2.7 Renal ca. TK-10 0.0 Brain (fetal) 17.3 Liver 0.0 Brain (whole) 42.9 Liver (fetal) 0.4 Brain (amygdala) 92.7 Liver ca. (hepatoblast) HepG2 0.0 Brain (cerebellum) 4.8 Lung 28.3 Brain (hippocampus) 100.0 Lung (fetal) 21.3 Brain (substantia nigra) 13.6 Lung ca. (small cell) LX-1 0.5 Brain (thalamus) 47.0 Lung ca. (small cell) NCI-H69 0.0 Cerebral Cortex 27.7 Lung ca. (s. cell var.) SHP-77 16.6 Spinal cord 11.0 Lung ca. (large cell) NCI-H460 6.1 glio/astro U87-MG 0.3 Lung ca. (non-sm. cell) A549 0.4 glio/astro U-118-MG 11.9 Lung ca. (non-s. cell) NCI-H23 13.6 astrocytoma SW1783 0.5 Lung ca. (non-s. cell) HOP-62 2.6 neuro*; met SK-N-AS 1.5 Lung ca. (non-s. cl) NCI-H522 0.0 astrocytoma SF-539 0.3 Lung ca. (squam.) SW 900 7.1 astrocytoma SNB-75 5.6 Lung ca. (squam.) NCI-H596 0.0 glioma SNB-19 0.2 Mammary gland 12.2 glioma U251 6.8 Breast ca.* (pl.ef) MCF-7 0.0 glioma SF-295 0.0 Breast ca.* (pl.ef) MDA-MB-231 1.0 Heart (fetal) 0.0 Breast ca.* (pl.ef) T47D 3.6 Heart 0.0 Breast ca. BT-549 0.2 Skeletal muscle (fetal) 1.2 Breast ca. MDA-N 3.1 Skeletal muscle 0.4 Ovary 0.9 Bone marrow 0.5 Ovarian ca. OVCAR-3 0.2 Thymus 3.7 Ovarian ca. OVCAR-4 0.2 Spleen 0.4 Ovarian ca. OVCAR-5 15.7 Lymph node 0.2 Ovarian ca. OVCAR-8 13.5 Colorectal 6.9 Ovarian ca. IGROV-1 0.0 Stomach 8.2 Ovarian ca.* (ascites) SK-OV-3 0.0 Small intestine 32.1 Uterus 6.0 Colon ca. SW480 0.2 Placenta 0.4 Colon ca.* SW620(SW480 met) 0.0 Prostate 6.5 Colon ca. HT29 1.4 Prostate ca.* (bone met)PC-3 0.0 Colon ca. HCT-116 1.0 Testis 0.4 Colon ca. CaCo-2 0.0 Melanoma Hs688(A).T 0.0 Colon ca. tissue(ODO3866) 1.0 Melanoma* (met) Hs688(B).T 0.1 Colon ca. HCC-2998 0.0 Melanoma UACC-62 0.6 Gastric ca.* (liver met) NCI-N87 5.8 Melanoma M14 0.0 Bladder 1.2 Melanoma LOX IMVI 0.0 Trachea 10.5 Melanoma* (met) SK-MEL-5 2.2 Kidney 0.0 Adipose 1.3 Colun A - Rel. Exp.(%) Ag2060, Run 160163887

[0676] 101 TABLE EH Panel 2.2 Tissue Name A Tissue Name A Normal Colon 21.8 Kidney Margin (OD04348) 11.6 Colon cancer (OD06064) 27.4 Kidney malignant cancer (OD06204B) 1.5 Colon Margin (OD06064) 32.8 Kidney normal adjacent tissue 3.2 (OD06204E) Colon cancer (OD06159) 0.1 Kidney Cancer (OD04450-01) 2.7 Colon Margin (OD06159) 31.0 Kidney Margin (OD04450-03) 1.6 Colon cancer (OD06297-04) 0.0 Kidney Cancer 8120613 0.0 Colon Margin (OD06297-05) 31.0 Kidney Margin 8120614 0.0 CC Gr.2 ascend colon (ODO3921) 0.0 Kidney Cancer 9010320 0.0 CC Margin (ODO3921) 2.8 Kidney Margin 9010321 0.0 Colon cancer metastasis (OD06104) 0.0 Kidney Cancer 8120607 0.0 Lung Margin (OD06104) 2.9 Kidney Margin 8120608 0.0 Colon mets to lung (OD04451-01) 3.5 Normal Uterus 8.8 Lung Margin (OD04451-02) 72.2 Uterine Cancer 064011 1.7 Normal Prostate 14.9 Normal Thyroid 2.0 Prostate Cancer (OD04410) 0.3 Thyroid Cancer 064010 5.7 Prostate Margin (OD04410) 27.0 Thyroid Cancer A302152 0.8 Normal Ovary 1.8 Thyroid Margin A302153 0.4 Ovarian cancer (OD06283-03) 0.0 Normal Breast 55.1 Ovarian Margin (OD06283-07) 4.3 Breast Cancer (OD04566) 1.3 Ovarian Cancer 064008 2.0 Breast Cancer 1024 32.8 Ovarian cancer (OD06145) 12.9 Breast Cancer (OD04590-01) 0.2 Ovarian Margin (OD06145) 5.5 Breast Cancer Mets (OD04590-03) 1.5 Ovarian cancer (OD06455-03) 39.5 Breast Cancer Metastasis (OD04655-05) 8.3 Ovarian Margin (OD06455-07) 32.3 Breast Cancer 064006 19.6 Normal Lung 24.7 Breast Cancer 9100266 6.2 Invasive poor diff. lung adeno 18.9 Breast Margin 9100265 4.4 (ODO4945-01 Lung Margin (ODO4945-03) 40.1 Breast Cancer A209073 14.2 Lung Malignant Cancer (OD03126) 45.4 Breast Margin A2090734 5.9 Lung Margin (OD03126) 6.2 Breast cancer (OD06083) 45.7 Lung Cancer (OD05014A) 3.1 Breast cancer node metastasis (OD06083) 9.3 Lung Margin (OD05014B) 100.0 Normal Liver 5.2 Lung cancer (OD06081) 0.0 Liver Cancer 1026 0.0 Lung Margin (OD06081) 18.7 Liver Cancer 1025 0.6 Lung Cancer (OD04237-01) 13.7 Liver Cancer 6004-T 2.8 Lung Margin (OD04237-02) 77.9 Liver Tissue 6004-N 1.4 Ocular Melanoma Metastasis 0.0 Liver Cancer 6005-T 0.0 Ocular Melanoma Margin (Liver) 0.0 Liver Tissue 6005-N 0.4 Melanoma Metastasis 0.0 Liver Cancer 064003 0.0 Melanoma Margin (Lung) 37.4 Normal Bladder 0.0 Normal Kidney 1.0 Bladder Cancer 1023 0.0 Kidney Ca, Nuclear grade 2 (OD04338) 3.2 Bladder Cancer A302173 3.6 Kidney Margin (OD04338) 2.8 Normal Stomach 67.4 Kidney Ca Nuclear grade 1/2 (OD04339) 16.0 Gastric Cancer 9060397 0.9 Kidney Margin (OD04339) 0.0 Stomach Margin 9060396 4.2 Kidney Ca, Clear cell type (OD04340) 0.5 Gastric Cancer 9060395 10.1 Kidney Margin (OD04340) 3.8 Stomach Margin 9060394 8.4 Kidney Ca, Nuclear grade 3 (OD04348) 0.0 Gastric Cancer 064005 8.4 Coumn A - Rel. Exp.(%) Ag2060, Run 174166860

[0677] 102 TABLE EI Panel 3D Tissue Name A Tissue Name A Daoy-Medulloblastoma 42.6 Ca Ski-Cervical epidermoid carcinoma 0.0 (metastasis) TE671-Medulloblastoma 0.0 ES-2-Ovarian clear cell carcinoma 0.0 D283 Med-Medulloblastoma 0.0 Ramos-Stimulated with PMA/ionomycin 6 h 0.0 PFSK-1-Primitive Neuroectodermal 100.0 Ramos-Stimulated with PMA/ionomycin 14 h 0.0 XF-498-CNS 37.9 MEG-01-Chronic myelogenous leukemia 0.0 (megokaryoblast) SNB-78-Glioma 0.0 Raji-Burkitt's lymphoma 0.0 SF-268-Glioblastoma 0.0 Daudi-Burkitt's lymphoma 0.0 T98G-Glioblastoma 0.5 U266-B-cell plasmacytoma 0.0 SK-N-SH-Neuroblastoma (metastasis) 0.5 CA46-Burkitt's lymphoma 0.0 SF-295-Glioblastoma 0.0 RL-non-Hodgkin's B-cell lymphoma 0.0 Cerebellum 34.6 JM1-pre-B-cell lymphoma 0.0 Cerebellum 1.2 Jurkat-T cell leukemia 0.0 NCI-H292-Mucoepidermoid lung 0.0 TF-1-Erythroleukemia 0.0 carcinoma DMS-114-Small cell lung cancer 0.7 HUT 78-T-cell lymphoma 0.0 DMS-79-Small cell lung cancer 5.3 U937-Histiocytic lymphoma 0.0 NCI-H146-Small cell lung cancer 5.3 KU-812-Myelogenous leukemia 32.1 NCI-H526-Small cell lung cancer 3.8 769-P-Clear cell renal carcinoma 0.0 NCI-N417-Small cell lung cancer 13.1 Caki-2-Clear cell renal carcinoma 2.0 NCI-H82-Small cell lung cancer 5.3 SW 839-Clear cell renal carcinoma 2.0 NCI-H157-Squamous cell lung cancer 0.0 Rhabdoid kidney tumor 0.3 (metastasis) NCI-H1155-Large cell lung cancer 0.8 Hs766T-Pancreatic carcinoma (LN 0.0 metastasis) NCI-H1299-Large cell lung cancer 4.5 CAPAN-1-Pancreatic adenocarcinoma (liver 2.8 metastasis) NCI-H727-Lung carcinoid 2.2 SU86.86-Pancreatic carcinoma (liver 3.6 metastasis) NCI-UMC-11-Lung carcinoid 0.6 BxPC-3-Pancreatic adenocarcinoma 0.0 LX-1-Small cell lung cancer 0.0 HPAC-Pancreatic adenocarcinoma 6.4 Colo-205-Colon cancer 0.0 MIA PaCa-2-Pancreatic carcinoma 0.0 KM12-Colon cancer 0.0 CFPAC-1-Pancreatic ductal adenocarcinoma 0.0 KM20L2-Colon cancer 2.2 PANC-1-Pancreatic epithelioid ductal 9.7 carcinoma NCI-H716-Colon cancer 13.4 T24-Bladder carcinma (transitional cell) 1.2 SW-48-Colon adenocarcinoma 0.0 5637-Bladder carcinoma 0.0 SW1116-Colon adenocarcinoma 0.0 HT-1197-Bladder carcinoma 0.0 LS 174T-Colon adenocarcinoma 0.0 UM-UC-3-Bladder carcinma (transitional 0.5 cell) SW-948-Colon adenocarcinoma 0.0 A204-Rhabdomyosarcoma 0.0 SW-480-Colon adenocarcinoma 0.0 HT-1080-Fibrosarcoma 0.0 NCI-SNU-5-Gastric carcinoma 0.0 MG-63-Osteosarcoma 0.8 KATO III-Gastric carcinoma 0.0 SK-LMS-1-Leiomyosarcoma (vulva) 80.7 NCI-SNU-16-Gastric carcinoma 1.8 SJRH30-Rhabdomyosarcoma (met to bone 0.0 marrow) NCI-SNU-1-Gastric carcinoma 28.9 A431-Epidermoid carcinoma 0.0 RF-1-Gastric adenocarcinoma 0.0 WM266-4-Melanoma 30.8 RF-48-Gastric adenocarcinoma 0.0 DU 145-Prostate carcinoma (brain metastasis) 0.0 MKN-45-Gastric carcinoma 0.0 MDA-MB-468-Breast adenocarcinoma 5.2 NCI-N87-Gastric carcinoma 1.4 SCC-4-Squamous cell carcinoma of tongue 0.0 OVCAR-5-Ovarian carcinoma 2.1 SCC-9-Squamous cell carcinoma of tongue 0.0 RL95-2-Uterine carcinoma 1.1 SCC-15-Squamous cell carcinoma of tongue 0.0 HelaS3-Cervical adenocarcinoma 0.0 CAL 27-Squamous cell carcinoma of tongue 0.3 Clumn A - Rel. Exp.(%) Ag2060, Run 358962242

