CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation-in-part of U.S. Ser. No. 10/714,333, filed Nov. 14, 2003, which claims the benefit of U.S. Provisional Application No. 60/426,137, filed Nov. 14, 2002, and also claims the benefit of U.S. Provisional Application No. 60/502,050, filed Sep. 10, 2003; this application is also a continuation-in-part of U.S. Ser. No. 10/940,892, filed Sep. 14, 2004, which is a continuation of PCT Application No. PCT/US04/14885, international filing date May 12, 2004. The disclosures of the priority applications, including the sequence listings and tables submitted in electronic form in lieu of paper, are incorporated by reference into the instant specification.
SEQUENCE LISTING The sequence listing for this application has been submitted in accordance with 37 CFR § 1.52(e) and 37 CFR § 1.821 on CD-ROM in lieu of paper on a disk containing the sequence listing file entitled “DHARMA—2100-US79_CRF.txt” created Sep. 28, 2007, 668 kb. Applicants hereby incorporate by reference the sequence listing provided on CD-ROM in lieu of paper into the instant specification.
FIELD OF INVENTION The present invention relates to RNA interference (“RNAi”).
BACKGROUND OF THE INVENTION Relatively recently, researchers observed that double stranded RNA (“dsRNA”) could be used to inhibit protein expression. This ability to silence a gene has broad potential for treating human diseases, and many researchers and commercial entities are currently investing considerable resources in developing therapies based on this technology.
Double stranded RNA induced gene silencing can occur on at least three different levels: (i) transcription inactivation, which refers to RNA guided DNA or histone methylation; (ii) siRNA induced mRNA degradation; and (iii) mRNA induced transcriptional attenuation.
It is generally considered that the major mechanism of RNA induced silencing (RNA interference, or RNAi) in mammalian cells is mRNA degradation. Initial attempts to use RNAi in mammalian cells focused on the use of long strands of dsRNA. However, these attempts to induce RNAi met with limited success, due in part to the induction of the interferon response, which results in a general, as opposed to a target-specific, inhibition of protein synthesis. Thus, long dsRNA is not a viable option for RNAi in mammalian systems.
More recently it has been shown that when short (18-30 bp) RNA duplexes are introduced into mammalian cells in culture, sequence-specific inhibition of target mRNA can be realized without inducing an interferon response. Certain of these short dsRNAs, referred to as small inhibitory RNAs (“siRNAs”), can act catalytically at sub-molar concentrations to cleave greater than 95% of the target mRNA in the cell. A description of the mechanisms for siRNA activity, as well as some of its applications are described in Provost et al (2002) Ribonuclease Activity and RNA Binding of Recombinant Human Dicer, EMBO J. 21(21): 5864-5874; Tabara et al. (2002) The dsRNA Binding Protein RDE-4 Interacts with RDE-1, DCR-1 and a DexH-box Helicase to Direct RNAi in C. elegans, Cell 109(7):861-71; Ketting et al. (2002) Dicer Functions in RNA Interference and in Synthesis of Small RNA Involved in Developmental Timing in C. elegans; Martinez et al., Single-Stranded Antisense siRNAs Guide Target RNA Cleavage in RNAi, Cell 110(5):563; Hutvagner & Zamore (2002) A microRNA in a multiple-turnover RNAi enzyme complex, Science 297:2056.
From a mechanistic perspective, introduction of long double stranded RNA into plants and invertebrate cells is broken down into siRNA by a Type III endonuclease known as Dicer. Sharp, RNA interference—2001, Genes Dev. 2001, 15:485. Dicer, a ribonuclease-III-like enzyme, processes the dsRNA into 19-23 base pair short interfering RNAs with characteristic two base 3′ overhangs. Bernstein, Caudy, Hammond, & Hannon (2001) Role for a bidentate ribonuclease in the initiation step of RNA interference, Nature 409:363. The siRNAs are then incorporated into an RNA-induced silencing complex (RISC) where one or more helicases unwind the siRNA duplex, enabling the complementary antisense strand to guide target recognition. Nykanen, Haley, & Zamore (2001) ATP requirements and small interfering RNA structure in the RNA interference pathway, Cell 107:309. Upon binding to the appropriate target mRNA, one or more endonucleases within the RISC cleaves the target to induce silencing. Elbashir, Lendeckel, & Tuschl (2001) RNA interference is mediated by 21- and 22-nucleotide RNAs, Genes Dev. 15:188, FIG. 1.
The interference effect can be long lasting and may be detectable after many cell divisions. Moreover, RNAi exhibits sequence specificity. Kisielow, M. et al. (2002) Isoform-specific knockdown and expression of adaptor protein ShcA using small interfering RNA, J. Biochem. 363:1-5. Thus, the RNAi machinery can specifically knock down one type of transcript, while not affecting closely related mRNA. These properties make siRNA a potentially valuable tool for inhibiting gene expression and studying gene function and drug target validation. Moreover, siRNAs are potentially useful as therapeutic agents against: (1) diseases that are caused by over-expression or misexpression of genes; and (2) diseases brought about by expression of genes that contain mutations.
Successful siRNA-dependent gene silencing depends on a number of factors. One of the most contentious issues in RNAi is the question of the necessity of siRNA design, i.e., considering the sequence of the siRNA used. Early work in C. elegans and plants circumvented the issue of design by introducing long dsRNA (see, for instance, Fire, A. et al. (1998) Nature 391:806-811). In this primitive organism, long dsRNA molecules are cleaved into siRNA by Dicer, thus generating a diverse population of duplexes that can potentially cover the entire transcript. While some fraction of these molecules are non-functional (i.e., induce little or no silencing) one or more have the potential to be highly functional, thereby silencing the gene of interest and alleviating the need for siRNA design. Unfortunately, due to the interferon response, this same approach is unavailable for mammalian systems. While this effect can be circumvented by bypassing the Dicer cleavage step and directly introducing siRNA, this tactic carries with it the risk that the chosen siRNA sequence may be non-functional or semi-functional.
A number of researches have expressed the view that siRNA design is not a crucial element of RNAi. On the other hand, others in the field have begun to explore the possibility that RNAi can be made more efficient by paying attention to the design of the siRNA. Unfortunately, none of the reported methods have provided a satisfactory scheme for reliably selecting siRNA with acceptable levels of functionality. Accordingly, there is a need to develop rational criteria by which to select siRNA with an acceptable level of functionality, and to identify siRNA that have this improved level of functionality, as well as to identify siRNAs that are hyperfunctional.
SUMMARY OF THE INVENTION The present invention is directed to increasing the efficiency of RNAi, particularly in mammalian systems. Accordingly, the present invention provides kits, siRNAs and methods for increasing siRNA efficacy.
According to a first embodiment, the present invention provides a kit for gene silencing, wherein said kit is comprised of a pool of at least two siRNA duplexes, each of which is comprised of a sequence that is complementary to a portion of the sequence of one or more target messenger RNA, and each of which is selected using non-target specific criteria.
According to a second embodiment, the present invention provides a method for selecting an siRNA, said method comprising applying selection criteria to a set of potential siRNA that comprise 18-30 base pairs, wherein said selection criteria are non-target specific criteria, and said set comprises at least two siRNAs and each of said at least two siRNAs contains a sequence that is at least substantially complementary to a target gene; and determining the relative functionality of the at least two siRNAs.