[0678] 103 TABLE EJ Panel 4D Tissue Name A Tissue Name A Secondary Th1 act 0.8 HUVEC IL-1beta 0.7 Secondary Th2 act 0.8 HUVEC IFN gamma 0.0 Secondary Tr1 act 0.0 HUVEC TNF alpha + IFN gamma 0.0 Secondary Th1 rest 0.0 HUVEC TNF alpha + IL4 0.0 Secondary Th2 rest 0.0 HUVEC IL-11 0.0 Secondary Tr1 rest 1.7 Lung Microvascular EC none 0.0 Primary Th1 act 0.0 Lung Microvascular EC TNF alpha + IL-1beta 0.3 Primary Th2 act 0.0 Microvascular Dermal EC none 0.0 Primary Tr1 act 0.0 Microsvasular Dermal EC TNF alpha + IL-1beta 0.0 Primary Th1 rest 0.0 Bronchial epithelium TNF alpha + IL1beta 3.1 Primary Th2 rest 0.0 Small airway epithelium none 2.5 Primary Tr1 rest 0.0 Small airway epithelium TNF alpha + IL-1beta 6.6 CD45RA CD4 lymphocyte act 0.0 Coronery artery SMC rest 0.0 CD45RO CD4 lymphocyte act 0.0 Coronery artery SMC TNF alpha + IL-1beta 0.0 CD8 lymphocyte act 0.0 Astrocytes rest 0.7 Secondary CD8 lymphocyte rest 0.0 Astrocytes TNF alpha + IL-1beta 7.0 Secondary CD8 lymphocyte act 0.0 KU-812 (Basophil) rest 61.6 CD4 lymphocyte none 0.0 KU-812 (Basophil) PMA/ionomycin 100.0 2ry Th1/Th2/Tr1_anti-CD95 CH11 0.0 CCD1106 (Keratinocytes) none 0.0 LAK cells rest 0.0 CCD1106 (Keratinocytes) TNF alpha + IL-1beta 0.0 LAK cells IL-2 1.2 Liver cirrhosis 23.0 LAK cells IL-2 + IL-12 0.0 Lupus kidney 1.9 LAK cells IL-2 + IFN gamma 0.0 NCI-H292 none 1.0 LAK cells IL-2 + IL-18 0.0 NCI-H292 IL-4 0.0 LAK cells PMA/ionomycin 0.0 NCI-H292 IL-9 0.0 NK Cells IL-2 rest 0.3 NCI-H292 IL-13 0.4 Two Way MLR 3 day 1.9 NCI-H292 IFN gamma 0.0 Two Way MLR 5 day 0.0 HPAEC none 0.0 Two Way MLR 7 day 0.0 HPAEC TNF alpha + IL-1beta 0.0 PBMC rest 0.0 Lung fibroblast none 7.7 PBMC PWM 0.0 Lung fibroblast TNF alpha + IL-1beta 0.0 PBMC PHA-L 0.0 Lung fibroblast IL-4 6.5 Ramos (B cell) none 0.0 Lung fibroblast IL-9 6.4 Ramos (B cell) ionomycin 0.0 Lung fibroblast IL-13 8.1 B lymphocytes PWM 0.0 Lung fibroblast IFN gamma 14.9 B lymphocytes CD40L and IL-4 0.0 Dermal fibroblast CCD1070 rest 1.7 EOL-1 dbcAMP 0.0 Dermal fibroblast CCD1070 TNF alpha 1.7 EOL-1 dbcAMP PMA/ionomycin 1.5 Dermal fibroblast CCD1070 IL-1beta 0.0 Dendritic cells none 0.0 Dermal fibroblast IFN gamma 6.9 Dendritic cells LPS 0.6 Dermal fibroblast IL-4 5.9 Dendritic cells anti-CD40 0.0 IBD Colitis 2 1.4 Monocytes rest 0.0 IBD Crohn's 18.7 Monocytes LPS 0.0 Colon 51.1 Macrophages rest 0.0 Lung 15.8 Macrophages LPS 0.0 Thymus 3.4 HUVEC none 0.6 Kidney 33.9 HUVEC starved 0.0 Coumn A - Rel. Exp.(%) Ag2060, Run 164295986

[0679] 104 TABLE EK Panel 5 Islet Tissue Name A Tissue Name A 97457_Patient-02go_adipose 10.4 94709_Donor 2 AM - A_adipose 0.0 97476_Patient-07sk_skeletal muscle 5.7 94710_Donor 2 AM - B_adipose 0.0 97477_Patient-07ut_uterus 3.2 94711_Donor 2 AM - C_adipose 0.0 97478_Patient-07pl_placenta 1.0 94712_Donor 2 AD - A_adipose 2.1 99167_Bayer Patient 1 0.6 94713_Donor 2 AD - B_adipose 0.0 97482_Patient-08ut_uterus 1.0 94714_Donor 2 AD - C_adipose 0.0 97483_Patient-08pl_placenta 5.3 94742_Donor 3 U - A_Mesenchymal Stem 0.0 Cells 97486_Patient-09sk_skeletal muscle 1.8 94743_Donor 3 U - B_Mesenchymal Stem 0.0 Cells 97487_Patient-09ut_uterus 5.6 94730_Donor 3 AM - A_adipose 0.0 97488_Patient-09pl_placenta 0.0 94731_Donor 3 AM - B_adipose 0.0 97492_Patient-10ut_uterus 2.6 94732_Donor 3 AM - C_adipose 0.0 97493_Patient-10pl_placenta 6.3 94733_Donor 3 AD - A_adipose 0.0 97495_Patient-11go_adipose 1.2 94734_Donor 3 AD - B_adipose 0.0 97496_Patient-11sk_skeletal muscle 2.6 94735_Donor 3 AD - C_adipose 0.0 97497_Patient-11ut_uterus 5.0 77138_Liver_HepG2untreated 0.0 97498_Patient-11pl_placenta 3.3 73556_Heart_Cardiac stromal cells 0.0 (primary) 97500_Patient-12go_adipose 2.2 81735_Small Intestine 100.0 97501_Patient-12sk_skeletal muscle 0.0 72409_Kidney_Proximal Convoluted 1.2 Tubule 97502_Patient-12ut_uterus 2.1 82685_Small intestine_Duodenum 17.4 97503_Patient-12pl_placenta 0.0 90650_Adrenal_Adrenocortical adenoma 1.4 94721_Donor 2 U - A_Mesenchymal 0.0 72410_Kidney_HRCE 0.9 Stem Cells 94722_Donor 2 U - B_Mesenchymal Stem 0.0 72411_Kidney_HRE 1.7 Cells 94723_Donor 2 U - C_Mesenchymal Stem 0.0 73139_Uterus_Uterine smooth muscle cells 1.6 Cells Colum A - Rel. Exp.(%) Ag2060, Run 267095055

[0680] 105 TABLE EL Panel CNS 1 Tissue Name A Tissue Name A BA4 Control 54.7 BA17 PSP 52.9 BA4 Control2 55.9 BA17 PSP2 26.6 BA4 Alzheimer's2 10.1 Sub Nigra Control 37.6 BA4 Parkinson's 32.8 Sub Nigra Control2 27.4 BA4 Parkinson's2 45.1 Sub Nigra Alzheimer's2 20.0 BA4 Huntington's 32.1 Sub Nigra Parkinson's2 41.5 BA4 Huntington's2 8.9 Sub Nigra Huntington's 74.7 BA4 PSP 10.7 Sub Nigra Huntington's2 55.5 BA4 PSP2 56.3 Sub Nigra PSP2 21.0 BA4 Depression 21.9 Sub Nigra Depression 10.6 BA4 Depression2 12.2 Sub Nigra Depression2 12.7 BA7 Control 32.8 Glob Palladus Control 4.1 BA7 Control2 34.9 Glob Palladus Control2 12.2 BA7 Alzheimer's2 13.3 Glob Palladus Alzheimer's 17.4 BA7 Parkinson's 7.5 Glob Palladus Alzheimer's2 3.6 BA7 Parkinson's2 23.8 Glob Palladus Parkinson's 40.6 BA7 Huntington's 41.5 Glob Palladus Parkinson's2 7.2 BA7 Huntington's2 24.7 Glob Palladus PSP 13.7 BA7 PSP 34.6 Glob Palladus PSP2 7.4 BA7 PSP2 31.2 Glob Palladus Depression 7.5 BA7 Depression 20.7 Temp Pole Control 18.8 BA9 Control 28.9 Temp Pole Control2 21.2 BA9 Control2 100.0 Temp Pole Alzheimer's 9.0 BA9 Alzheimer's 10.9 Temp Pole Alzheimer's2 4.6 BA9 Alzheimer's2 10.6 Temp Pole Parkinson's 18.0 BA9 Parkinson's 16.4 Temp Pole Parkinson's2 23.0 BA9 Parkinson's2 39.8 Temp Pole Huntington's 32.5 BA9 Huntington's 28.1 Temp Pole PSP 11.7 BA9 Huntington's2 8.4 Temp Pole PSP2 6.0 BA9 PSP 33.2 Temp Pole Depression2 13.8 BA9 PSP2 9.3 Cing Gyr Control 64.6 BA9 Depression 16.4 Cing Gyr Control2 35.6 BA9 Depression2 10.1 Cing Gyr Alzheimer's 35.4 BA17 Control 50.7 Cing Gyr Alzheimer's2 10.2 BA17 Control2 62.4 Cing Gyr Parkinson's 17.2 BA17 Alzheimer's2 33.9 Cing Gyr Parkinson's2 21.6 BA17 Parkinson's 27.5 Cing Gyr Huntington's 43.8 BA17 Parkinson's2 42.3 Cing Gyr Huntington's2 14.7 BA17 Huntington's 62.0 Cing Gyr PSP 30.1 BA17 Huntington's2 26.2 Cing Gyr PSP2 6.1 BA17 Depression 17.4 Cing Gyr Depression 10.3 BA17 Depression2 35.6 Cing Gyr Depression2 21.8 Colum A - Rel. Exp.(%) Ag2060, Run 171628579

[0681] 106 TABLE EM general oncology screening panel_v_2.4 Tissue Name A Tissue Name A Colon cancer 1 0.3 Bladder cancer NAT 2 1.2 Colon cancer NAT 1 1.0 Bladder cancer NAT 3 0.5 Colon cancer 2 2.5 Bladder cancer NAT 4 7.8 Colon cancer NAT 2 1.8 Prostate adenocarcinoma 1 100.0 Colon cancer 3 0.2 Prostate adenocarcinoma 2 3.6 Colon cancer NAT 3 9.0 Prostate adenocarcinoma 3 5.0 Colon malignant cancer 4 0.2 Prostate adenocarcinoma 4 2.0 Colon normal adjacent tissue 1.2 Prostate cancer NAT 5 4.9 4 Lung cancer 1 0.4 Prostate adenocarcinoma 6 4.5 Lung NAT 1 0.6 Prostate adenocarcinoma 7 9.5 Lung cancer 2 6.2 Prostate adenocarcinoma 8 3.1 Lung NAT 2 2.4 Prostate adenocarcinoma 9 50.0 Squamous cell carcinoma 3 0.5 Prostate cancer NAT 10 1.3 Lung NAT 3 0.5 Kidney cancer 1 0.0 metastatic melanoma 1 1.1 KidneyNAT 1 0.5 Melanoma 2 0.2 Kidney cancer 2 0.1 Melanoma 3 1.6 Kidney NAT 2 0.7 metastatic melanoma 4 0.2 Kidney cancer 3 0.1 metastatic melanoma 5 0.5 Kidney NAT 3 0.6 Bladder cancer 1 3.2 Kidney cancer 4 0.0 Bladder cancer NAT 1 0.0 Kidney NAT 4 0.2 Bladder cancer 2 16.7 Column A - Rel. Exp.(%) Ag2060, Run 267145079

[0682] AI_comprehensive panel_v1.0 Summary: Ag2060 Highest expression of this gene is seen in osteooarthritis cartilage sample (CT=24.4). High expression of this gene is seen in normal and osteooarthitis/rheumatoid arthritis bone and adjacent bone, cartilage, synovium and synovial fluid samples. In addition, moderate to low expression of this gene is also seen in normal lung, COPD lung, emphysema, atopic asthma, asthma, allergy, Crohn's disease (normal matched control and diseased), ulcerative colitis (normal matched control and diseased), and psoriasis (normal matched control and diseased). Therefore, therapeutic modulation of this gene product may ameliorate symptoms/conditions associated with autoimmune and inflammatory disorders including psoriasis, allergy, asthma, inflammatory bowel disease, rheumatoid arthritis and osteoarthritis.

[0683] Ardais Panel v.1.0 Summary: Ag2060 Highest expression of this gene is seen in a lung cancer sample (CT=27.7). High expression of this gene is seen in cancer and normal adjacent samples from lung. Interestingly, expression of this gene is higher in the normal adjacent lung compared to the corresponding cancer samples. Therefore, this gene could be acting as a tumor suppressor through a potential chemo repulsive effect on vascular endothelial cells. Thus, therapeutic modulation of the activity of this gene or its protein product may be useful in the treatment of lung cancer.

[0684] CNS_neurodegeneration_v1.0 Summary: Ag2060 This panel confirms the expression of this gene at low levels in the brains of an independent group of individuals.

[0685] HASS Panel v1.0 Summary: Ag2060 Highest expression of this gene is seen in adult glioma sample (CT=25). Moderate to low expression of this gene is also seen in adult glioma, brain cancer cell U87-MG cell line, primary astrocytes, renal proximal tubule epithlial cell and melanocytes. Therefore, therapeutic modulation of this gene or its protein product may be useful in the treatment of brain cancer and brain related diseases.

[0686] Oncology_cell_line_screening_panel_v3.2 Summary: Ag2060 Highest expression of this gene is seen in a brain cancer PFSK-1 cell line (CT=29.7). Moderate to low expression of this gene is also seen in number of cancer cell lines derived from brain, breast, melanoma, leiomyosarcoma, pancreatic, myelogenous leukemia, gastric, colon and lung cancers. Therefore, therapeutic modulation of this gene or its protein product may be useful in the treatement of brain, breast, melanoma, leiomyosarcoma, pancreatic, myelogenous leukemia, gastric, colon and lung cancers.

[0687] Panel 1.3D Summary: Ag2060 Highest expression of this gene is seen in brain hippocampus sample (CT=28.3). This gene is expressed at moderate to high levels in all regions of the central nervous system examined, including amygdala, hippocampus, substantia nigra, thalamus, cerebellum, cerebral cortex, and spinal cord. This gene codes for semaphorin 3E protein. The semaphorin family of molecules are largely involved in axon guidance and modulation of CNS motility. Semaphorin 3E has been shown to be involved in the chemo-repulsion and collapse of neuron growth cones (Pozas E, Pascual M, Nguyen Ba-Charvet K T, Guijarro P, Sotelo C, Chedotal A, Del Rio J A, Soriano E. Age-dependent effects of secreted Semaphorins 3A, 3F, and 3E on developing hippocampal axons: in vitro effects and phenotype of Semaphorin 3A (−/−) mice. Mol Cell Neurosci 2001 July; 18(1):26-43.). Therefore, therapeutic modulation of this gene product may be useful in the treatment of central nervous system disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, schizophrenia and depression.

[0688] Moderate to low expression of this gene is also seen in number of cancer cell lines derived from brain, melanoma, breast, ovarian, lung, renal, gastric and colon cancers. Therefore, therapeutic modulation of this gene or its protein product may be useful in the treatment of brain, melanoma, breast, ovarian, lung, renal, gastric and colon cancers.

[0689] Among tissues with metabolic or endocrine function, this gene is expressed at low levels in adrenal gland, thyroid, pituitary gland, fetal skeletal muscle, and the gastrointestinal tract. Therefore, therapeutic modulation of the activity of this gene may prove useful in the treatment of endocrine/metabolically related diseases, such as obesity and diabetes.

[0690] Panel 2.2 Summary: Ag2060 Highest expression of this gene is seen in normal lung (CT=29.6). Moderate to low expression of this gene is also seen in cancer and normal adjacent samples derived from lung, stomach, liver, breast, thyroid, uterus, kidney, ovary, prostate and colon. Interestingly, expression of this gene is higher in normal samples compared to the corresponding cancer samples. Therefore, therapeutic modulation of this gene or its protein product may be useful in the treatment of lung, stomach, liver, breast, thyroid, uterus, kidney, ovary, prostate and colon cancers.

[0691] Panel 3D Summary: Ag2060 Highest expression of this gene is seen in a brain cancer PFSK-1 cell line (CT=28.7). The expression pattern of this gene correlates with the expression seen in panel 3.2.

[0692] Panel 4D Summary: Ag2060 Highest expression of this gene is seen in activated basophils (CT=30.2). In addition, moderate to low expression of this gene is also seen in activated astrocytes, resting basophils, resting and activated lung fibroblasts, activated dermal fibroblasts, liver cirrhosis, IBD Crohn's and normal tissues represented by colon, lung and kidney. Therefore, therapeutic modulation of the activity of this gene or its protein product may be useful in the treatment of asthma, allergies, hypersensitivity reactions, psoriasis, viral infections, liver cirrhosis, and Crohn's disease.

[0693] Panel 5 Islet Summary: Ag2060 Moderate to low expression of this gene is seen mainly in small intestine samples (CTs=32-34.5).

[0694] Panel CNS—1 Summary: Ag2060 This panel confirms the expression of this gene at low levels in the brains of an independent group of individuals.

[0695] General oncology screening panel_v—2.4 Summary: Ag2060 Highest expression of this gene is seen in a prostate cancer sample (CT=26.6). Moderate to low expression of this gene is also seen in cancer and normal samples derived from lung, colon, prostate and melanoma. Low expression of this gene is also seen in normal kidney samples. Therefore, therapeutic modulation of this gene or its protein product may be useful in the treatment of lung, colon, prostate and melanoma cancers.

[0696] F. CG55023-01: Transforming Growth Factor Alpha Precursor.

[0697] Expression of gene CG55023-01 was assessed using the primer-probe sets Ag692, Ag264 and Ag264b, described in Tables FA, FB and FC. Results of the RTQ-PCR runs are shown in Tables FD, FE, FF, FG, FH, FI and FJ. 107 TABLE FA Probe Name Ag692 Start SEQ ID Primers Sequences Length Position No Forward 5′-cttgaagttctcacacctttgc-3′ 22 207 165 Probe TET-5′-tcataacagttactgcatcaacggtg-3′-TAMRA 26 237 166 Reverse 5′-tcatggtggaatgcacaag-3′ 19 263 167

[0698] 108 TABLE FB Probe Name Ag264 Start SEQ ID Primers Sequences Length Position No Forward 5′-gtctatcttttattcaacgcaatgaca-3′ 27 73 168 Probe TET-5′-agtcacggctgcctcttcggtca-3′-TAMRA 23 104 169 Reverse 5′-gggctgtgattggaggtgtt-3′ 20 129 170

[0699] 109 TABLE FC Probe Name Ag264b Start SEQ ID Primers Sequences Length Position No Forward 5′-gtctatcttttattcaacgcaatgaca-3′ 27 73 171 Probe TET-5′-cacggctgcctcttcggtcagtg-3′-TAMRA 23 101 172 Reverse 5′-gggctgtgattggaggtgtta-3′ 21 128 173

[0700] 110 TABLE FD Ardais Prostate 1.0 Tissue Name A Tissue Name A 145904_Prostate cancer(9E2) 2.7 153680_Prostate NAT(D69) 3.6 149776_Prostate cancer(AD5) 19.5 155799_Prostate cancer(EA8) 2.3 151135_Prostate NAT(B87) 4.6 145909_Prostate cancer(9E7) 2.3 151143_Prostate NAT(B8A) 5.0 151131_Prostate NAT(B85) 5.8 153653_Prostate cancer(D4E) 4.7 151139_Prostate NAT(B8E) 13.1 153661_Prostate cancer(D56) 8.8 153649_Prostate cancer(D4A) 17.6 153669_Prostate NAT(D5E) 5.6 153657_Prostate cancer(D52) 1.4 153677_Prostate NAT(D66) 0.5 153665_Prostate cancer(D5A) 5.7 153685_Prostate NAT(D6E) 2.2 153673_Prostate NAT(D62) 6.3 145905_Prostate NAT(A0C) 3.1 153681_Prostate NAT(D6A) 0.9 151128_Prostate cancer(B8C) 13.7 145910_Prostate NAT(9C3) 2.4 151136_Prostate cancer(B8B) 13.4 151132_Prostate cancer(B88) 8.1 151144_Prostate cancer(B8F) 2.7 151140_Prostate cancer(B95) 2.6 153654_Prostate cancer(D4F) 3.4 153650_Prostate cancer(D4B) 5.2 153662_Prostate cancer(D57) 2.2 153658_Prostate cancer(D53) 2.4 153670_Prostate NAT(D5F) 5.2 153666_Prostate cancer(D5B) 14.1 153678_Prostate NAT(D67) 7.5 153674_Prostate NAT(D63) 7.6 153686_Prostate NAT(D6F) 8.6 153682_Prostate NAT(D6B) 9.9 145906_Prostate NAT(A09) 2.6 149773_Prostate NAT(AD8) 0.0 151129_Prostate NAT(B93) 26.4 151133_Prostate NAT(B94) 4.1 151137_Prostate NAT(B86) 100.0 151141_Prostate NAT(B96) 23.0 151145_Prostate NAT(B91) 16.5 153651_Prostate cancer(D4C) 4.8 153655_Prostate cancer(D50) 20.4 153659_Prostate cancer(D54) 5.8 153663_Prostate cancer(D58) 4.1 153667_Prostate cancer(D5C) 28.9 153671_Prostate NAT(D60) 8.8 153675_Prostate NAT(D64) 4.9 153679_Prostate NAT(D68) 1.0 153683_Prostate NAT(D6C) 30.8 153687_Prostate NAT(D70) 2.1 149774_Prostate cancer(AD7) 1.7 145907_Prostate cancer(A0A) 2.6 151134_Prostate cancer(B92) 10.7 151130_Prostate cancer(B90) 7.3 151142_Prostate cancer(B89) 1.6 151138_Prostate cancer(B8D) 4.5 153652_Prostate cancer(D4D) 4.0 153648_Prostate cancer(D49) 4.2 153660_Prostate cancer(D55) 1.2 153656_Prostate cancer(D51) 1.8 153668_Prostate NAT(D5D) 56.3 153664_Prostate cancer(D59) 1.2 153676_Prostate NAT(D65) 9.5 153672_Prostate NAT(D61) 8.9 153684_Prostate NAT(D6D) 4.2 Column A - el. Exp.(%) Ag692, Run 320985784

[0701] 111 TABLE FE Oncology_cell_line_screening_panel_v3.1 Tissue Name A Tissue Name A Daoy Medulloblastoma/Cerebellum 0.0 Ca Ski_Cervical epidermoid carcinoma 46.7 (metastasis) TE671 Medulloblastom/Cerebellum 0.0 ES-2_Ovarian clear cell carcinoma 0.0 D283 Med Medulloblastoma/Cerebellum 0.0 Ramos/6 h stim_Stimulated with 0.0 PMA/ionomycin 6 h PFSK-1 Primitive 0.0 Ramos/14 h stim_Stimulated with 0.0 Neuroectodermal/Cerebellum PMA/ionomycin 14 h XF-498_CNS 0.0 MEG-01_Chronic myelogenous leukemia 7.3 (megokaryoblast) SNB-78_CNS/glioma 0.0 Raji_Burkitt's lymphoma 0.0 SF-268_CNS/glioblastoma 0.0 Daudi_Burkitt's lymphoma 0.0 T98G_Glioblastoma 0.0 U266_B-cell plasmacytoma/myeloma 0.0 SK-N-SH_Neuroblastoma (metastasis) 0.0 CA46_Burkitt's lymphoma 0.0 SF-295_CNS/glioblastoma 0.0 RL_non-Hodgkin's B-cell lymphoma 0.0 Cerebellum 0.0 JM1_pre-B-cell lymphoma/leukemia 0.0 Cerebellum 0.0 Jurkat_T cell leukemia 0.0 NCI-H292_Mucoepidermoid lung ca. 5.0 TF-1_Erythroleukemia 0.0 DMS-114_Small cell lung cancer 0.0 HUT 78_T-cell lymphoma 6.4 DMS-79_Small cell lung 0.0 U937_Histiocytic lymphoma 0.0 cancer/neuroendocrine NCI-H146_Small cell lung 0.0 KU-812_Myelogenous leukemia 0.0 cancer/neuroendocrine NCI-H526_Small cell lung 0.0 769-P_Clear cell renal ca. 0.0 cancer/neuroendocrine NCI-N417_Small cell lung 0.0 Caki-2_Clear cell renal ca. 0.0 cancer/neuroendocrine NCI-H82_Small cell lung 0.0 SW 839_Clear cell renal ca. 0.0 cancer/neuroendocrine NCI-H157_Squamous cell lung cancer 0.0 G401_Wilms' tumor 0.0 (metastasis) NCI-H1155_Large cell lung 0.0 Hs766T_Pancreatic ca. (LN metastasis) 0.0 cancer/neuroendocrine NCI-H1299_Large cell lung 0.0 CAPAN-1_Pancreatic adenocarcinoma (liver 0.0 cancer/neuroendocrine metastasis) NCI-H727_Lung carcinoid 0.0 SU86.86_Pancreatic carcinoma (liver 6.7 metastasis) NCI-UMC-11_Lung carcinoid 0.0 BxPC-3_Pancreatic adenocarcinoma 0.0 LX-1_Small cell lung cancer 0.0 HPAC_Pancreatic adenocarcinoma 0.0 Colo-205_Colon cancer 0.0 MIA PaCa-2_Pancreatic ca. 0.0 KM12_Colon cancer 0.0 CFPAC-1_Pancreatic ductal adenocarcinoma 0.0 KM20L2_Colon cancer 0.0 PANC-1_Pancreatic epithelioid ductal ca. 0.0 NCI-H716_Colon cancer 0.0 T24_Bladder ca. (transitional cell) 0.0 SW-48_Colon adenocarcinoma 0.0 5637_Bladder ca. 0.0 SW1116_Colon adenocarcinoma 0.0 HT-1197_Bladder ca. 100.0 LS 174T_Colon adenocarcinoma 0.0 UM-UC-3_Bladder ca. (transitional cell) 0.0 SW-948_Colon adenocarcinoma 0.0 A204_Rhabdomyosarcoma 0.0 SW-480_Colon adenocarcinoma 0.0 HT-1080_Fibrosarcoma 0.0 NCI-SNU-5_Gastric ca. 0.0 MG-63_Osteosarcoma (bone) 0.0 KATO III_Stomach 0.0 SK-LMS-1_Leiomyosarcoma (vulva) 0.0 NCI-SNU-16_Gastric ca. 0.0 SJRH30_Rhabdomyosarcoma (met to bone 0.0 marrow) NCI-SNU-1_Gastric ca. 0.0 A431_Epidermoid ca. 0.0 RF-1_Gastric adenocarcinoma 0.0 WM266-4_Melanoma 0.0 RF-48_Gastric adenocarcinoma 0.0 DU 145_Prostate 0.0 MKN-45_Gastric ca. 0.0 MDA-MB-468_Breast adenocarcinoma 0.0 NCI-N87_Gastric ca. 0.0 SSC-4_Tongue 1.5 OVCAR-5_Ovarian ca. 0.0 SSC-9_Tongue 26.8 RL95-2_Uterine carcinoma 16.0 SSC-15_Tongue 0.0 HelaS3_Cervical adenocarcinoma 30.6 CAL 27_Squamous cell ca. of tongue 0.0 Column A - Rel. Exp.(%) Ag264, Run 223120410