According to a third embodiment, the present invention also provides a method for selecting an siRNA wherein said selection criteria are embodied in a formula comprising:
(−14)*G13−13*A1−12*U7−11*U2−10*A11−10*U4−10*C3−10*C5−10*C6−9*A10−9*U9−9*C18−8*G10−7*U1−7*U16−7*C17−7*C19+7*U17+8*A2+8*A4+8*A5+8*C4+9*G8+10*A7+10*U18+11*A19+11*C9+15*G1+18*A3+19*U10−Tm−3*(GCtotal)−6*(GC15-19)−30*X; or Formula VIII
(−8)*A1+(−1)*A2+(12)*A3+(7)*A4+(18)*A5+(12)*A6+(19)*A7+(6)*A8+(−4)*A9+(−5)*A10+(−2)*A11+(−5)*A12+(17)*A13+(−3)*A14+(4)*A15+(2)*A16+(8)*A17+(11)*A18+(30)*A19+(−13)*U1+(−10)*U2+(2)*U3+(−2)*U4+(−5)*U5+(5)*U6+(−2)*U7+(−10)*U8+(−5)*U9+(15)*U10+(−1)*U11+(0)*U12+(10)*U13+(−9)*U14+(−13)*U15+(−10)*U16+(3)*U17+(9)*U18+(9)*U19+(7)*C1+(3)*C2+(−21)*C3+(5)*C4+(−9)*C5+(−20)*C6+(−18)*C7+(−5)*C8+(5)*C9+(1)*C10+(2)*C11+(−5)*C12+(−3)*C13+(−6)*C14+(−2)*C15+(−5)*C16+(−3)*C17+(−12)*C18+(−18)*C19+(14)*G1+(8)*G2+(7)*G3+(−10)*G4+(−4)*G5+(2)*G6+(1)*G7+(9)*G8+(5)*G9+(−11)*G10+(1)*G11+(9)*G12+(−24)*G13+(18)*G14+(11)*G15+(13)*G16+(−7)*G17+(−9)*G18+(−22)*G19+6*(number of A+U in position 15-19)-3*(number of G+C in whole siRNA), Formula X
wherein position numbering begins at the 5′-most position of a sense strand, and
A1=1 if A is the base at position 1 of the sense strand, otherwise its value is 0;
A2=1 if A is the base at position 2 of the sense strand, otherwise its value is 0;
A3=1 if A is the base at position 3 of the sense strand, otherwise its value is 0;
A4=1 if A is the base at position 4 of the sense strand, otherwise its value is 0;
A5=1 if A is the base at position 5 of the sense strand, otherwise its value is 0;
A6=1 if A is the base at position 6 of the sense strand, otherwise its value is 0;
A7=1 if A is the base at position 7 of the sense strand, otherwise its value is 0;
A10=1 if A is the base at position 10 of the sense strand, otherwise its value is 0;
A11=1 if A is the base at position 11 of the sense strand, otherwise its value is 0;
A13=1 if A is the base at position 13 of the sense strand, otherwise its value is 0;
A19=1 if A is the base at position 19 of the sense strand, otherwise if another base is present or the sense strand is only 18 base pairs in length, its value is 0;
C3=1 if C is the base at position 3 of the sense strand, otherwise its value is 0;
C4=1 if C is the base at position 4 of the sense strand, otherwise its value is 0;
C5=1 if C is the base at position 5 of the sense strand, otherwise its value is 0;
C6=1 if C is the base at position 6 of the sense strand, otherwise its value is 0;
C7=1 if C is the base at position 7 of the sense strand, otherwise its value is 0;
C9=1 if C is the base at position 9 of the sense strand, otherwise its value is 0;
C17=1 if C is the base at position 17 of the sense strand, otherwise its value is 0;
C18=1 if C is the base at position 18 of the sense strand, otherwise its value is 0;
C19=1 if C is the base at position 19 of the sense strand, otherwise if another base is present or the sense strand is only 18 base pairs in length, its value is 0;
G1=1 if G is the base at position 1 on the sense strand, otherwise its value is 0;
G2=1 if G is the base at position 2 of the sense strand, otherwise its value is 0;
G8=1 if G is the base at position 8 on the sense strand, otherwise its value is 0;
G10=1 if G is the base at position 10 on the sense strand, otherwise its value is 0;
G13=1 if G is the base at position 13 on the sense strand, otherwise its value is 0;
G19=1 if G is the base at position 19 of the sense strand, otherwise if another base is present or the sense strand is only 18 base pairs in length, its value is 0;
U1=1 if U is the base at position 1 on the sense strand, otherwise its value is 0;
U2=1 if U is the base at position 2 on the sense strand, otherwise its value is 0;
U3=1 if U is the base at position 3 on the sense strand, otherwise its value is 0;
U4=1 if U is the base at position 4 on the sense strand, otherwise its value is 0;
U7=1 if U is the base at position 7 on the sense strand, otherwise its value is 0;
U9=1 if U is the base at position 9 on the sense strand, otherwise its value is 0;
U10=1 if U is the base at position 10 on the sense strand, otherwise its value is 0;
U15=1 if U is the base at position 15 on the sense strand, otherwise its value is 0;
U16=1 if U is the base at position 16 on the sense strand, otherwise its value is 0;
U17=1 if U is the base at position 17 on the sense strand, otherwise its value is 0;
U18=1 if U is the base at position 18 on the sense strand, otherwise its value is 0.
GC5-19=the number of G and C bases within positions 15-19 of the sense strand, or within positions 15-18 if the sense strand is only 18 base pairs in length;
GCtotal=the number of G and C bases in the sense strand;
Tm=100 if the siRNA oligo has the internal repeat longer then 4 base pairs, otherwise its value is 0; and
X=the number of times that the same nucleotide repeats four or more times in a row.
According to a fourth embodiment, the invention provides a method for developing an algorithm for selecting siRNA, said method comprising: (a) selecting a set of siRNA; (b) measuring gene silencing ability of each siRNA from said set; (c) determining relative functionality of each siRNA; (d) determining improved functionality by the presence or absence of at least one variable selected from the group consisting of the presence or absence of a particular nucleotide at a particular position, the total number of As and Us in positions 15-19, the number of times that the same nucleotide repeats within a given sequence, and the total number of Gs and Cs; and (e) developing an algorithm using the information of step (d).
According to a fifth embodiment, the present invention provides a kit, wherein said kit is comprised of at least two siRNAs, wherein said at least two siRNAs comprise a first optimized siRNA and a second optimized siRNA, wherein said first optimized siRNA and said second optimized siRNA are optimized according a formula comprising Formula X.
The present invention also provides a method for identifying a hyperfunctional siRNA, comprising applying selection criteria to a set of potential siRNA that comprise 18-30 base pairs, wherein said selection criteria are non-target specific criteria, and said set comprises at least two siRNAs and each of said at least two siRNAs contains a sequence that is at least substantially complementary to a target gene; determining the relative functionality of the at least two siRNAs and assigning each of the at least two siRNAs a functionality score; and selecting siRNAs from the at least two siRNAs that have a functionality score that reflects greater than 80 percent silencing at a concentration in the picomolar range, wherein said greater than 80 percent silencing endures for greater than 120 hours.
According to a sixth embodiment, the present invention provides a hyperfunctional siRNA that is capable of silencing Bcl2.
According to a seventh embodiment, the present invention provides a method for developing an siRNA algorithm for selecting functional and hyperfunctional siRNAs for a given sequence. The method comprises:
(a) selecting a set of siRNAs;
(b) measuring the gene silencing ability of each siRNA from said set;
(c) determining the relative functionality of each siRNA;
(d) determining the amount of improved functionality by the presence or absence of at least one variable selected from the group consisting of the total GC content, melting temperature of the siRNA, GC content at positions 15-19, the presence or absence of a particular nucleotide at a particular position, relative thermodynamic stability at particular positions in a duplex, and the number of times that the same nucleotide repeats within a given sequence; and
(e) developing an algorithm using the information of step (d).
According to this embodiment, preferably the set of siRNAs comprises at least 90 siRNAs from at least one gene, more preferably at least 180 siRNAs from at least two different genes, and most preferably at least 270 and 360 siRNAs from at least three and four different genes, respectively. Additionally, in step (d) the determination is made with preferably at least two, more preferably at least three, even more preferably at least four, and most preferably all of the variables. The resulting algorithm is not target sequence specific.
In another embodiment, the present invention provides rationally designed siRNAs identified using the formulas above.
In yet another embodiment, the present invention is directed to hyperfunctional siRNA.
The ability to use the above algorithms, which are not sequence or species specific, allows for the cost-effective selection of optimized siRNAs for specific target sequences. Accordingly, there will be both greater efficiency and reliability in the use of siRNA technologies.
In various embodiments, siRNAs that target nucleotide sequences for deubiquitination enzymes are provided. In various embodiments, the siRNAs are rationally designed. In various embodiments, the siRNAs are functional or hyperfunctional.
In various embodiments, an siRNA that targets nucleotide sequence for a deubiquitination enzyme is provided, wherein the siRNA is selected from the group consisting of various siRNA sequences targeting nucleotide sequences for deubiquitination enzymes that are disclosed herein. In various embodiments, the siRNA sequence is selected from the group consisting of SEQ ID NO. 438 to SEQ ID NO. 3940.
In various embodiments, siRNA comprising a sense region and an antisense region are provided, said sense region and said antisense region together form a duplex region comprising 18-30 base pairs, and said sense region comprises a sequence that is at least 90% similar to a sequence selected from the group consisting of siRNA sequences targeting nucleotide sequences for deubiquitination enzymes that are disclosed herein. In various embodiments, the siRNA sequence is selected from the group consisting of SEQ ID NO. 438 to SEQ ID NO. 3940.
In various embodiments, an siRNA comprising a sense region and an antisense region is provided, said sense region and said antisense region together form a duplex region comprising 18-30 base pairs, and said sense region comprises a sequence that is identical to a contiguous stretch of at least 18 bases of a sequence selected from the group consisting of SEQ ID NO. 438 to SEQ ID NO. 3940. In various embodiments, the duplex region is 19-30 base pairs, and the sense region comprises a sequence that is identical to a sequence selected from the group consisting of SEQ ID NO. 438 to SEQ ID NO. 3940.
In various embodiments, a pool of at least two siRNAs is provided, wherein said pool comprises a first siRNA and a second siRNA, said first siRNA comprising a duplex region of length 18-30 base pairs that has a first sense region that is at least 90% similar to 18 bases of a first sequence selected from the group consisting of SEQ ID NO. 438 to SEQ ID NO. 3940, and said second siRNA comprises a duplex region of length 18-30 base pairs that has a second sense region that is at least 90% similar to 18 bases of a second sequence selected from the group consisting of SEQ ID NO. 438 to SEQ ID NO. 3940, wherein said first sense region and said second sense region are not identical.
In various embodiments, the first sense region comprises a sequence that is identical to at least 18 bases of a sequence selected from the group consisting of SEQ ID NO. 438 to SEQ ID NO. 3940, and said second sense region comprises a sequence that is identical to at least 18 bases of a sequence selected from the group consisting of SEQ ID NO. 438 to SEQ ID NO. 3940. In various embodiments, the duplex of said first siRNA is 19-30 base pairs, and said first sense region comprises a sequence that is at least 90% similar to a sequence selected from the group consisting of SEQ ID NO. 438 to SEQ ID NO. 3940, and said duplex of said second siRNA is 19-30 base pairs and comprises a sequence that is at least 90% similar to a sequence selected from the group consisting of SEQ ID NO. 438 to SEQ ID NO. 3940.
In various embodiments, the duplex of said first siRNA is 19-30 base pairs and said first sense region comprises a sequence that is identical to at least 18 bases of a sequence selected from the group consisting of SEQ ID NO. 438 to SEQ ID NO. 3940, and said duplex of said second siRNA is 19-30 base pairs and said second region comprises a sequence that is identical to a sequence selected from the group consisting of SEQ ID NO. 438 to SEQ ID NO. 3940.
For a better understanding of the present invention together with other and further advantages and embodiments, reference is made to the following description taken in conjunction with the examples, the scope of which is set forth in the appended claims.
BRIEF DESCRIPTION OF THE FIGURES FIG. 1 shows a model for siRNA-RISC interactions. RISC has the ability to interact with either end of the siRNA or miRNA molecule. Following binding, the duplex is unwound, and the relevant target is identified, cleaved, and released.
FIG. 2 is a representation of the functionality of two hundred and seventy siRNA duplexes that were generated to target human cyclophilin, human diazepam-binding inhibitor (DB), and firefly luciferase.
FIG. 3a is a representation of the silencing effect of 30 siRNAs in three different cells lines, HEK293, DU145, and Hela. FIG. 3b shows the frequency of different functional groups (>95% silencing (black), >80% silencing (gray), >50% silencing (dark gray), and <50% silencing (white)) based on GC content. In cases where a given bar is absent from a particular GC percentage, no siRNA were identified for that particular group. FIG. 3c shows the frequency of different functional groups based on melting temperature (Tm).
FIG. 4 is a representation of a statistical analysis that revealed correlations between silencing and five sequence-related properties of siRNA: (A) an A at position 19 of the sense strand, (B) an A at position 3 of the sense strand, (C) a U at position 10 of the sense strand, (D) a base other than G at position 13 of the sense strand, and (E) a base other than C at position 19 of the sense strand. All variables were correlated with siRNA silencing of firefly luciferase and human cyclophilin. siRNAs satisfying the criterion are grouped on the left (Selected) while those that do not, are grouped on the right (Eliminated). Y-axis is “% Silencing of Control.” Each position on the X-axis represents a unique siRNA.
FIGS. 5A and 5B are representations of firefly luciferase and cyclophilin siRNA panels sorted according to functionality and predicted values using Formula VIII. The siRNA found within the circle represent those that have Formula VIII values (SMARTSCORES™, or siRNA rank) above zero. siRNA outside the indicated area have calculated Formula VIII values that are below zero. Y-axis is “Expression (% Control).” Each position on the X-axis represents a unique siRNA.
FIG. 6A is a representation of the average internal stability profile (AISP) derived from 270 siRNAs taken from three separate genes (cyclophilin B, DBI and firefly luciferase). Graphs represent AISP values of highly functional, functional, and non-functional siRNA. FIG. 6B is a comparison between the AISP of naturally derived GFP siRNA (filled squares) and the AISP of siRNA from cyclophilin B, DBI, and luciferase having >90% silencing properties (no fill) for the antisense strand. “DG” is the symbol for ΔG, free energy.
FIG. 7 is a histogram showing the differences in duplex functionality upon introduction of base pair mismatches. The X-axis shows the mismatch introduced in the siRNA and the position it is introduced (e.g., 8C>A reveals that position 8 (which normally has a C) has been changed to an A). The Y-axis is “% Silencing (Normalized to Control).” The samples on the X-axis represent siRNAs at 100 nM and are, reading from left to right: 1A to C, 1A to G, 1A to U; 2A to C, 2A to G, 2A to U; 3A to C, 3A to G, 3A to U; 4G to A, 4G to C; 4G to U; 5U to A, 5U to C, 5U to G; 6U to A, 6U to C, 6U to G; 7G to A, 7G to C, 7G to U; 8C to A, 8C to G, 8C to U; 9G to A, 9G to C, 9G to U; 10C to A, 10C to G, 10C to U; 11G to A, 11G to C, 11G to U; 12G to A, 12G to C, 12G to U; 13A to C, 13A to G, 13A to U; 14G to A, 14G to C, 14G to U; 15G to A, 15G to C, 15G to U; 16A to C, 16A to G, 16A to U; 17G to A, 17G to C, 17G to U; 18U to A, 18U to C, 18U to G; 19U to A, 19U to C, 19U to G; 20 wt; Control.