[0702] 112 TABLE FF Panel 1 Tissue Name A B C Tissue Name A B C Endothelial cells 0.0 0.0 2.5 Renal ca. 786-0 0.0 0.0 2.4 Endothelial cells (treated) 0.0 0.0 2.6 Renal ca. A498 0.0 0.0 2.3 Pancreas 0.0 0.0 3.5 Renal ca. RXF 393 0.0 0.0 3.1 Pancreatic ca. CAPAN 2 0.0 0.0 2.2 Renal ca. ACHN 0.0 0.0 3.5 Adrenal gland 0.0 0.0 3.6 Renal ca. UO-31 0.0 0.0 2.5 Thyroid 0.0 0.0 3.7 Renal ca. TK-10 0.0 0.0 2.3 Salivary gland 0.0 0.0 2.8 Liver 0.0 0.0 2.6 Pituitary gland 0.0 0.0 2.4 Liver (fetal) 0.0 0.0 3.0 Brain (fetal) 0.0 0.0 3.2 Liver ca. (hepatoblast) HepG2 0.0 0.0 2.2 Brain (whole) 0.0 0.0 2.5 Lung 0.0 0.0 4.5 Brain (amygdala) 0.0 0.0 2.7 Lung (fetal) 0.0 0.0 3.4 Brain (cerebellum) 0.0 0.0 3.2 Lung ca. (small cell) LX-1 0.0 0.0 3.0 Brain (hippocampus) 0.0 0.0 4.6 Lung ca. (small cell) NCI-H69 0.0 0.0 2.4 Brain (substantia nigra) 0.0 0.0 3.1 Lung ca. (s.cell var.) SHP-77 0.0 0.0 2.0 Brain (thalamus) 0.0 0.0 4.0 Lung ca. (large cell)NCI-H460 37.1 39.8 68.8 Brain (hypothalamus) 0.0 0.0 4.7 Lung ca. (non-sm. cell) A549 0.0 0.0 2.1 Spinal cord 0.0 0.0 2.9 Lung ca. (non-s. cell) NCI-H23 0.0 0.0 3.7 glio/astro U87-MG 0.0 0.0 3.3 Lung ca. (non-s. cell) HOP-62 0.0 0.0 3.2 gilo/astro U-118-MG 0.0 0.0 2.4 Lung ca. (non-s. cl) NCI-H522 0.0 0.0 2.9 astrocytoma SW1783 0.0 0.0 3.1 Lung ca. (squam.) SW 900 0.0 0.0 3.4 neuro*; met SK-N-AS 0.0 0.0 3.0 Lung ca. (squam.) NCI-H596 0.0 0.0 2.9 astrocytoma SF-539 0.0 0.0 2.3 Mammary gland 0.0 0.0 2.9 astrocytoma SNB-75 0.0 0.0 2.6 Breast ca.* (pl. ef) MCF-7 0.0 0.0 2.1 glioma SNB-19 0.0 0.0 2.8 Breast ca.* (pl. ef) 0.0 0.0 2.9 MDA-MB-231 glioma U251 0.0 0.0 2.1 Breast ca.* (pl. ef) T47D 0.0 0.0 3.8 glioma SF-295 0.0 0.0 4.1 Breast ca. BT-549 0.0 0.0 2.0 Heart 0.0 0.0 4.5 Breast ca. MDA-N 0.0 0.0 2.4 Skeletal muscle 0.0 0.0 2.8 Ovary 0.0 0.0 3.0 Bone marrow 0.0 0.0 2.8 Ovarian ca. OVCAR-3 0.0 0.0 6.9 Thymus 0.0 0.0 4.6 Ovarian ca. OVCAR-4 0.0 0.0 2.2 Spleen 0.0 0.0 2.2 Ovarian ca. OVCAR-5 0.0 0.0 2.7 Lymph node 0.0 0.0 2.4 Ovarian ca. OVCAR-8 0.0 0.0 3.0 Colon (ascending) 0.0 0.0 2.0 Ovarian ca. IGROV-1 0.0 0.0 2.6 Stomach 0.0 0.0 3.6 Ovarian ca. (ascites) SK-OV-3 0.0 0.0 2.8 Small intestine 0.0 0.0 2.5 Uterus 0.0 0.0 2.3 Colon ca. SW480 0.0 0.0 2.4 Placenta 0.0 0.0 4.7 Colon ca.* SW620 (SW480 met) 0.0 0.0 2.7 Prostate 0.0 0.0 2.4 Colon ca. HT29 0.0 0.0 2.5 Prostate ca.* (bone met) PC-3 100.0 100.0 100.0 Colon ca. HCT-116 0.0 0.0 2.8 Testis 0.0 10.0 5.3 Colon ca. CaCo-2 0.0 0.0 4.0 Melanoma Hs688(A).T 0.0 0.0 2.4 Colon ca. HCT-15 0.0 0.0 2.0 Melanoma* (met) Hs688(B).T 0.0 0.0 3.7 Colon ca. HCC-2998 0.0 0.0 2.6 Melanoma UACC-62 0.0 0.0 3.1 Gastric ca.* (liver met) 0.0 0.0 3.1 Melanoma M14 0.0 0.0 2.4 NCI-N87 Bladder 0.0 0.0 2.8 Melanoma LOX IMVI 0.0 0.0 3.3 Trachea 0.0 0.0 2.7 Melanoma* (met) SK-MEL-5 0.0 0.0 2.5 Kidney 0.0 0.0 2.4 Melanoma SK-MEL-28 0.0 0.0 2.6 Kidney (fetal) 0.0 0.0 3.3 Column A - Rel. Exp. (%) Ag264, Run 87590466 Column B - Rel. Exp. (%) Ag264, Run 88794920 Column C - Rel. Exp. (%) Ag264b, Run 97806010

[0703] 113 TABLE FG Panel 1.2 Tissue Name A B Tissue Name A B Endothelial cells 2.9 0.0 Renal ca. 786-0 1.6 0.4 Heart (Fetal) 0.2 0.0 Renal ca. A498 1.1 0.0 Pancreas 4.5 0.1 Renal ca. RXF 393 0.1 0.0 Pancreatic ca. CAPAN 2 2.3 0.4 Renal ca. ACHN 3.4 0.6 Adrenal Gland 1.6 0.1 Renal ca. UO-31 4.5 0.1 Thyroid 0.9 0.0 Renal ca. TK-10 8.0 2.2 Salivary gland 3.8 0.7 Liver 1.0 0.0 Pituitary gland 1.3 0.0 Liver (fetal) 1.1 0.3 Brain (fetal) 1.0 0.0 Liver ca. (hepatoblast) HepG2 1.3 0.0 Brain (whole) 1.0 0.0 Lung 6.7 5.1 Brain (amygdala) 0.2 0.0 Lung (fetal) 1.5 0.9 Brain (cerebellum) 1.4 0.0 Lung ca. (small cell) LX-1 6.5 1.2 Brain (hippocampus) 0.4 0.0 Lung ca. (small cell) NCI-H69 0.9 0.1 Brain (thalamus) 0.6 0.0 Lung ca. (s. cell var.) SHP-77 0.4 0.0 Cerebral Cortex 2.0 0.0 Lung ca. (large cell)NCI-H460 41.8 36.3 Spinal cord 2.6 0.3 Lung ca. (non-sm. cell) A549 3.3 0.8 glio/astro U87-MG 13.5 6.5 Lung ca. (non-s. cell) NCI-H23 1.1 0.0 glio/astro U-118-MG 2.2 0.9 Lung ca. (non-s. cell) HOP-62 6.8 3.7 astrocytoma SW1783 1.6 0.9 Lung ca. (non-s. cl) NCI-H522 20.6 10.1 neuro*; met SK-N-AS 4.9 0.0 Lung ca. (squam.) SW 900 10.4 6.5 astrocytoma SF-539 0.5 0.0 Lung ca. (squam.) NCI-H596 1.5 0.0 astrocytoma SNB-75 0.1 0.0 Mammary gland 5.5 0.8 glioma SNB-19 4.4 1.0 Breast ca.* (pl. ef) MCF-7 0.4 0.0 glioma U251 0.8 0.0 Breast ca.* (pl. ef) MDA-MB-231 2.2 0.8 glioma SF-295 4.0 0.0 Breast ca.* (pl. ef) T47D 4.0 1.9 Heart 5.3 3.4 Breast ca. BT-549 0.7 0.1 Skeletal Muscle 1.4 0.0 Breast ca. MDA-N 15.0 0.0 Bone marrow 1.7 2.1 Ovary 0.2 0.0 Thymus 0.0 0.2 Ovarian ca. OVCAR-3 16.3 6.9 Spleen 0.6 0.0 Ovarian ca. OVCAR-4 0.5 0.0 Lymph node 0.8 0.0 Ovarian ca. OVCAR-5 6.9 2.6 Colorectal Tissue 0.1 0.0 Ovarian ca. OVCAR-8 0.2 0.0 Stomach 3.7 1.8 Ovarian ca. IGROV-1 12.6 8.5 Small intestine 1.1 0.1 Ovarian ca. (ascites) SK-OV-3 3.1 0.9 Colon ca. SW480 0.3 0.0 Uterus 0.4 0.0 Colon ca.* SW620 (SW480 met) 1.9 0.0 Placenta 6.5 4.7 Colon ca. HT29 2.2 0.3 Prostate 0.8 0.0 Colon ca. HCT-116 3.4 1.4 Prostate ca.* (bone met) PC-3 100.0 100.0 Colon ca. CaCo-2 1.2 0.2 Testis 8.7 8.0 Colon ca. Tissue (ODO3866) 0.3 0.0 Melanoma Hs688(A).T 0.5 0.0 Colon ca. HCC-2998 5.8 2.0 Melanoma* (met) Hs688(B).T 1.4 0.7 Gastric ca.* (liver met) NCI-N87 11.9 2.9 Melanoma UACC-62 1.0 0.0 Bladder 2.5 0.8 Melanoma M14 4.0 0.0 Trachea 1.2 0.0 Melanoma LOX IMVI 1.5 0.3 Kidney 2.3 0.0 Melanoma* (met) SK-MEL-5 5.1 0.0 Kidney (fetal) 2.5 0.2 Coumn A - Rel. Exp. (%) Ag692, Run 114250175 Column B - Rel. Exp. (%) Ag692, Run 117052376

[0704] 114 TABLE FH Panel 2D Tissue Name A B Tissue Name A B Normal Colon 3.1 3.2 Kidney Margin 8120608 0.0 0.0 CC Well to Mod Diff (ODO3866) 0.0 0.3 Kidney Cancer 8120613 0.0 0.0 CC Margin (ODO3866) 0.0 1.0 Kidney Margin 8120614 0.0 0.0 CC Gr.2 rectosigmoid (ODO3868) 0.7 0.0 Kidney Cancer 9010320 0.0 0.0 CC Margin (ODO3868) 0.0 0.6 Kidney Margin 9010321 0.0 0.3 CC Mod Diff (ODO3920) 0.0 0.0 Normal Uterus 0.0 0.0 CC Margin (ODO3920) 0.0 0.3 Uterus Cancer 064011 0.0 0.5 CC Gr. 2 ascend colon (ODO3921) 0.0 0.7 Normal Thyroid 0.2 0.0 CC Margin (ODO3921) 0.0 1.3 Thyroid Cancer 064010 0.0 0.3 CC from Partial Hepatectomy 0.0 0.3 Thyroid Cancer A302152 0.3 0.0 (ODO4309) Mets Liver Margin (ODO4309) 0.0 0.0 Thyroid Margin A302153 0.0 0.3 Colon mets to lung (OD04451-01) 0.3 1.0 Normal Breast 2.6 2.4 Lung Margin (OD04451-02) 4.5 1.3 Breast Cancer (OD04566) 0.0 0.0 Normal Prostate 6546-1 0.0 1.4 Breast Cancer (OD04590-01) 0.0 0.0 Prostate Cancer (OD04410) 0.5 0.9 Breast Cancer Mets 0.3 0.0 (OD04590-03) Prostate Margin (OD04410) 0.0 0.3 Breast Cancer Metastasis 0.0 0.3 (OD04655-05) Prostate Cancer (OD04720-01) 0.4 0.3 Breast Cancer 064006 11.9 7.4 Prostate Margin (OD04720-02) 1.7 2.7 Breast Cancer 1024 3.1 3.1 Normal Lung 061010 0.3 1.1 Breast Cancer 9100266 0.4 0.0 Lung Met to Muscle (ODO4286) 100.0 98.6 Breast Margin 9100265 0.0 0.3 Muscle Margin (ODO4286) 0.0 0.9 Breast Cancer A209073 22.7 16.2 Lung Malignant Cancer (OD03126) 0.3 0.9 Breast Margin A209073 2.2 1.6 Lung Margin (OD03126) 0.8 2.3 Normal Liver 0.0 0.7 Lung Cancer (OD04404) 81.2 100.0 Liver Cancer 064003 0.0 0.5 Lung Margin (OD04404) 3.7 3.8 Liver Cancer 1025 0.0 0.3 Lung Cancer (OD04565) 5.8 3.8 Liver Cancer 1026 0.0 0.0 Lung Margin (OD04565) 0.0 0.7 Liver Cancer 6004-T 0.0 0.7 Lung Cancer (OD04237-01) 0.7 1.0 Liver Tissue 6004-N 0.0 0.1 Lung Margin (OD04237-02) 4.9 8.8 Liver Cancer 6005-T 0.0 0.2 Ocular Mel Met to Liver (ODO4310) 0.0 0.0 Liver Tissue 6005-N 0.0 0.0 Liver Margin (ODO4310) 0.0 0.5 Normal Bladder 0.7 0.0 Melanoma Mets to Lung (OD04321) 0.0 0.0 Bladder Cancer 1023 0.0 0.0 Lung Margin (OD04321) 8.8 7.5 Bladder Cancer A302173 50.7 48.6 Normal Kidney 0.0 1.0 Bladder Cancer (OD04718-01) 7.3 7.0 Kidney Ca, Nuclear grade 2 1.6 1.6 Bladder Normal Adjacent 0.3 0.5 (OD04338) (OD04718-03) Kidney Margin (OD04338) 0.0 0.6 Normal Ovary 0.0 0.0 Kidney Ca Nuclear grade 1/2 0.0 1.8 Ovarian Cancer 064008 3.8 5.6 (OD04339) Kidney Margin (OD04339) 0.2 0.6 Ovarian Cancer (OD04768-07) 0.0 0.0 Kidney Ca, Clear cell type (OD04340) 0.3 1.3 Ovary Margin (OD04768-08) 34.2 28.1 Kidney Margin (OD04340) 0.8 2.4 Normal Stomach 0.0 0.0 Kidney Ca, Nuclear grade 3 0.0 0.0 Gastric Cancer 9060358 0.0 0.0 (OD04348) Kidney Margin (OD04348) 1.4 0.8 Stomach Margin 9060359 0.0 0.0 Kidney Cancer (OD04622-01) 0.3 0.3 Gastric Cancer 9060395 0.3 0.5 Kidney Margin (OD04622-03) 0.3 0.3 Stomach Margin 9060394 0.0 0.0 Kidney Cancer (OD04450-01) 0.0 0.0 Gastric Cancer 9060397 0.0 0.0 Kidney Margin (OD04450-03) 0.0 0.6 Stomach Margin 9060396 0.0 0.0 Kidney Cancer 8120607 0.3 0.0 Gastric Cancer 064005 0.0 0.2 Coumn A - Rel. Exp. (%) Ag264, Run 144872209 Column B - Rel. Exp. (%) Ag692, Run 145177146

[0705] 115 TABLE FI Panel 4D Tissue Name A Tissue Name A Secondary Th1 act 2.2 HUVEC IL-1beta 0.3 Secondary Th2 act 2.8 HUVEC IFN gamma 1.3 Secondary Tr1 act 8.4 HUVEC TNF alpha + IFN gamma 0.0 Secondary Th1 rest 0.4 HUVEC TNF alpha + IL4 0.0 Secondary Th2 rest 3.5 HUVEC IL-11 0.5 Secondary Tr1 rest 0.4 Lung Microvascular EC none 1.0 Primary Th1 act 0.4 Lung Microvascular EC TNF alpha + IL-1beta 0.4 Primary Th2 act 1.2 Microvascular Dermal EC none 2.1 Primary Tr1 act 1.4 Microsvasular Dermal EC TNF alpha + IL-1beta 0.4 Primary Th1 rest 1.6 Bronchial epithelium TNF alpha + IL1beta 12.3 Primary Th2 rest 2.5 Small airway epithelium none 15.6 Primary Tr1 rest 2.4 Small airway epithelium TNF alpha + IL-1beta 100.0 CD45RA CD4 lymphocyte act 1.4 Coronery artery SMC rest 3.6 CD45RO CD4 lymphocyte act 1.8 Coronery artery SMC TNF alpha + IL-1beta 0.6 CD8 lymphocyte act 0.5 Astrocytes rest 1.0 Secondary CD8 lymphocyte rest 1.5 Astrocytes TNF alpha + IL-1beta 1.1 Secondary CD8 lymphocyte act 0.0 KU-812 (Basophil) rest 19.1 CD4 lymphocyte none 2.7 KU-812 (Basophil) PMA/ionomycin 48.3 2ry Th1/Th2/Tr1_anti-CD95 CH11 4.2 CCD1106 (Keratinocytes) none 14.6 LAK cells rest 0.0 CCD1106 (Keratinocytes) TNF alpha + IL-1beta 14.3 LAK cells IL-2 1.2 Liver cirrhosis 3.2 LAK cells IL-2 + IL-12 1.8 Lupus kidney 0.3 LAK cells IL-2 + IFN gamma 2.5 NCI-H292 none 8.5 LAK cells IL-2 + IL-18 1.6 NCI-H292 IL-4 9.3 LAK cells PMA/ionomycin 3.0 NCI-H292 IL-9 13.2 NK Cells IL-2 rest 0.0 NCI-H292 IL-13 4.5 Two Way MLR 3 day 2.4 NCI-H292 IFN gamma 9.7 Two Way MLR 5 day 0.8 HPAEC none 0.4 Two Way MLR 7 day 0.0 HPAEC TNF alpha + IL-1beta 1.9 PBMC rest 0.8 Lung fibroblast none 0.9 PBMC PWM 4.6 Lung fibroblast TNF alpha + IL-1beta 0.0 PBMC PHA-L 0.0 Lung fibroblast IL-4 1.0 Ramos (B cell) none 0.8 Lung fibroblast IL-9 1.0 Ramos (B cell) ionomycin 0.8 Lung fibroblast IL-13 1.0 B lymphocytes PWM 0.4 Lung fibroblast IFN gamma 1.1 B lymphocytes CD40L and IL-4 0.7 Dermal fibroblast CCD1070 rest 2.6 EOL-1 dbcAMP 5.6 Dermal fibroblast CCD1070 TNF alpha 2.1 EOL-1 dbcAMP PMA/ionomycin 6.3 Dermal fibroblast CCD1070 IL-1beta 1.9 Dendritic cells none 0.0 Dermal fibroblast IFN gamma 1.1 Dendritic cells LPS 0.3 Dermal fibroblast IL-4 0.6 Dendritic cells anti-CD40 0.9 IBD Colitis 2 0.6 Monocytes rest 0.4 IBD Crohn's 0.4 Monocytes LPS 9.0 Colon 0.1 Macrophages rest 1.2 Lung 0.7 Macrophages LPS 0.1 Thymus 1.3 HUVEC none 0.0 Kidney 2.7 HUVEC starved 0.7 Clumn A - Rel. Exp.(%) Ag692, Run 164318656

[0706] 116 TABLE FJ Panel 5D Tissue Name A Tissue Name A 97457_Patient-02go_adipose 12.8 94709_Donor 2 AM - A_adipose 14.5 97476_Patient-07sk_skeletal muscle 0.0 94710_Donor 2 AM - B_adipose 14.2 97477_Patient-07ut_uterus 0.0 94711_Donor 2 AM - C_adipose 10.8 97478_Patient-07pl_placenta 1.8 94712_Donor 2 AD - A_adipose 33.4 97481_Patient-08sk_skeletal muscle 0.0 94713_Donor 2 AD - B_adipose 48.6 97482_Patient-08ut_uterus 0.0 94714_Donor 2 AD - C_adipose 42.9 97483_Patient-08pl_placenta 3.7 94742_Donor 3 U - A_Mesenchymal Stem 19.6 Cells 97486_Patient-09sk_skeletal muscle 0.0 94743_Donor 3 U - B_Mesenchymal Stem 21.3 Cells 97487_Patient-09ut_uterus 0.0 94730_Donor 3 AM - A_adipose 5.4 97488_Patient-09pl_placenta 0.0 94731_Donor 3 AM - B_adipose 10.3 97492_Patient-10ut_uterus 0.0 94732_Donor 3 AM - C_adipose 4.0 97493_Patient-10pl_placenta 2.0 94733_Donor 3 AD - A_adipose 100.0 97495_Patient-11go_adipose 20.6 94734_Donor 3 AD - B_adipose 57.0 97496_Patient-11sk_skeletal muscle 1.3 94735_Donor 3 AD - C_adipose 51.8 97497_Patient-11ut_uterus 0.0 77138_Liver_HepG2untreated 16.3 97498_Patient-11pl_placenta 0.0 73556_Heart_Cardiac stromal cells 0.0 (primary) 97500_Patient-12go_adipose 19.8 81735_Small Intestine 0.0 97501_Patient-12sk_skeletal muscle 3.3 72409_Kidney_Proximal Convoluted 3.4 Tubule 97502_Patient-12ut_uterus 0.0 82685_Small intestine_Duodenum 0.0 97503_Patient-12pl_placenta 0.0 90650_Adrenal_Adrenocortical adenoma 0.0 94721_Donor 2 U - A_Mesenchymal 57.0 72410_Kidney_HRCE 32.8 Stem Cells 94722_Donor 2 U - B_Mesenchymal Stem 50.7 72411_Kidney_HRE 68.8 Cells 94723_Donor 2 U - C_Mesenchymal Stem 56.6 73139_Uterus_Uterine smooth muscle cells 0.0 Cells Clumn A - Rel. Exp.(%) Ag692, Run 258587750

[0707] Ardais Prostate 1.0 Summary: Ag692 Highest expression of this gene is detected in normal prostate (CT=30). Moderate expression of this gene is also seen in normal and cancer samples derived from prostate.

[0708] Oncology_cell_line_screening_panel_v3.1 Summary: Ag264 Highest expression of this gene is seen in a bladder cancer cell line (CT=29). Moderate to low expression of this gene is also seen in a number of cancer cell line derived from tongue, pancreatic, T cell lymphoma, cervical, uterine and lung cancers. Therefore, therapeutic modulation of this gene or its protein product may be useful in the treatment of tongue, pancreatic, T cell lymphoma, cervical, uterine and lung cancers.

[0709] Panel 1 Summary: Ag264/Ag264b Results of three experiments with this gene show reasonable concordance. The expression of this gene is found to be highest in a sample derived from a prostate cancer cell line (CTs=24-26). In addition, there is substantial expression in a lung cancer cell line. Moreover, therapeutic modulation of this gene, through the use of small molecule drugs, protein therapeutics or antibodies might be of benefit in the treatment of prostate or lung cancer.

[0710] Panel 1.2 Summary: Ag692 The expression of this gene was assessed in two independent runs in this panel with excellent concordance between the results. The expression of this gene is found to be highest in a sample derived from a prostate cancer cell line (CTs=23-24). In addition there is substantial expression in a lung cancer cell line. This expression profile is consistent with the expression seen in Panel 1. Thus, the expression of this gene could be used to distinguish this prostate cell line sample from the other samples in the panel. Moreover, therapeutic modulation of this gene, through the use of small molecule drugs, protein therapeutics or antibodies might be of benefit in the treatment of prostate or lung cancer.

[0711] This gene also shows moderate expression in all CNS regions examined. TGF alpha has numerous roles in the CNS, including regulation of astrocyte reactivity, neuronal differentialtion and survivial, and protection of motor neurons (Boillee S, Cadusseau J, Coulpier M, Grannec G, Junier M P. Transforming growth factor alpha: a promoter of motoneuron survival of potential biological relevance. J Neurosci 2001 September 15;21(18):7079-88; Xian C J, Zhou X F. Roles of transforming growth factor-alpha and related molecules in the nervous system. Mol Neurobiol 1999 October-December;20(2-3):157-83; Junier M P. What role(s) for TGFalpha in the central nervous system? Prog Neurobiol 2000 December;62(5):443-73). Because of its possible neuroprotective effects, this molecule may be of use in the treatment of multiple sclerosis, ALS, Alzheimer's, Parkinson's, or Huntington's diseases, stroke, or brain or spinal cord trauma.

[0712] In addition, this gene is moderately expressed in pancreas, adrenal, thyroid, pituitary, skeletal muscle, and adult and fetal liver. Thus, this gene product may be an antibody target for the treatment of metabolic and endocrine disease, including obesity and Types 1 and 2 diabetes. Among metabolic tissues, this gene has highest expression in heart (CT values=27-29), and is 79% identical to mouse epigen protein. Epigen stimulates epithelial cell proliferation (Strachan L., Murison J. G., Prestidge R. L., Sleeman M. A., Watson J. D., Kumble K. D., 2001, Cloning and biological activity of Epigen, a novel member of the epidermal growth factor superfamily. J. Biol. Chem. 276:18265-18271.), suggesting that an antibody to this gene product may be useful for prevention of cardiomyocyte proliferation in diseases of cardiac hypertrophy.

[0713] Panel 2D Summary: Ag264/692 The expression of this gene was assessed in two independent runs on panel 2D using two different probe/primer pairs. The expression of this gene appears to be highest in samples derived from lung cancer tissue (CTs=28-30). In addition, there is substantial expression in samples derived from two breast cancers, bladder cancer and a sample of normal ovarian tissue. Thus, the expression of this gene could be used to distinguish these lung cancer samples from other samples in the panel. Moreover, therapeutic modulation of this gene, through the use of small molecule drugs, antibodies or protein therapeutics may be of benefit to the treatment of lung cancer, breast cancer or bladder cancer.

[0714] Panel 4D Summary: Ag692 This gene, a TGF-alpha-like Epigen protein homolog, is most highly expressed in small airway epithelium activated with TNFalpha+IL-1beta (CT=28.71) and in KU-812 basophil cells activated with phorbol ester and ionomycin (CT=29.76). Epigne has been shown to stimulate the growth of epithelial cells (Strachan L, Murison J G, Prestidge R L, Sleeman M A, Watson J D, Kumble K D. Cloning and biological activity of epigen, a novel member of the epidermal growth factor superfamily. J Biol Chem. 2001 May 25;276(21):18265-71, PMID: 11278323). Therefore, antibodies that block the action of this gene product may be useful as therapeutics to reduce or eliminate the symptoms in patients with asthma, emphysema, and allergy.

[0715] Panel 5D Summary: Ag692 Highest expression of this gene is detected in differentiated adipose tissue (CT=31.8). Significant expression of this gene is detected in undifferentiated mesenchymal cells, midway and fully differentiated adipose tissues, adipose samples from non-diabetic and diabetic patients, and kidney samples. This gene codes for a TGF-alpha like epigen/epidermal growth factor (EGF) protein homolog. EGF/TGF-alpha and of PGF2 alpha have been shown to act as differentiation inhibitors for adipocyte precursors in primary culture (Serrero G, Lepak N., 1996, Int J Obes Relat Metab Disord 20 Suppl 3:S58-64, PMID: 8680479). In addition, Matsumoto et al. (2002, Biochem Biophys Res Commun 292(3):781-6) have shown that heparin binding epidermal growth factor (HB-EGF) mRNA is abundantly expressed in human adipose tissue, and is increased in the fat tissues of obese mice. Therefore, therapeutic modulation of this gene or its protein product may be useful in the treatment of metabolic related diseases such as diabetes and obesity.

[0716] G. CG56136-01: IL1-Epsilon.

[0717] Expression of gene CG56136-01 was assessed using the primer-probe sets Ag2460 and Ag349, described in Tables GA and GB. Results of the RTQ-PCR runs are shown in Tables GC, GD, GE and GF. 117 TABLE GA Probe Name Ag2460 Start SEQ ID Primers Sequences Length Position No Forward 5′-tcatagcagtcccgaggaa-3′ 19 89 174 Probe TET-5′-tcactattgccttaatctcatgccga-3′-TAMRA 26 125 175 Reverse 5′-ttctcaagggtctccacatg-3′ 20 151 176

[0718] 118 TABLE GB Probe Name Ag349 Start SEQ ID Primers Sequences Length Position No Forward 5′-gggaaagccacagactcgaa-3′ 20 352 177 Probe TET-5′-cttctaccacagccagagtggcaggaact-3′-TAMRA 291 318 178 Reverse 5′-acccgagcctgtgaagtcct-3′ 20 294 1179

[0719] 119 TABLE GC Panel 1 Tissue Name A Tissue Name A Endothelial cells 0.0 Renal ca. 786-0 0.0 Endothelial cells (treated) 0.0 Renal ca. A498 0.2 Pancreas 0.0 Renal ca. RXF 393 0.0 Pancreatic ca. CAPAN 2 0.0 Renal ca. ACHN 0.0 Adrenal gland 0.0 Renal ca. UO-31 0.0 Thyroid 0.5 Renal ca. TK-10 0.0 Salivary gland 25.5 Liver 0.0 Pituitary gland 0.0 Liver (fetal) 0.0 Brain (fetal) 0.0 Liver ca. (hepatoblast) HepG2 0.0 Brain (whole) 0.0 Lung 0.0 Brain (amygdala) 0.0 Lung (fetal) 0.0 Brain (cerebellum) 0.0 Lung ca. (small cell) LX-1 0.0 Brain (hippocampus) 0.0 Lung ca. (small cell) NCI-H69 1.5 Brain (substantia nigra) 0.0 Lung ca. (s.cell var.) SHP-77 0.0 Brain (thalamus) 0.0 Lung ca. (large cell) NCI-H460 1.3 Brain (hypothalamus) 0.0 Lung ca. (non-sm. cell) A549 0.0 Spinal cord 0.0 Lung ca. (non-s.cell) NCI-H23 0.0 glio/astro U87-MG 59.0 Lung ca. (non-s.cell) HOP-62 0.0 glio/astro U-118-MG 0.0 Lung ca. (non-s.cl) NCI-H522 0.0 astrocytoma SW1783 0.0 Lung ca. (squam.) SW 900 0.0 neuro*; met SK-N-AS 0.0 Lung ca. (squam.) NCI-H596 0.0 astrocytoma SF-539 0.0 Mammary gland 0.0 astrocytoma SNB-75 0.0 Breast ca.* (pl.ef) MCF-7 0.0 glioma SNB-19 3.1 Breast ca.* (pl.ef) MDA-MB-231 0.0 glioma U251 0.0 Breast ca.* (pl. ef) T47D 0.0 glioma SF-295 0.0 Breast ca. BT-549 0.0 Heart 0.0 Breast ca. MDA-N 0.0 Skeletal muscle 0.0 Ovary 0.0 Bone marrow 0.0 Ovarian ca. OVCAR-3 0.0 Thymus 66.4 Ovarian ca. OVCAR-4 0.0 Spleen 0.1 Ovarian ca. OVCAR-5 1.5 Lymph node 3.1 Ovarian ca. OVCAR-8 0.0 Colon (ascending) 29.9 Ovarian ca. IGROV-1 0.0 Stomach 77.4 Ovarian ca (ascites) SK-OV-3 0.0 Small intestine 0.0 Uterus 0.0 Colon ca. SW480 0.0 Placenta 0.0 Colon ca.* SW620 (SW480 met) 0.0 Prostate 0.0 Colon ca. HT29 0.0 Prostate ca.* (bone met) PC-3 0.0 Colon ca. HCT-116 0.0 Testis 0.0 Colon ca. CaCo-2 0.0 Melanoma Hs688(A).T 0.0 Colon ca. HCT-15 0.0 Melanoma* (met) Hs688(B).T 0.0 Colon ca. HCC-2998 0.0 Melanoma UACC-62 0.0 Gastric ca.* (liver met) NCI-N87 0.0 Melanoma M14 0.0 Bladder 0.0 Melanoma LOX IMVI 0.0 Trachea 15.5 Melanoma* (met) SK-MEL-5 0.0 Kidney 0.0 Melanoma SK-MEL-28 100.0 Kidney (fetal) 0.0 Column A - Rel. Exp.(%) Ag349, Run 97804233