FIG. 8 is histogram that shows the effects of 5′sense and antisense strand modification with 2′-O-methylation on functionality.
FIG. 9 shows a graph of SMARTSCORES™, or siRNA rank, versus RNAi silencing values for more than 360 siRNA directed against 30 different genes. SiRNA to the right of the vertical bar represent those siRNA that have desirable SMARTSCORES™, or siRNA rank.
FIGS. 10A-E compare the RNAi of five different genes (SEAP, DBI, PLK, Firefly Luciferase, and Renilla Luciferase) by varying numbers of randomly selected siRNA and four rationally designed (SMART-selected) siRNA chosen using the algorithm described in Formula VIII. In addition, RNAi induced by a pool of the four SMART-selected siRNA is reported at two different concentrations (100 and 400 nM). 10F is a comparison between a pool of randomly selected EGFR siRNA (Pool 1) and a pool of SMART-selected EGFR siRNA (Pool 2). Pool 1, S1-S4 and Pool 2 S1-S4 represent the individual members that made up each respective pool. Note that numbers for random siRNAs represent the position of the 5′ end of the sense strand of the duplex. The Y-axis represents the % expression of the control(s). The X-axis is the percent expression of the control.
FIG. 11 shows the Western blot results from cells treated with siRNA directed against twelve different genes involved in the clathrin-dependent endocytosis pathway (CHC, DynII, CALM, CLCa, CLCb, Eps15, Eps15R, Rab5a, Rab5b, Rab5c, P2 subunit of AP-2 and EEA.1). siRNA were selected using Formula VIII. “Pool” represents a mixture of duplexes 1-4. Total concentration of each siRNA in the pool is 25 nM. Total concentration=4×25=100 nM.
FIG. 12 is a representation of the gene silencing capabilities of rationally-selected siRNA directed against ten different genes (human and mouse cyclophilin, C-myc, human lamin A/C, QB (ubiquinol-cytochrome c reductase core protein I), MEK1 and MEK2, ATE1 (arginyl-tRNA protein transferase), GAPDH, and Eg5). The Y-axis is the percent expression of the control. Numbers 1, 2, 3 and 4 represent individual rationally selected siRNA. “Pool” represents a mixture of the four individual siRNA.
FIG. 13 is the sequence of the top ten Bcl2 siRNAs as determined by Formula VIII. Sequences are listed 5′ to 3′.
FIG. 14 is the knockdown by the top ten Bcl2 siRNAs at 100 nM concentrations. The Y-axis represents the amount of expression relative to the non-specific (ns) and transfection mixture control.
FIG. 15 represents a functional walk where siRNA beginning on every other base pair of a region of the luciferase gene are tested for the ability to silence the luciferase gene. The Y-axis represents the percent expression relative to a control. The X-axis represents the position of each individual siRNA. Reading from left to right across the X-axis, the position designations are 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, 87, 89, and Plasmid.
FIGS. 16A and 16B are histograms demonstrating the inhibition of target gene expression by pools of 2 (16A) and 3 (16B) siRNA duplexes taken from the walk described in FIG. 15. The Y-axis in each represents the percent expression relative to control. The X-axis in each represents the position of the first siRNA in paired pools, or trios of siRNAs. For instance, the first paired pool contains siRNAs 1 and 3. The second paired pool contains siRNAs 3 and 5. Pool 3 (of paired pools) contains siRNAs 5 and 7, and so on. For each of 16A and 16B, the X-axis from left to right reads 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, 87, 89, and Plasmid.
FIGS. 17A and 17B are histograms demonstrating the inhibition of target gene expression by pools of 4 (17A) and 5 (17B) siRNA duplexes. The Y-axis in each represents the percent expression relative to control. The X-axis in each represents the position of the first siRNA in each pool. For each of 17A and 17B, the X-axis from left to right reads 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, 87, 89, and Plasmid.
FIGS. 18A and 18B are histograms demonstrating the inhibition of target gene expression by siRNAs that are ten (18A) and twenty (18B) base pairs base pairs apart. The Y-axis represents the percent expression relative to a control. The X-axis represents the position of the first siRNA in each pool. For each of 18A and 18B, the X-axis from left to right reads 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, 87, 89, and Plasmid.
FIG. 19 shows that pools of siRNAs (dark gray bar) work as well (or better) than the best siRNA in the pool (light gray bar). The Y-axis represents the percent expression relative to a control. The X-axis represents the position of the first siRNA in each pool. The X-axis from left to right reads 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, 87, 89, and Plasmid.
FIG. 20 shows that the combination of several semifunctional siRNAs (dark gray) result in a significant improvement of gene expression inhibition over individual (semi-functional; light gray) siRNA. The Y-axis represents the percent expression relative to a control.
FIGS. 21A, 21B and 21C show both pools (Library, Lib) and individual siRNAs in inhibition of gene expression of Beta-Galactosidase, Renilla Luciferase and SEAP (alkaline phosphatase). Numbers on the X-axis indicate the position of the 5′-most nucleotide of the sense strand of the duplex. The Y-axis represents the percent expression of each gene relative to a control. Libraries contain 19 nucleotide long siRNAs (not including overhangs) that begin at the following nucleotides: SEAP: Lib 1: 206, 766, 812, 923, Lib 2: 1117, 1280, 1300, 1487, Lib 3: 206, 766, 812, 923, 1117, 1280, 1300, 1487, Lib 4: 206, 812, 1117, 1300, Lib 5: 766, 923, 1280, 1487, Lib 6: 206, 1487; Bgal: Lib 1: 979, 1339, 2029, 2590, Lib 2: 1087, 1783, 2399, 3257, Lib 3: 979, 1783, 2590, 3257, Lib 4: 979, 1087, 1339, 1783, 2029, 2399, 2590, 3257, Lib 5: 979, 1087, 1339, 1783, Lib 6: 2029, 2399, 2590, 3257; Renilla: Lib 1: 174, 300, 432, 568, Lib 2: 592, 633, 729, 867, Lib 3: 174, 300, 432, 568, 592, 633, 729, 867, Lib 4: 174, 432, 592, 729, Lib 5: 300, 568, 633, 867, Lib 6: 592, 568.
FIG. 22 shows the results of an EGFR and TfnR internalization assay when single gene knockdowns are performed. The Y-axis represents percent internalization relative to control.
FIG. 23 shows the results of an EGFR and TfnR internalization assay when multiple genes are knocked down (e.g., Rab5a, b, c). The Y-axis represents the percent internalization relative to control.
FIG. 24 shows the simultaneous knockdown of four different genes. siRNAs directed against G6PD, GAPDH, PLK, and UQC were simultaneously introduced into cells. Twenty-four hours later, cultures were harvested and assayed for mRNA target levels for each of the four genes. A comparison is made between cells transfected with individual siRNAs vs. a pool of siRNAs directed against all four genes.
FIG. 25 shows the functionality of ten siRNAs at 0.3 nM concentrations.
DETAILED DESCRIPTION Definitions Unless stated otherwise, the following terms and phrases have the meanings provided below:
Complementary
The term “complementary” refers to the ability of polynucleotides to form base pairs with one another. Base pairs are typically formed by hydrogen bonds between nucleotide units in antiparallel polynucleotide strands. Complementary polynucleotide strands can base pair in the Watson-Crick manner (e.g., A to T, A to U, C to G), or in any other manner that allows for the formation of duplexes. As persons skilled in the art are aware, when using RNA as opposed to DNA, uracil rather than thymine is the base that is considered to be complementary to adenosine. However, when a U is denoted in the context of the present invention, the ability to substitute a T is implied, unless otherwise stated.