[0720] 120 TABLE GD Panel 1.3D Tissue Name A Tissue Name A Liver adenocarcinoma 0.0 Kidney (fetal) 0.0 Pancreas 0.0 Renal ca. 786-0 0.0 Pancreatic ca. CAPAN 2 0.0 Renal ca. A498 9.6 Adrenal gland 0.0 Renal ca. RXF 393 0.0 Thyroid 5.6 Renal ca. ACHN 0.0 Salivary gland 19.8 Renal ca. UO-31 0.0 Pituitary gland 0.0 Renal ca. TK-10 0.0 Brain (fetal) 0.0 Liver 0.0 Brain (whole) 0.0 Liver (fetal) 0.0 Brain (amygdala) 0.0 Liver ca. (hepatoblast) HepG2 0.0 Brain (cerebellum) 0.0 Lung 2.2 Brain (hippocampus) 0.0 Lung (fetal) 0.0 Brain (substantia nigra) 0.0 Lung ca. (small cell) LX-1 0.0 Brain (thalamus) 0.0 Lung ca. (small cell) NCI-H69 0.0 Cerebral Cortex 0.0 Lung ca. (s.cell var.) SHP-77 0.0 Spinal cord 45.7 Lung ca. (large cell) NCI-H460 0.0 glio/astro U87-MG 2.4 Lung ca. (non-sm. cell) A549 0.0 glio/astro U-118-MG 2.5 Lung ca. (non-s.cell) NCI-H23 0.0 astrocytoma SW1783 0.0 Lung ca. (non-s.cell) HOP-62 0.0 neuro*; met SK-N-AS 0.0 Lung ca. (non-s.cl) NCI-H522 0.0 astrocytoma SF-539 0.0 Lung ca. (squam.) SW 900 0.0 astrocytoma SNB-75 0.0 Lung ca. (squam.) NCI-H596 0.0 glioma SNB-19 0.0 Mammary gland 100.0 glioma U251 0.0 Breast ca.* (pl.ef) MCF-7 0.0 glioma SF-295 0.0 Breast ca.* (pl.ef) MDA-MB-231 0.0 Heart (fetal) 0.0 Breast ca.* (pl.ef) T47D 0.0 Heart 0.0 Breast ca. BT-549 0.0 Skeletal muscle (fetal) 0.0 Breast ca. MDA-N 0.0 Skeletal muscle 0.0 Ovary 0.0 Bone marrow 0.0 Ovarian ca. OVCAR-3 0.0 Thymus 61.1 Ovarian ca. OVCAR-4 0.0 Spleen 0.0 Ovarian ca. OVCAR-5 0.0 Lymph node 8.4 Ovarian ca. OVCAR-8 0.0 Colorectal 0.0 Ovarian ca. IGROV-1 0.0 Stomach 77.4 Ovarian ca.* (ascites) SK-OV-3 0.0 Small intestine 0.0 Uterus 0.0 Colon ca. SW480 0.0 Placenta 0.0 Colon ca.* SW620(SW480 met) 0.0 Prostate 2.3 Colon ca. HT29 0.0 Prostate ca.* (bone met) PC-3 0.0 Colon ca. HCT-116 0.0 Testis 0.0 Colon ca.CaCo-2 0.0 Melanoma Hs688(A).T 0.0 Colon ca. tissue(ODO3866) 0.0 Melanoma* (met) Hs688(B).T 0.0 Colon ca. HCC-2998 0.0 Melanoma UACC-62 0.0 Gastric ca.* (liver met) NCI-N87 0.0 Melanoma M14 0.0 Bladder 0.0 Melanoma LOX IMVI 0.0 Trachea 59.5 Melanoma* (met) SK-MEL-5 0.0 Kidney 0.0 Adipose 0.0 Column A - Rel. Exp.(%) Ag2460, Run 157914666

[0721] 121 TABLE GE Panel 2D Tissue Name A Tissue Name A Normal Colon 0.0 Kidney Margin 8120608 0.0 CC Well to Mod Diff (ODO3866) 0.0 Kidney Cancer 8120613 0.0 CC Margin (ODO3866) 0.0 Kidney Margin 8120614 0.0 CC Gr.2 rectosigmoid (ODO3868) 0.0 Kidney Cancer 9010320 0.0 CC Margin (ODO3868) 0.0 Kidney Margin 9010321 0.0 CC Mod Diff (ODO3920) 0.0 Normal Uterus 0.0 CC Margin (ODO3920) 0.0 Uterus Cancer 064011 0.0 CC Gr.2 ascend colon (ODO3921) 0.0 Normal Thyroid 0.9 CC Margin (ODO3921) 0.0 Thyroid Cancer 064010 0.0 CC from Partial Hepatectomy (ODO4309) 0.0 Thyroid Cancer A302152 0.0 Mets Liver Margin (ODO4309) 0.0 Thyroid Margin A302153 0.0 Colon mets to lung (OD04451-01) 0.0 Normal Breast 0.0 Lung Margin (OD04451-02) 0.0 Breast Cancer (OD04566) 0.0 Normal Prostate 6546-1 0.0 Breast Cancer (OD04590-01) 0.0 Prostate Cancer (OD04410) 0.0 Breast Cancer Mets (OD04590-03) 0.2 Prostate Margin (OD04410) 0.0 Breast Cancer Metastasis (OD04655-05) 0.6 Prostate Cancer (OD04720-01) 0.0 Breast Cancer 064006 0.0 Prostate Margin (OD04720-02) 0.0 Breast Cancer 1024 0.0 Normal Lung 061010 0.4 Breast Cancer 9100266 0.0 Lung Met to Muscle (ODO4286) 0.0 Breast Margin 9100265 0.0 Muscle Margin (ODO4286) 0.0 Breast Cancer A209073 0.0 Lung Malignant Cancer (OD03126) 0.0 Breast Margin A209073 0.0 Lung Margin (OD03126) 0.0 Normal Liver 0.0 Lung Cancer (OD04404) 100.0 Liver Cancer 064003 0.0 Lung Margin (OD04404) 0.0 Liver Cancer 1025 0.1 Lung Cancer (OD04565) 0.5 Liver Cancer 1026 0.0 Lung Margin (OD04565) 0.0 Liver Cancer 6004-T 0.0 Lung Cancer (OD04237-01) 0.0 Liver Tissue 6004-N 0.0 Lung Margin (OD04237-02) 0.0 Liver Cancer 6005-T 0.0 Ocular Mel Met to Liver (ODO4310) 0.0 Liver Tissue 6005-N 0.0 Liver Margin (ODO4310) 0.0 Normal Bladder 0.0 Melanoma Mets to Lung (OD04321) 0.0 Bladder Cancer 1023 0.0 Lung Margin (OD04321) 0.0 Bladder Cancer A302173 0.0 Normal Kidney 0.0 Bladder Cancer (OD04718-01) 0.0 Kidney Ca, Nuclear grade 2 (OD04338) 0.0 Bladder Normal Adjacent 0.0 (OD04718-03) Kidney Margin (OD04338) 0.0 Normal Ovary 0.0 Kidney Ca Nuclear grade 1/2 (OD04339) 0.0 Ovarian Cancer 064008 0.0 Kidney Margin (OD04339) 0.0 Ovarian Cancer (OD04768-07) 0.0 Kidney Ca, Clear cell type (OD04340) 0.0 Ovary Margin (OD04768-08) 0.0 Kidney Margin (OD04340) 0.0 Normal Stomach 0.0 Kidney Ca, Nuclear grade 3 (OD04348) 0.0 Gastric Cancer 9060358 0.0 Kidney Margin (OD04348) 0.0 Stomach Margin 9060359 0.0 Kidney Cancer (OD04622-01) 0.0 Gastric Cancer 9060395 0.0 Kidney Margin (OD04622-03) 0.0 Stomach Margin 9060394 0.0 Kidney Cancer (OD04450-01) 0.0 Gastric Cancer 9060397 0.0 Kidney Cancer (OD04450-03) 0.0 Stomach Margin 9060396 0.0 Kidney Cancer 8120607 0.0 Gastric Cancer 064005 0.6 Column A - Rel. Exp.(%) Ag2460, Run 157914720

[0722] 122 TABLE GF Panel 4D Tissue Name A Tissue Name A Secondary Th1 act 0.4 HUVEC IL-1beta 0.0 Secondary Th2 act 0.0 HUVEC IFN gamma 0.0 Secondary Tr1 act 0.5 HUVEC TNF alpha + IFN gamma 0.0 Secondary Th1 rest 2.3 HUVEC TNF alpha + IL4 0.0 Secondary Th2 rest 0.5 HUVEC IL-11 0.0 Secondary Tr1 rest 3.7 Lung Microvascular EC none 0.0 Primary Th1 act 0.6 Lung Microvascular EC TNF alpha + IL-1beta 0.0 Primary Th2 act 1.1 Microvascular Dermal EC none 0.0 Primary Tr1 act 1.0 Microsvasular Dermal EC TNF alpha + IL-1beta 0.0 Primary Th1 rest 15.0 Bronchial epithelium TNF alpha + IL-1beta 0.0 Primary Th2 rest 9.2 Small airway epithelium none 2.1 Primary Tr1 rest 4.3 Small airway epithelium TNF alpha + IL-1beta 100.0 CD45RA CD4 lymphocyte act 0.9 Coronery artery SMC rest 0.0 CD45RO CD4 lymphocyte act 1.0 Coronery artery SMC TNF alpha + IL-1beta 0.0 CD8 lymphocyte act 1.1 Astrocytes rest 0.0 Secondary CD8 lymphocyte rest 0.5 Astrocytes TNF alpha + IL-1beta 0.0 Secondary CD8 lymphocyte act 0.5 KU-812 (Basophil) rest 0.0 CD4 lymphocyte none 1.0 KU-812 (Basophil) PMA/ionomycin 0.0 2ry Th1/Th2/Tr1_anti-CD95 CH11 2.6 CCD1106 (Keratinocytes) none 0.0 LAK cells rest 0.7 CCD1106 (Keratinocytes) TNF alpha + IL-1beta 0.5 LAK cells IL-2 0.0 Liver cirrhosis 0.0 LAK cells IL-2 + IL-12 0.0 Lupus kidney 0.0 LAK cells IL-2 + IFN gamma 0.5 NCI-H292 none 0.3 LAK cells IL-2 + IL-18 0.0 NCI-H292 IL-4 0.6 LAK cells PMA/ionomycin 0.0 NCI-H292 IL-9 1.1 LAK Cells IL-2 rest 0.0 NCI-H292 IL-13 0.0 Two Way MLR 3 day 0.0 NCI-H292 IFN gamma 0.0 Two Way MLR 5 day 0.0 HPAEC none 0.0 Two Way MLR 7 day 0.8 HPAEC TNF alpha + IL-1beta 0.0 PBMC rest 2.1 Lung fibroblast none 0.0 PBMC PWM 0.0 Lung fibroblast TNF alpha + IL-1beta 0.0 PBMC PHA-L 2.0 Lung fibroblast IL-4 0.0 Ramos (B cell) none 0.0 Lung fibroblast IL-9 0.0 Ramos (B cell) ionomycin 0.0 Lung fibroblast IL-13 0.0 B lymphocytes PWM 1.8 Lung fibroblast IFN gamma 0.0 B lymphocytes CD40L and IL-4 1.6 Dermal fibroblast CCD1070 rest 0.0 EOL-1 dbcAMP 0.0 Dermal fibroblast CCD1070 TNF alpha 0.8 EOL-1 dbcAMP PMA/ionomycin 0.0 Dermal fibroblast CCD1070 IL-1beta 0.0 Dendritic cells none 0.0 Dermal fibroblast IFN gamma 0.0 Dendritic cells LPS 0.0 Dermal fibroblast IL-4 0.0 Dendritic cells anti-CD40 0.0 IBD Colitis 2 0.0 Monocytes rest 0.0 IBD Crohn's 0.0 Monocytes LPS 1.1 Colon 0.0 Macrophages rest 0.6 Lung 0.0 Macrophages LPS 0.0 Thymus 0.0 HUVEC none 0.0 Kidney 9.9 HUVEC starved 0.0 Column A - Rel. Exp.(%) Ag2460, Run 157914794

[0723] Panel 1 Summary: Ag349 Highest expression of this gene is seen in a melanoma cell line (CT=28.7). There is also significant expression in thymus. Panel 4D further discusses the role of this gene in autoimmunity.

[0724] Panel 1.3D Summary: Ag2460 Expression of this gene is limited to a few samples that are all derived from normal tissue. Significant levels of expression are seen in mammary gland, trachea, stomach, thymus, and spinal cord. Thus, expression of this gene can be used to differentiate between these samples and other samples on this panel.