Perfect complementarity or 100% complementarity refers to the situation in which each nucleotide unit of one polynucleotide strand can hydrogen bond with a nucleotide unit of a second polynucleotide strand. Less than perfect complementarity refers to the situation in which some, but not all, nucleotide units of two strands can hydrogen bond with each other. For example, for two 20-mers, if only two base pairs on each strand can hydrogen bond with each other, the polynucleotide strands exhibit 10% complementarity. In the same example, if 18 base pairs on each strand can hydrogen bond with each other, the polynucleotide strands exhibit 90% complementarity.
Deoxynucleotide
The term “deoxynucleotide” refers to a nucleotide or polynucleotide lacking a hydroxyl group (OH group) at the 2′ and/or 3′ position of a sugar moiety. Instead, it has a hydrogen bonded to the 2′ and/or 3′ carbon. Within an RNA molecule that comprises one or more deoxynucleotides, “deoxynucleotide” refers to the lack of an OH group at the 2′ position of the sugar moiety, having instead a hydrogen bonded directly to the 2′ carbon.
Deoxyribonucleotide
The terms “deoxyribonucleotide” and “DNA” refer to a nucleotide or polynucleotide comprising at least one sugar moiety that has an H, rather than an OH, at its 2′ and/or 3′position.
Duplex Region
The phrase “duplex region” refers to the region in two complementary or substantially complementary polynucleotides that form base pairs with one another, either by Watson-Crick base pairing or any other manner that allows for a stabilized duplex between polynucleotide strands that are complementary or substantially complementary. For example, a polynucleotide strand having 21 nucleotide units can base pair with another polynucleotide of 21 nucleotide units, yet only 19 bases on each strand are complementary or substantially complementary, such that the “duplex region” has 19 base pairs. The remaining bases may, for example, exist as 5′ and 3′ overhangs. Further, within the duplex region, 100% complementarity is not required; substantial complementarity is allowable within a duplex region. Substantial complementarity refers to 79% or greater complementarity. For example, a mismatch in a duplex region consisting of 19 base pairs results in 94.7% complementarity, rendering the duplex region substantially complementary.
Filters
The term “filter” refers to one or more procedures that are performed on sequences that are identified by the algorithm. In some instances, filtering includes in silico procedures where sequences identified by the algorithm can be screened to identify duplexes carrying desirable or undesirable motifs. Sequences carrying such motifs can be selected for, or selected against, to obtain a final set with the preferred properties. In other instances, filtering includes wet lab experiments. For instance, sequences identified by one or more versions of the algorithm can be screened using any one of a number of procedures to identify duplexes that have hyperfunctional traits (e.g., they exhibit a high degree of silencing at subnanomolar concentrations and/or exhibit high degrees of silencing longevity).
Gene Silencing
The phrase “gene silencing” refers to a process by which the expression of a specific gene product is lessened or attenuated. Gene silencing can take place by a variety of pathways. Unless specified otherwise, as used herein, gene silencing refers to decreases in gene product expression that results from RNA interference (RNAi), a defined, though partially characterized pathway whereby small inhibitory RNA (siRNA) act in concert with host proteins (e.g., the RNA induced silencing complex, RISC) to degrade messenger RNA (mRNA) in a sequence-dependent fashion. The level of gene silencing can be measured by a variety of means, including, but not limited to, measurement of transcript levels by Northern Blot Analysis, B-DNA techniques, transcription-sensitive reporter constructs, expression profiling (e.g., DNA chips), and related technologies. Alternatively, the level of silencing can be measured by assessing the level of the protein encoded by a specific gene. This can be accomplished by performing a number of studies including Western Analysis, measuring the levels of expression of a reporter protein that has e.g., fluorescent properties (e.g., GFP) or enzymatic activity (e.g., alkaline phosphatases), or several other procedures.
miRNA
The term “miRNA” refers to microRNA.
Nucleotide
The term “nucleotide” refers to a ribonucleotide or a deoxyribonucleotide or modified form thereof, as well as an analog thereof. Nucleotides include species that comprise purines, e.g., adenine, hypoxanthine, guanine, and their derivatives and analogs, as well as pyrimidines, e.g., cytosine, uracil, thymine, and their derivatives and analogs.
Nucleotide analogs include nucleotides having modifications in the chemical structure of the base, sugar and/or phosphate, including, but not limited to, 5-position pyrimidine modifications, 8-position purine modifications, modifications at cytosine exocyclic amines, and substitution of 5-bromo-uracil; and 2′-position sugar modifications, including but not limited to, sugar-modified ribonucleotides in which the 2′-OH is replaced by a group such as an H, OR, R, halo, SH, SR, NH2, NHR, NR2, or CN, wherein R is an alkyl moiety. Nucleotide analogs are also meant to include nucleotides with bases such as inosine, queuosine, xanthine, sugars such as 2′-methyl ribose, non-natural phosphodiester linkages such as methylphosphonates, phosphorothioates and peptides.
Modified bases refer to nucleotide bases such as, for example, adenine, guanine, cytosine, thymine, uracil, xanthine, inosine, and queuosine that have been modified by the replacement or addition of one or more atoms or groups. Some examples of types of modifications that can comprise nucleotides that are modified with respect to the base moieties include but are not limited to, alkylated, halogenated, thiolated, aminated, amidated, or acetylated bases, individually or in combination. More specific examples include, for example, 5-propynyluridine, 5-propynylcytidine, 6-methyladenine, 6-methylguanine, N,N,-dimethyladenine, 2-propyladenine, 2-propylguanine, 2-aminoadenine, 1-methylinosine, 3-methyluridine, 5-methylcytidine, 5-methyluridine and other nucleotides having a modification at the 5 position, 5-(2-amino)propyl uridine, 5-halocytidine, 5-halouridine, 4-acetylcytidine, 1-methyladenosine, 2-methyladenosine, 3-methylcytidine, 6-methyluridine, 2-methylguanosine, 7-methylguanosine, 2,2-dimethylguanosine, 5-methylaminoethyluridine, 5-methyloxyuridine, deazanucleotides such as 7-deaza-adenosine, 6-azouridine, 6-azocytidine, 6-azothymidine, 5-methyl-2-thiouridine, other thio bases such as 2-thiouridine and 4-thiouridine and 2-thiocytidine, dihydrouridine, pseudouridine, queuosine, archaeosine, naphthyl and substituted naphthyl groups, any O- and N-alkylated purines and pyrimidines such as N6-methyladenosine, 5-methylcarbonylmethyluridine, uridine 5-oxyacetic acid, pyridine-4-one, pyridine-2-one, phenyl and modified phenyl groups such as aminophenol or 2,4,6-trimethoxy benzene, modified cytosines that act as G-clamp nucleotides, 8-substituted adenines and guanines, 5-substituted uracils and thymines, azapyrimidines, carboxyhydroxyalkyl nucleotides, carboxyalkylaminoalkyl nucleotides, and alkylcarbonylalkylated nucleotides. Modified nucleotides also include those nucleotides that are modified with respect to the sugar moiety, as well as nucleotides having sugars or analogs thereof that are not ribosyl. For example, the sugar moieties may be, or be based on, mannoses, arabinoses, glucopyranoses, galactopyranoses, 4′-thioribose, and other sugars, heterocycles, or carbocycles.
The term nucleotide is also meant to include what are known in the art as universal bases. By way of example, universal bases include but are not limited to 3-nitropyrrole, 5-nitroindole, or nebularine. The term “nucleotide” is also meant to include the N3′ to P5′ phosphoramidate, resulting from the substitution of a ribosyl 3′ oxygen with an amine group.