[0725] Panel 2D Summary: Ag2460 Expression of this gene is limited to a few samples, with highest expression in a lung cancer (CT=27.5). Thus, expression of this gene could be used to differentiate between this sample and other samples on this panel and as a marker to detect the presence of lung cancer. Furthermore, therapeutic modulation of the expression or function of this gene may be effective in the treatment of lung cancer.

[0726] Panel 4D Summary: Ag2460 This gene encodes a homolog of the IL-1 epsilon. Interleukin 1 (IL-1) is a member of a large family of cytokines, which modulates immune and inflammatory responses (Smith, D. E., Renshaw, B. R., Ketchem, R. R., Kubin, M., Garka, K. E. and Sims, J. E., 2000, Four new members expand the interleukin-1 superfamily J. Biol. Chem. 275 (2), 1169-1175). IL-1 molecules such as IL-1alpha, -beta, -delta, -gamma, and IL1-receptor agonist (IL-1ra) are typically secreted by macrophages, mononuclear cells, epithelial and endothelial cells. IL-1 molecules are first produced as precursors of about 30 kDa and do not contain a signal sequence. The IL-1 precursors are then proteolytically cleaved into their secreted active forms (˜17 kDa). Their immuno-modulatory functions are mediated by two IL-1 receptors, which are members of the immunoglobulin superfamily. The biological functions of IL-1 include: activation of vascular endothelial cells to secrete IL-6, increase leukocyte adhesion and activate mononuclear phagocytes which activate inflammatory leukocytes; tissue destruction, and fever. Given the biological potency of the IL-1 family of proteins, a need exists to identify new members of this family as well as understand the biological function of its members. The high levels of expression of this gene in small airway epithelium activated by treatment with TNF-alpha+IL-1 beta(CT=28.9) indicate that CG56136-01 may play a substantial role in mediating inflammation in the lung. Thus, therapeutic targeting of CG56136-01 with a monoclonal antibody is anticipated to limit or block the extent of inflammation potential and thus the symptoms, caused by pro-inflammatory cytokines such as IL-1 epsilon, when these cytokines are induced in allergic, asthma and COPD patients.

Example D Identification of Single Nucleotide Polymorphisms in NOVX Nucleic Acid Sequences

[0727] Variant sequences are also included in this application. A variant sequence can include a single nucleotide polymorphism (SNP). A SNP can, in some instances, be referred to as a “cSNP” to denote that the nucleotide sequence containing the SNP originates as a cDNA. A SNP can arise in several ways. For example, a SNP may be due to a substitution of one nucleotide for another at the polymorphic site. Such a substitution can be either a transition or a transversion. A SNP can also arise from a deletion of a nucleotide or an insertion of a nucleotide, relative to a reference allele. In this case, the polymorphic site is a site at which one allele bears a gap with respect to a particular nucleotide in another allele. SNPs occurring within genes may result in an alteration of the amino acid encoded by the gene at the position of the SNP. Intragenic SNPs may also be silent, when a codon including a SNP encodes the same amino acid as a result of the redundancy of the genetic code. SNPs occurring outside the region of a gene, or in an intron within a gene, do not result in changes in any amino acid sequence of a protein but may result in altered regulation of the expression pattern. Examples include alteration in temporal expression, physiological response regulation, cell type expression regulation, intensity of expression, and stability of transcribed message.

[0728] SeqCalling assemblies produced by the exon linking process were selected and extended using the following criteria. Genomic clones having regions with 98% identity to all or part of the initial or extended sequence were identified by BLASTN searches using the relevant sequence to query human genomic databases. The genomic clones that resulted were selected for further analysis because this identity indicates that these clones contain the genomic locus for these SeqCalling assemblies. These sequences were analyzed for putative coding regions as well as for similarity to the known DNA and protein sequences. Programs used for these analyses include Grail, Genscan, BLAST, HMMER, FASTA, Hybrid and other relevant programs.

[0729] Some additional genomic regions may have also been identified because selected SeqCalling assemblies map to those regions. Such SeqCalling sequences may have overlapped with regions defined by homology or exon prediction. They may also be included because the location of the fragment was in the vicinity of genomic regions identified by similarity or exon prediction that had been included in the original predicted sequence. The sequence so identified was manually assembled and then may have been extended using one or more additional sequences taken from CuraGen Corporation's human SeqCalling database. SeqCalling fragments suitable for inclusion were identified by the CuraTools™ program SeqExtend or by identifying SeqCalling fragments mapping to the appropriate regions of the genomic clones analyzed.

[0730] The regions defined by the procedures described above were then manually integrated and corrected for apparent inconsistencies that may have arisen, for example, from miscalled bases in the original fragments or from discrepancies between predicted exon junctions, EST locations and regions of sequence similarity, to derive the final sequence disclosed herein. When necessary, the process to identify and analyze SeqCalling assemblies and genomic clones was reiterated to derive the full length sequence (Alderborn et al., Determination of Single Nucleotide Polymorphisms by Real-time Pyrophosphate DNA Sequencing. Genome Research. 10 (8)1249-1265, 2000).

[0731] Variants are reported individually but any combination of all or a select subset of variants are also included as contemplated NOVX embodiments of the invention.

[0732] NOV1a SNP Data:

[0733] One polymorphic variant of NOV1a have been identified and are shown in Table D1. 123 TABLE D1 SNP Variants for CG50907-03. Nucleotides Amino Acids Variant Position Initial Modified Position Initial Modified 13382241 135 G A 43 Gly Gly

[0734] NOV2a SNP Data:

[0735] Nine polymorphic variants of NOV2a have been identified and are shown in Table D2. 124 TABLE D2 SNP Variants for CG51896-04. Nucleotides Amino Acids Variant Position Initial Modified Position Initial Modified 13379621 272 T C 8 Leu Pro 13376060 410 A G 54 His Arg 13376059 416 T C 56 Leu Pro 13374940 523 A G 92 Ser Gly 13375101 869 T C 207 Leu Pro 13379747 967 G C 240 Ala Pro 13381632 2366 A G 706 Lys Arg 13381633 2921 T C 891 Leu Pro 13381634 3018 G A 923 Met Ile

[0736] NOV3a SNP Data:

[0737] Seven polymorphic variants of NOV3a have been identified and are shown in Table D3. 125 TABLE D3 SNP Variants for CG52324-01. Nucleotides Amino Acids Variant Position Initial Modified Position Initial Modified 13382239 181 C T 23 Asp Asp 13376383 278 A G 56 Ile Val 13373853 426 C T 105 Pro Leu 13374241 485 G A 125 Glu Lys 13376382 591 A G 160 Lys Arg 13373851 661 T C 183 Arg Arg 13373849 756 A G 215 Glu Gly

[0738] NOV4a SNP Data:

[0739] One polymorphic variant of NOV4a have been identified and are shown in Table D4. 126 TABLE D4 SNP Variants for CG53054-02. Nucleotides Amino Acids Variant Position Initial Modified Position Initial Modified 13381656 685 C T 219 Arg Trp

[0740] NOV5a SNP Data:

[0741] One polymorphic variant of NOV5a have been identified and are shown in Table D5. 127 TABLE D5 SNP Variants for CG54818-01. Nucleotides Amino Acids Variant Position Initial Modified Position Initial Modified 13381700 1874 G A 470 Glu Lys

[0742] NOV6a SNP Data:

[0743] Three polymorphic variants of NOV6a have been identified and are shown in Table D6. 128 TABLE D6 SNP Variants for CG55023-01. Nucleotides Amino Acids Variant Position Initial Modified Position Initial Modified 13375083 80 T C 11 Leu Pro 13375081 383 T C 112 Ile Thr 13375082 482 A G 145 Asn Ser

[0744] NOV7a SNP Data:

[0745] Eighteen polymorphic variants of NOV7a have been identified and are shown in Table D7. 129 TABLE D7 SNP Variants for CG56136-01. Nucleotides Amino Acids Variant Position Initial Modified Position Initial Modified 13374788 35 A G 12 Gln Arg 13374176 112 C T 38 Arg Cys 13374789 160 A G 54 Thr Ala 13374790 194 T C 65 Leu Pro 13376575 197 G A 66 Gly Asp 13374179 206 G A 69 Gly Glu 13376735 240 G A 80 Gly Gly 13382221 269 A G 90 Lys Arg 13374181 273 T C 91 Asp Asp 13374870 287 A G 96 Tyr Cys 13374869 298 G T 100 Glu STOP 13374868 301 C T 101 Pro Ser 13376576 305 T C 102 Val Ala 13374177 340 A G 114 Arg Gly 13374867 365 C T 122 Ala Val 13374866 374 G A 125 Gly Asp 13376577 376 T C 126 Trp Arg 13379530 400 G A 134 Gly Arg 13374865 404 G A 135 Gly Asp 13374864 431 T C 144 Leu Pro 13374863 442 A G 148 Asn Asp 13374862 461 T C 154 Leu Ser 13374861 463 A G 155 Thr Ala 13374860 468 G A 156 Met Ile

Example E1 Expression of CG54818-03 Using Baculovirus Expression System

[0746] A 2.6 kb SalI-KpnI fragment containing the CG54818-03 sequence was subcloned into XhoI-KpnI digested pBlueBac4.5/V5-His (CuraGen Corporation) insect expression vector to generate plasmid, 2080. Following standard procedures (Invitrogen pBlueBac protocol), recombinant baculovirus was generated and plaque-purified. Fresh Sf9 cells in adherent culture were infected with the recombinant baculovirus. The culture media were harvested 5 days post-infection and assayed for CG54818-03 protein expression by Western blot under reducing conditions using an anti-V5 antibody. CG54818-03 is expressed as a 104 kDa protein. (FIG. E1.)

Example E2 Expression of CG55023-06 in Human Embryonic Kidney 293 Cells

[0747] A 0.266 kb BamHI-XhoI fragment containing the CG55023-06 sequence was subcloned into BamHI-XhoI digested pCEP4/Sec to generate plasmid 1939. The resulting plasmid 1939 was transfected into 293 cells using the LipofectaminePlus reagent following the manufacturer's instructions (Gibco/BRL). The cell pellet and supernatant were harvested 72 h post transfection and examined for CG55023-06 expression by Western blot (reducing conditions) using an anti-V5 antibody. CG55023-06 is expressed as a 16 kDa protein secreted by 293 cells (FIG. E2).

Example E3 Expression of CG55023-06 in Escherichia coli Strains E3381.s

[0748] A 0.266 kb BamHI-XhoI fragment containing the CG55023-06 sequence was subcloned into BamHI-XhoI digested pFLAG-CTS (Invitrogen) to generate plasmid 1922. The resulting plasmid 1922 was transformed into E. coli using the standard transformation protocol. The cell pellet and supernatant were harvested 2 h post induction with IPTG and examined for CG55023-06 expression by Western blot (reducing conditions) using an anti-FLAG antibody. CG55023-06 is expressed as a 16 kDa protein. (FIG. E3)

Example E4 Expression of CG55023-06 Using Baculovirus Expression System

[0749] A 0.266 kb BamHI-XhoI fragment containing the CG55023-06 sequence was subcloned into the pMelV5His (CuraGen Corporation) insect expression vector to generate plasmid 1940. Following standard procedures (Invitrogen pBlueBac protocol), recombinant baculovirus was generated and plaque-purified. Fresh Sf9 cells in adherent culture were infected with the recombinant baculovirus. The culture media was harvested after 5 days post-infection and assayed for CG55023-06 protein expression by Western blot (reducing conditions) using an anti-V5 antibody. CG55023-06 is expressed as a 16 kDa protein (FIG. E4).

Example E5 Expression of CG56136-03 in Human Embryonic Kidney 293 Cells

[0750] A 0.474 kb BamHI-XhoI fragment containing the CG56136-03 sequence was subcloned into BamHI-XhoI digested pCEP4/Sec to generate plasmid 837. The resulting plasmid 1837 was transfected into 293 cells using the LipofectaminePlus reagent following the manufacturer's instructions (Gibco/BRL). The cell pellet and supernatant were harvested 72 h post transfection and examined for CG56136-03 expression by Western blot (reducing conditions) using an anti-V5 antibody. CG56136-03 is expressed as a 30 kDa protein secreted by 293 cells. (FIG. E5.)

Example F PathCalling™ Data

[0751] See Above Example B for Description of PathCalling Technology.

[0752] As shown in FIG. F1 below, data obtained from PathCalling shows that CG54818-01, a Sema 3E protein, interacts with dickkopf (DKK1) (AC094907) protein. Table F1 summarizes the amino acid sequences of the bait and prey used to detect this novel interaction. 130 TABLE F1 Yeast Two-hybrid Interaction Information Interaction Sema 3E Interaction DKK1 Interaction Number of Yeast Frame Domain (aa) Domain (aa) Colonies Observed 1 (+) Bait: 506-595 Prey: 130-266 1

[0753] Both Sema 3E and DKK1 proteins are extracellular. In a recent paper Sema 3E from chicken has been shown to inhibit growing retinal axons (Steinbach K, Volkmer H, Schlosshauer B., 2002, Semaphorin 3E/collapsin-5 inhibits growing retinal axons. Exp Cell Res. 279(1):52-61. PMID:12213213). Sema 3E is highly expressed in brain (See Table EG) and DKK1 is also known to regulate the spatial patterning/morphogenesis of the mammalian central nervous system. Thus, Sema 3E may play a role during CNS development.

[0754] In addition, human DKK-1 is shown to be a pro-apoptotic gene (Shou J, Ali-Osman F, Multani A S, Pathak S, Fedi P, Srivenugopal K S, 2002, Human Dkk-1, a gene encoding a Wnt antagonist, responds to DNA damage and its overexpression sensitizes brain tumor cells to apoptosis following alkylation damage of DNA. Oncogene 21(6):878-89, PMID: 11840333). DKK1 is a powerful inhibitor of the Wnt signaling pathway. It binds and inhibits the function of Wnt-co-receptor LRP6. Wnt proteins transmit myriad intercellular signals crucial for the development and homeostasis of metazoan animals from Hydra to human. Abnormal Wnt signaling causes a growing number of diseases, including cancer and osteoporosis (Wharton K A Jr., 2003, Runnin' with the Dvl: proteins that associate with Dsh/Dvl and their significance to Wnt signal transduction. Dev Biol. 2003 January 1;253(l):1-17. PMID: 12490194). Binding of Sema3E with DKK1 may relieve the Wnt-inhibitory activity of DKK1, potentiating Wnt signaling.

[0755] The function of SEMA3E outside the nervous system is not known. However, based on its expression in number of cancer samples and cancer cell line (See Tables EC, EF, EG, EH, and EM) it may play a role in tumorigenesis. The interaction between Sema3E and DKK1 suggest a mechanism by which Sema3E may be linked to cancer. The C-terminal domain of DKK1 binds Sema3E and interestingly, the same region has been shown to bind LRP protein (Brott B K, Sokol S Y., 2002, Regulation of Wnt/LRP signaling by distinct domains of Dickkopf proteins. Mol Cell Biol. 2002 September;22(17):6100-10. PMID 12167704). Therefore, binding of sema3E with DKK1 is likely to prevent interaction between DKK1 and LRP resulting in a loss of DKK1 antagonism. The region of sema3E that binds DKK1 is shared by other class 3 semaphorins suggesting that one of the function of this class of semaphorin may be to potentiate Wnt signaling.

OTHER EMBODIMENTS

[0756] Although particular embodiments have been disclosed herein in detail, this has been done by way of example for purposes of illustration only, and is not intended to be limiting with respect to the scope of the appended claims, which follow. In particular, it is contemplated by the inventors that various substitutions, alterations, and modifications may be made to the invention without departing from the spirit and scope of the invention as defined by the claims. The choice of nucleic acid starting material, clone of interest, or library type is believed to be a matter of routine for a person of ordinary skill in the art with knowledge of the embodiments described herein. Other aspects, advantages, and modifications considered to be within the scope of the following claims. The claims presented are representative of the inventions disclosed herein. Other, unclaimed inventions are also contemplated. Applicants reserve the right to pursue such inventions in later claims.

Claims

1. An isolated polypeptide comprising the mature form of an amino acid sequenced selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 64.

2. An isolated polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 64.

3. An isolated polypeptide comprising an amino acid sequence which is at least 95% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 64.

4. An isolated polypeptide, wherein the polypeptide comprises an amino acid sequence comprising one or more conservative substitutions in the amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 64.

5. The polypeptide of claim 1 wherein said polypeptide is naturally occurring.

6. A composition comprising the polypeptide of claim 1 and a carrier.

7. A kit comprising, in one or more containers, the composition of claim 6.

8. The use of a therapeutic in the manufacture of a medicament for treating a syndrome associated with a human disease, the disease selected from a pathology associated with the polypeptide of claim 1, wherein the therapeutic comprises the polypeptide of claim 1.

9. A method for determining the presence or amount of the polypeptide of claim 1 in a sample, the method comprising:

(a) providing said sample;

(b) introducing said sample to an antibody that binds immunospecifically to the polypeptide; and

(c) determining the presence or amount of antibody bound to said polypeptide, thereby determining the presence or amount of polypeptide in said sample.

10. A method for determining the presence of or predisposition to a disease associated with altered levels of expression of the polypeptide of claim 1 in a first mammalian subject, the method comprising:

a) measuring the level of expression of the polypeptide in a sample from the first mammalian subject; and

b) comparing the expression of said polypeptide in the sample of step (a) to the expression of the polypeptide present in a control sample from a second mammalian subject known not to have, or not to be predisposed to, said disease,

wherein an alteration in the level of expression of the polypeptide in the first subject as compared to the control sample indicates the presence of or predisposition to said disease.

11. A method of identifying an agent that binds to the polypeptide of claim 1, the method comprising:

(a) introducing said polypeptide to said agent; and

(b) determining whether said agent binds to said polypeptide.

12. The method of claim 11 wherein the agent is a cellular receptor or a downstream effector.

13. A method for identifying a potential therapeutic agent for use in treatment of a pathology, wherein the pathology is related to aberrant expression or aberrant physiological interactions of the polypeptide of claim 1, the method comprising:

(a) providing a cell expressing the polypeptide of claim 1 and having a property or function ascribable to the polypeptide;

(b) contacting the cell with a composition comprising a candidate substance; and

(c) determining whether the substance alters the property or function ascribable to the polypeptide;

whereby, if an alteration observed in the presence of the substance is not observed when the cell is contacted with a composition in the absence of the substance, the substance is identified as a potential therapeutic agent.

14. A method for screening for a modulator of activity of or of latency or predisposition to a pathology associated with the polypeptide of claim 1, said method comprising:

(a) administering a test compound to a test animal at increased risk for a pathology associated with the polypeptide of claim 1, wherein said test animal recombinantly expresses the polypeptide of claim 1;

(b) measuring the activity of said polypeptide in said test animal after administering the compound of step (a); and

(c) comparing the activity of said polypeptide in said test animal with the activity of said polypeptide in a control animal not administered said polypeptide, wherein a change in the activity of said polypeptide in said test animal relative to said control animal indicates the test compound is a modulator activity of or latency or predisposition to, a pathology associated with the polypeptide of claim 1.

15. The method of claim 14, wherein said test animal is a recombinant test animal that expresses a test protein transgene or expresses said transgene under the control of a promoter at an increased level relative to a wild-type test animal, and wherein said promoter is not the native gene promoter of said transgene.

16. A method for modulating the activity of the polypeptide of claim 1, the method comprising contacting a cell sample expressing the polypeptide of claim 1 with a compound that binds to said polypeptide in an amount sufficient to modulate the activity of the polypeptide.

17. A method of treating or preventing a pathology associated with the polypeptide of claim 1, the method comprising administering the polypeptide of claim 1 to a subject in which such treatment or prevention is desired in an amount sufficient to treat or prevent the pathology in the subject.

18. The method of claim 17, wherein the subject is a human.

19. A method of treating a pathological state in a mammal, the method comprising administering to the mammal a polypeptide in an amount that is sufficient to alleviate the pathological state, wherein the polypeptide is a polypeptide having an amino acid sequence at least 95% identical to a polypeptide comprising the amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 64, or a biologically active fragment thereof.

20. An isolated nucleic acid molecule comprising a nucleic acid sequence selected from the group consisting of SEQ ID NO:2n-1, wherein n is an integer between 1 and 64.

21. The nucleic acid molecule of claim 20, wherein the nucleic acid molecule is naturally occurring.

22. A nucleic acid molecule, wherein the nucleic acid molecule differs by a single nucleotide from a nucleic acid sequence selected from the group consisting of SEQ ID NO: 2n-1, wherein n is an integer between 1 and 64.

23. An isolated nucleic acid molecule encoding the mature form of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:2n, wherein n is an integer between 1 and 64.

24. An isolated nucleic acid molecule comprising a nucleic acid selected from the group consisting of 2n-1, wherein n is an integer between 1 and 64.

25. The nucleic acid molecule of claim 20, wherein said nucleic acid molecule hybridizes under stringent conditions to the nucleotide sequence selected from the group consisting of SEQ ID NO: 2n-1, wherein n is an integer between 1 and 64, or a complement of said nucleotide sequence.

26. A vector comprising the nucleic acid molecule of claim 20.

27. The vector of claim 26, further comprising a promoter operably linked to said nucleic acid molecule.

28. A cell comprising the vector of claim 26.

29. An antibody that immunospecifically binds to the polypeptide of claim 1.

30. The antibody of claim 29, wherein the antibody is a monoclonal antibody.

31. The antibody of claim 29, wherein the antibody is a humanized antibody.

32. A method for determining the presence or amount of the nucleic acid molecule of claim 20 in a sample, the method comprising:

(a) providing said sample;

(b) introducing said sample to a probe that binds to said nucleic acid molecule; and

(c) determining the presence or amount of said probe bound to said nucleic acid molecule,

thereby determining the presence or amount of the nucleic acid molecule in said sample.

33. The method of claim 32 wherein presence or amount of the nucleic acid molecule is used as a marker for cell or tissue type.

34. The method of claim 33 wherein the cell or tissue type is cancerous.

35. A method for determining the presence of or predisposition to a disease associated with altered levels of expression of the nucleic acid molecule of claim 20 in a first mammalian subject, the method comprising:

a) measuring the level of expression of the nucleic acid in a sample from the first mammalian subject; and

b) comparing the level of expression of said nucleic acid in the sample of step (a) to the level of expression of the nucleic acid present in a control sample from a second mammalian subject known not to have or not be predisposed to, the disease;

wherein an alteration in the level of expression of the nucleic acid in the first subject as compared to the control sample indicates the presence of or predisposition to the disease.

36. A method of producing the polypeptide of claim 1, the method comprising culturing a cell under conditions that lead to expression of the polypeptide, wherein said cell comprises a vector comprising an isolated nucleic acid molecule comprising a nucleic acid sequence selected from the group consisting of SEQ ID NO:2n-1, wherein n is an integer between 1 and 64.

37. The method of claim 36 wherein the cell is a bacterial cell.

38. The method of claim 36 wherein the cell is an insect cell.

39. The method of claim 36 wherein the cell is a yeast cell.

40. The method of claim 36 wherein the cell is a mammalian cell.

41. A method of producing the polypeptide of claim 2, the method comprising culturing a cell under conditions that lead to expression of the polypeptide, wherein said cell comprises a vector comprising an isolated nucleic acid molecule comprising a nucleic acid sequence selected from the group consisting of SEQ ID NO:2n-1, wherein n is an integer between 1 and 64.

42. The method of claim 41 wherein the cell is a bacterial cell.

43. The method of claim 41 wherein the cell is an insect cell.

44. The method of claim 41 wherein the cell is a yeast cell.

45. The method of claim 41 wherein the cell is a mammalian cell.

46. An isolated polypeptide comprising an amino acid sequence at least 95% similar to SEQ ID NO: 2, wherein said amino acid sequence comprises at least one amino acid substitution, wherein said substitution is at amino acid position 43 when numbered in accordance with SEQ ID NO: 2.

47. An isolated nucleic acid molecule comprising an nucleic acid sequence at least 95% similar to SEQ ID NO: 1, wherein said nucleic acid sequence comprises at least one nucleic acid substitution, wherein said substitution is at nucleic acid position 135 when numbered in accordance with SEQ ID NO: 1.

48. An isolated polypeptide comprising an amino acid sequence at least 95% similar to SEQ ID NO: 14, wherein said amino acid sequence comprises at least one amino acid substitution, wherein said substitution is at the amino acid position selected from the group consisting of 8, 54, 56, 92, 207, 240, 706, 891 and 923 when numbered in accordance with SEQ ID NO: 14.

49. An isolated nucleic acid molecule comprising an nucleic acid sequence at least 95% similar to SEQ ID NO: 13, wherein said nucleic acid sequence comprises at least one nucleic acid substitution, wherein said substitution is at the nucleic acid position selected from the group consisting of 272, 410, 416, 523, 869, 967, 2366, 2921 and 3018 when numbered in accordance with SEQ ID NO: 13.

50. An isolated polypeptide comprising an amino acid sequence at least 95% similar to SEQ ID NO: 58, wherein said amino acid sequence comprises at least one amino acid substitution, wherein said substitution is at the amino acid position selected from the group consisting of 23, 56, 105, 125, 160, 183 and 215 when numbered in accordance with SEQ ID NO: 58.

51. An isolated nucleic acid molecule comprising an nucleic acid sequence at least 95% similar to SEQ ID NO: 57, wherein said nucleic acid sequence comprises at least one nucleic acid substitution, wherein said substitution is at the nucleic acid position selected from the group consisting of 181, 278, 426, 485, 591, 661 and 756 when numbered in accordance with SEQ ID NO: 57.

52. An isolated polypeptide comprising an amino acid sequence at least 95% similar to SEQ ID NO: 80, wherein said amino acid sequence comprises at least one amino acid substitution, wherein said substitution is at amino acid position 219 when numbered in accordance with SEQ ID NO: 80.

53. An isolated nucleic acid molecule comprising an nucleic acid sequence at least 95% similar to SEQ ID NO: 79, wherein said nucleic acid sequence comprises at least one nucleic acid substitution, wherein said substitution is at nucleic acid position 685 when numbered in accordance with SEQ ID NO: 79.

54. An isolated polypeptide comprising an amino acid sequence at least 95% similar to SEQ ID NO: 92, wherein said amino acid sequence comprises at least one amino acid substitution, wherein said substitution is at amino acid position 470 when numbered in accordance with SEQ ID NO: 92.

55. An isolated nucleic acid molecule comprising an nucleic acid sequence at least 95% similar to SEQ ID NO: 91, wherein said nucleic acid sequence comprises at least one nucleic acid substitution, wherein said substitution is at nucleic acid position 1874 when numbered in accordance with SEQ ID NO: 91.

56. An isolated polypeptide comprising an amino acid sequence at least 95% similar to SEQ ID NO: 100, wherein said amino acid sequence comprises at least one amino acid substitution, wherein said substitution is at the amino acid position selected from the group consisting of 11, 112 and 145 when numbered in accordance with SEQ ID NO: 100.

57. An isolated nucleic acid molecule comprising an nucleic acid sequence at least 95% similar to SEQ ID NO: 99, wherein said nucleic acid sequence comprises at least one nucleic acid substitution, wherein said substitution is at the nucleic acid position selected from the group consisting of 80, 383 and 482 when numbered in accordance with SEQ ID NO: 99.

58. An isolated polypeptide comprising an amino acid sequence at least 95% similar to SEQ ID NO: 122, wherein said amino acid sequence comprises at least one amino acid substitution, wherein said substitution is at the amino acid position selected from the group consisting of 12, 38, 54, 65, 66, 69, 80, 90, 91, 96, 100, 101, 102, 114, 122, 125, 126, 134, 135, 144, 148, 154, 155 and 156 when numbered in accordance with SEQ ID NO: 122.

59. An isolated nucleic acid molecule comprising an nucleic acid sequence at least 95% similar to SEQ ID NO: 121, wherein said nucleic acid sequence comprises at least one nucleic acid substitution, wherein said substitution is at the nucleic acid position selected from the group consisting of 35, 112, 160, 194, 197, 206, 240, 269, 273, 287, 298, 301, 305, 340, 365, 374, 376, 400, 404, 431, 442, 461, 463 and 468 when numbered in accordance with SEQ ID NO: 121.