Further, the term nucleotide also includes those species that have a detectable label, such as for example a radioactive or fluorescent moiety, or mass label attached to the nucleotide.
Off-Target Silencing and Off-Target Interference
The phrases “off-target silencing” and “off-target interference” are defined as degradation of mRNA other than the intended target mRNA due to overlapping and/or partial homology with secondary mRNA messages.
Polynucleotide
The term “polynucleotide” refers to polymers of nucleotides, and includes but is not limited to DNA, RNA, DNA/RNA hybrids including polynucleotide chains of regularly and/or irregularly alternating deoxyribosyl moieties and ribosyl moieties (i.e., wherein alternate nucleotide units have an —OH, then and —H, then an —OH, then an —H, and so on at the 2′ position of a sugar moiety), and modifications of these kinds of polynucleotides, wherein the attachment of various entities or moieties to the nucleotide units at any position are included.
Polyribonucleotide
The term “polyribonucleotide” refers to a polynucleotide comprising two or more modified or unmodified ribonucleotides and/or their analogs. The term “polyribonucleotide” is used interchangeably with the term “oligoribonucleotide.”
Ribonucleotide and Ribonucleic Acid
The term “ribonucleotide” and the phrase “ribonucleic acid” (RNA), refer to a modified or unmodified nucleotide or polynucleotide comprising at least one ribonucleotide unit. A ribonucleotide unit comprises an hydroxyl group attached to the 2′ position of a ribosyl moiety that has a nitrogenous base attached in N-glycosidic linkage at the 1′ position of a ribosyl moiety, and a moiety that either allows for linkage to another nucleotide or precludes linkage.
siRNA
The term “siRNA” refers to small inhibitory RNA duplexes that induce the RNA interference (RNAi) pathway. These molecules can vary in length (generally 18-30 base pairs) and contain varying degrees of complementarity to their target mRNA in the antisense strand. Some, but not all, siRNA have unpaired overhanging bases on the 5′ or 3′ end of the sense strand and/or the antisense strand. The term “siRNA” includes duplexes of two separate strands, as well as single strands that can form hairpin structures comprising a duplex region.
siRNA may be divided into five (5) groups (non-functional, semi-functional, functional, highly functional, and hyper-functional) based on the level or degree of silencing that they induce in cultured cell lines. As used herein, these definitions are based on a set of conditions where the siRNA is transfected into said cell line at a concentration of 100 nM and the level of silencing is tested at a time of roughly 24 hours after transfection, and not exceeding 72 hours after transfection. In this context, “non-functional siRNA” are defined as those siRNA that induce less than 50% (<50%) target silencing. “Semi-functional siRNA” induce 50-79% target silencing. “Functional siRNA” are molecules that induce 80-95% gene silencing. “Highly-functional siRNA” are molecules that induce greater than 95% gene silencing. “Hyperfunctional siRNA” are a special class of molecules. For purposes of this document, hyperfunctional siRNA are defined as those molecules that: (1) induce greater than 95% silencing of a specific target when they are transfected at subnanomolar concentrations (i.e., less than one nanomolar); and/or (2) induce functional (or better) levels of silencing for greater than 96 hours. These relative functionalities (though not intended to be absolutes) may be used to compare siRNAs to a particular target for applications such as functional genomics, target identification and therapeutics.
SMARTSCORE™, or siRNA rank
The term “SMARTSCORE™”, or “siRNA rank” refers to a number determined by applying any of the formulas to a given siRNA sequence. The term “SMART-selected” or “rationally selected” or “rational selection” refers to siRNA that have been selected on the basis of their SMARTSCORES™, or siRNA ranking.
Substantially Similar
The phrase “substantially similar” refers to a similarity of at least 90% with respect to the identity of the bases of the sequence.
Target
The term “target” is used in a variety of different forms throughout this document and is defined by the context in which it is used. “Target mRNA” refers to a messenger RNA to which a given siRNA can be directed against. “Target sequence” and “target site” refer to a sequence within the mRNA to which the sense strand of an siRNA shows varying degrees of homology and the antisense strand exhibits varying degrees of complementarity. The phrase “siRNA target” can refer to the gene, mRNA, or protein against which an siRNA is directed. Similarly, “target silencing” can refer to the state of a gene, or the corresponding mRNA or protein.
Transfection
The term “transfection” refers to a process by which agents are introduced into a cell. The list of agents that can be transfected is large and includes, but is not limited to, siRNA, sense and/or anti-sense sequences, DNA encoding one or more genes and organized into an expression plasmid, proteins, protein fragments, and more. There are multiple methods for transfecting agents into a cell including, but not limited to, electroporation, calcium phosphate-based transfections, DEAE-dextran-based transfections, lipid-based transfections, molecular conjugate-based transfections (e.g., polylysine-DNA conjugates), microinjection and others.
The present invention is directed to improving the efficiency of gene silencing by siRNA. Through the inclusion of multiple siRNA sequences that are targeted to a particular gene and/or selecting an siRNA sequence based on certain defined criteria, improved efficiency may be achieved.
The present invention will now be described in connection with preferred embodiments. These embodiments are presented in order to aid in an understanding of the present invention and are not intended, and should not be construed, to limit the invention in any way. All alternatives, modifications and equivalents that may become apparent to those of ordinary skill upon reading this disclosure are included within the spirit and scope of the present invention.
Furthermore, this disclosure is not a primer on RNA interference. Basic concepts known to persons skilled in the art have not been set forth in detail.
The present invention is directed to increasing the efficiency of RNAi, particularly in mammalian systems. Accordingly, the present invention provides kits, siRNAs and methods for increasing siRNA efficacy.
According to a first embodiment, the present invention provides a kit for gene silencing, wherein said kit is comprised of a pool of at least two siRNA duplexes, each of which is comprised of a sequence that is complementary to a portion of the sequence of one or more target messenger RNA, and each of which is selected using non-target specific criteria. Each of the at least two siRNA duplexes of the kit complementary to a portion of the sequence of one or more target mRNAs is preferably selected using Formula X.
According to a second embodiment, the present invention provides a method for selecting an siRNA, said method comprising applying selection criteria to a set of potential siRNA that comprise 18-30 base pairs, wherein said selection criteria are non-target specific criteria, and said set comprises at least two siRNAs and each of said at least two siRNAs contains a sequence that is at least substantially complementary to a target gene; and determining the relative functionality of the at least two siRNAs.
In one embodiment, the present invention also provides a method wherein said selection criteria are embodied in a formula comprising:
(−14)*G13−13*A1−12*U7−11*U2−10*A11−10*U4−10*C3−10*C5−1*C6−9*A10−9*U9−9*C18−8*G10−7*U1−7*U16−7*C17−7*C19+7*U17+8*A2+8*A4+8*A5+8*C4+9*G8+10*A7+10*U18+11*A19+11*C9+15*G1+18*A3+19*U10−Tm−3*(GCtotal)−6*(GC15-19)−30*X; or Formula VIII
(−8)*A1+(−1)*A2+(12)*A3+(7)*A4+(18)*A5+(12)*A6+(19)*A7+(6)*A8+(−4)*A9+(−5)*A10+(−2)*A11+(−5)*A12+(17)*A13+(−3)*A14+(4)*A15+(2)*A16+(8)*A17+(11)*A18+(30)*A19+(−13)*U1+(−10)*U2+(2)*U3+(−2)*U4+(−5)*U5+(5)*U6+(−2)*U7+(−10)*U8+(−5)*U9+(15)*U10+(−1)*U11+(0)*U12+(10)*U13+(−9)*U14+(−13)*U15+(−10)*U16+(3)*U17+(9)*U18+(9)*U19+(7)*C1+(3)*C2+(−21)*C3+(5)*C4+(−9)*C5+(−20)*C6+(−18)*C7+(−5)*C8+(5)*C9+(1)*C10+(2)*C11+(−5)*C12+(−3)*C13+(−6)*C14+(−2)*C15+(−5)*C16+(−3)*C17+(−12)*C18+(−18)*C19+(14)*G1+(8)*G2+(7)*G3+(−10)*G4+(−4)*G5+(2)*G6+(1)*G7+(9)*G8+(5)*G9+(−11)*G10+(1)*G11+(9)*G12+(−24)*G13+(18)*G14+(11)*G15+(13)*G16+(−7)*G17+(−9)*G18+(−22)*G19+6*(number of A+U in position 15-19)−3*(number of G+C in whole siRNA), Formula X
wherein position numbering begins at the 5′-most position of a sense strand, and
A1=1 if A is the base at position 1 of the sense strand, otherwise its value is 0;
A2=1 if A is the base at position 2 of the sense strand, otherwise its value is 0;
A3=1 if A is the base at position 3 of the sense strand, otherwise its value is 0;
A4=1 if A is the base at position 4 of the sense strand, otherwise its value is 0;
A5=1 if A is the base at position 5 of the sense strand, otherwise its value is 0;
A6=1 if A is the base at position 6 of the sense strand, otherwise its value is 0;
A7=1 if A is the base at position 7 of the sense strand, otherwise its value is 0;
A10=1 if A is the base at position 10 of the sense strand, otherwise its value is 0;
A11=1 if A is the base at position 11 of the sense strand, otherwise its value is 0;
A13=1 if A is the base at position 13 of the sense strand, otherwise its value is 0;
A19=1 if A is the base at position 19 of the sense strand, otherwise if another base is present or the sense strand is only 18 base pairs in length, its value is 0;
C3=1 if C is the base at position 3 of the sense strand, otherwise its value is 0;
C4=1 if C is the base at position 4 of the sense strand, otherwise its value is 0;
C5=1 if C is the base at position 5 of the sense strand, otherwise its value is 0;
C6=1 if C is the base at position 6 of the sense strand, otherwise its value is 0;
C7=1 if C is the base at position 7 of the sense strand, otherwise its value is 0;
C9=1 if C is the base at position 9 of the sense strand, otherwise its value is 0;
C17=1 if C is the base at position 17 of the sense strand, otherwise its value is 0;
C18=1 if C is the base at position 18 of the sense strand, otherwise its value is 0;
C19=1 if C is the base at position 19 of the sense strand, otherwise if another base is present or the sense strand is only 18 base pairs in length, its value is 0;
G1=1 if G is the base at position 1 on the sense strand, otherwise its value is 0;
G2=1 if G is the base at position 2 of the sense strand, otherwise its value is 0;
G8=1 if G is the base at position 8 on the sense strand, otherwise its value is 0;
G10=1 if G is the base at position 10 on the sense strand, otherwise its value is 0;
-
- G13=1 if G is the base at position 13 on the sense strand, otherwise its value is 0;
G19=1 if G is the base at position 19 of the sense strand, otherwise if another base is present or the sense strand is only 18 base pairs in length, its value is 0;
U1=1 if U is the base at position 1 on the sense strand, otherwise its value is 0;
U2=1 if U is the base at position 2 on the sense strand, otherwise its value is 0;
U3=1 if U is the base at position 3 on the sense strand, otherwise its value is 0;
U4=1 if U is the base at position 4 on the sense strand, otherwise its value is 0;
U7=1 if U is the base at position 7 on the sense strand, otherwise its value is 0;
U9=1 if U is the base at position 9 on the sense strand, otherwise its value is 0;
U10=1 if U is the base at position 10 on the sense strand, otherwise its value is 0;
U15=1 if U is the base at position 15 on the sense strand, otherwise its value is 0;
U16=1 if U is the base at position 16 on the sense strand, otherwise its value is 0;
U17=1 if U is the base at position 17 on the sense strand, otherwise its value is 0;
U18=1 if U is the base at position 18 on the sense strand, otherwise its value is 0.
GC15-19=the number of G and C bases within positions 15-19 of the sense strand, or within positions 15-18 if the sense strand is only 18 base pairs in length;
GCtotal=the number of G and C bases in the sense strand;
Tm=100 if the siRNA oligo has the internal repeat longer then 4 base pairs, otherwise its value is 0; and
X=the number of times that the same nucleotide repeats four or more times in a row.
Any of the methods of selecting siRNA in accordance with the invention can further comprise comparing the internal stability profiles of the siRNAs to be selected, and selecting those siRNAs with the most favorable internal stability profiles. Any of the methods of selecting siRNA can further comprise selecting either for or against sequences that contain motifs that induce cellular stress. Such motifs include, for example, toxicity motifs. Any of the methods of selecting siRNA can further comprise either selecting for or selecting against sequences that comprise stability motifs.
In another embodiment, the present invention provides a method of gene silencing, comprising introducing into a cell at least one siRNA selected according to any of the methods of the present invention. The siRNA can be introduced by allowing passive uptake of siRNA, or through the use of a vector.
According to a third embodiment, the invention provides a method for developing an algorithm for selecting siRNA, said method comprising: (a) selecting a set of siRNA; (b) measuring gene silencing ability of each siRNA from said set; (c) determining relative functionality of each siRNA; (d) determining improved functionality by the presence or absence of at least one variable selected from the group consisting of the presence or absence of a particular nucleotide at a particular position, the total number of As and Us in positions 15-19, the number of times that the same nucleotide repeats within a given sequence, and the total number of Gs and Cs; and (e) developing an algorithm using the information of step (d).
In another embodiment, the invention provides a method for selecting an siRNA with improved functionality, comprising using the above-mentioned algorithm to identify an siRNA of improved functionality.
According to a fourth embodiment, the present invention provides a kit, wherein said kit is comprised of at least two siRNAs, wherein said at least two siRNAs comprise a first optimized siRNA and a second optimized siRNA, wherein said first optimized siRNA and said second optimized siRNA are optimized according a formula comprising Formula X.
According to a fifth embodiment, the present invention provides a method for identifying a hyperfunctional siRNA, comprising applying selection criteria to a set of potential siRNA that comprise 18-30 base pairs, wherein said selection criteria are non-target specific criteria, and said set comprises at least two siRNAs and each of said at least two siRNAs contains a sequence that is at least substantially complementary to a target gene; determining the relative functionality of the at least two siRNAs and assigning each of the at least two siRNAs a functionality score; and selecting siRNAs from the at least two siRNAs that have a functionality score that reflects greater than 80 percent silencing at a concentration in the picomolar range, wherein said greater than 80 percent silencing endures for greater than 120 hours.
In other embodiments, the invention provides kits and/or methods wherein the siRNA are comprised of two separate polynucleotide strands; wherein the siRNA are comprised of a single contiguous molecule such as, for example, a unimolecular siRNA (comprising, for example, either a nucleotide or non-nucleotide loop); wherein the siRNA are expressed from one or more vectors; and wherein two or more genes are silenced by a single administration of siRNA.
According to a sixth embodiment, the present invention provides a hyperfunctional siRNA that is capable of silencing Bcl2.
According to a seventh embodiment, the present invention provides a method for developing an siRNA algorithm for selecting functional and hyperfunctional siRNAs for a given sequence. The method comprises:
(a) selecting a set of siRNAs;
(b) measuring the gene silencing ability of each siRNA from said set;
(c) determining the relative functionality of each siRNA;
(d) determining the amount of improved functionality by the presence or absence of at least one variable selected from the group consisting of the total GC content, melting temperature of the siRNA, GC content at positions 15-19, the presence or absence of a particular nucleotide at a particular position, relative thermodynamic stability at particular positions in a duplex, and the number of times that the same nucleotide repeats within a given sequence; and
(e) developing an algorithm using the information of step (d).
According to this embodiment, preferably the set of siRNAs comprises at least 90 siRNAs from at least one gene, more preferably at least 180 siRNAs from at least two different genes, and most preferably at least 270 and 360 siRNAs from at least three and four different genes, respectively. Additionally, in step (d) the determination is made with preferably at least two, more preferably at least three, even more preferably at least four, and most preferably all of the variables. The resulting algorithm is not target sequence specific.
In another embodiment, the present invention provides rationally designed siRNAs identified using the formulas above.
In yet another embodiment, the present invention is directed to hyperfunctional siRNA.
The ability to use the above algorithms, which are not sequence or species specific, allows for the cost-effective selection of optimized siRNAs for specific target sequences. Accordingly, there will be both greater efficiency and reliability in the use of siRNA technologies.
The methods disclosed herein can be used in conjunction with comparing internal stability profiles of selected siRNAs, and designing an siRNA with a desirable internal stability profile; and/or in conjunction with a selection either for or against sequences that contain motifs that induce cellular stress, for example, cellular toxicity.
Any of the methods disclosed herein can be used to silence one or more genes by introducing an siRNA selected, or designed, in accordance with any of the methods disclosed herein. The siRNA(s) can be introduced into the cell by any method known in the art, including passive uptake or through the use of one or more vectors.
Any of the methods and kits disclosed herein can employ either unimolecular siRNAs, siRNAs comprised of two separate polynucleotide strands, or combinations thereof. Any of the methods disclosed herein can be used in gene silencing, where two or more genes are silenced by a single administration of siRNA(s). The siRNA(s) can be directed against two or more target genes, and administered in a single dose or single transfection, as the case may be.
Optimizing siRNA
According to one embodiment, the present invention provides a method for improving the effectiveness of gene silencing for use to silence a particular gene through the selection of an optimal siRNA. An siRNA selected according to this method may be used individually, or in conjunction with the first embodiment, i.e., with one or more other siRNAs, each of which may or may not be selected by this criteria in order to maximize their efficiency.
The degree to which it is possible to select an siRNA for a given mRNA that maximizes these criteria will depend on the sequence of the mRNA itself. However, the selection criteria will be independent of the target sequence. According to this method, an siRNA is selected for a given gene by using a rational design. That said, rational design can be described in a variety of ways. Rational design is, in simplest terms, the application of a proven set of criteria that enhance the probability of identifying a functional or hyperfunctional siRNA. In one method, rationally designed siRNA can be identified by maximizing one or more of the following criteria:
(1) A low GC content, preferably between about 30-52%.
(2) At least 2, preferably at least 3 A or U bases at positions 15-19 of the siRNA on the sense strand.
(3) An A base at position 19 of the sense strand.
(4) An A base at position 3 of the sense strand.
(5) A U base at position 10 of the sense strand.
(6) An A base at position 14 of the sense strand.
(7) A base other than C at position 19 of the sense strand.
(8) A base other than G at position 13 of the sense strand.
(9) A Tm, which refers to the character of the internal repeat that results in inter- or intramolecular structures for one strand of the duplex, that is preferably not stable at greater than 50° C., more preferably not stable at greater than 37° C., even more preferably not stable at greater than 30° C. and most preferably not stable at greater than 20° C.
(10) A base other than U at position 5 of the sense strand.
(11) A base other than A at position 11 of the sense strand.
(12) A base other than an A at position 1 of the sense strand.
(13) A base other than an A at position 2 of the sense strand.
(14) An A base at position 4 of the sense strand.
(15) An A base at position 5 of the sense strand.
(16) An A base at position 6 of the sense strand.
(17) An A base at position 7 of the sense strand.
(18) An A base at position 8 of the sense strand.
(19) A base other than an A at position 9 of the sense strand.
(20) A base other than an A at position 10 of the sense strand.
(21) A base other than an A at position 11 of the sense strand.
(22) A base other than an A at position 12 of the sense strand.
(23) An A base at position 13 of the sense strand.
(24) A base other than an A at position 14 of the sense strand.
(25) An A base at position 15 of the sense strand
(26) An A base at position 16 of the sense strand.
(27) An A base at position 17 of the sense strand.
(28) An A base at position 18 of the sense strand.
(29) A base other than a U at position 1 of the sense strand.
(30) A base other than a U at position 2 of the sense strand.
(31) A U base at position 3 of the sense strand.
(32) A base other than a U at position 4 of the sense strand.
(33) A base other than a U at position 5 of the sense strand.
(34) A U base at position 6 of the sense strand.
(35) A base other than a U at position 7 of the sense strand.
(36) A base other than a U at position 8 of the sense strand.
(37) A base other than a U at position 9 of the sense strand.
(38) A base other than a U at position 11 of the sense strand.
(39) A U base at position 13 of the sense strand.
(40) A base other than a U at position 14 of the sense strand.
(41) A base other than a U at position 15 of the sense strand.
(42) A base other than a U at position 16 of the sense strand.
(43) A U base at position 17 of the sense strand.
(44) A U base at position 18 of the sense strand.
(45) A U base at position 19 of the sense strand.
(46) A C base at position 1 of the sense strand.
(47) A C base at position 2 of the sense strand.
(48) A base other than a C at position 3 of the sense strand.
(49) A C base at position 4 of the sense strand.
(50) A base other than a C at position 5 of the sense strand.
(51) A base other than a C at position 6 of the sense strand.
(52) A base other than a C at position 7 of the sense strand.
(53) A base other than a C at position 8 of the sense strand.
(54) A C base at position 9 of the sense strand.
(55) A C base at position 10 of the sense strand.
(56) A C base at position 11 of the sense strand.
(57) A base other than a C at position 12 of the sense strand.
(58) A base other than a C at position 13 of the sense strand.
(59) A base other than a C at position 14 of the sense strand.
(60) A base other than a C at position 15 of the sense strand.
(61) A base other than a C at position 16 of the sense strand.
(62) A base other than a C at position 17 of the sense strand.
(63) A base other than a C at position 18 of the sense strand.
(64) A G base at position 1 of the sense strand.
(65) A G base at position 2 of the sense strand.
(66) A G base at position 3 of the sense strand.
(67) A base other than a G at position 4 of the sense strand.
(68) A base other than a G at position 5 of the sense strand.
(69) A G base at position 6 of the sense strand.
(70) A G base at position 7 of the sense strand.
(71) A G base at position 8 of the sense strand.
(72) A G base at position 9 of the sense strand.
(73) A base other than a G at position 10 of the sense strand.
(74) A G base at position 11 of the sense strand.
(75) A G base at position 12 of the sense strand.
(76) A G base at position 14 of the sense strand.
(77) A G base at position 15 of the sense strand.
(78) A G base at position 16 of the sense strand.
(79) A base other than a G at position 17 of the sense strand.
(80) A base other than a G at position 18 of the sense strand.
(81) A base other than a G at position 19 of the sense strand.
The importance of various criteria can vary greatly. For instance, a C base at position 10 of the sense strand makes a minor contribution to duplex functionality. In contrast, the absence of a C at position 3 of the sense strand is very important. Accordingly, preferably an siRNA will satisfy as many of the aforementioned criteria as possible.
With respect to the criteria, GC content, as well as a high number of AU in positions 15-19 of the sense strand, may be important for easement of the unwinding of double stranded siRNA duplex. Duplex unwinding has been shown to be crucial for siRNA functionality in vivo.
With respect to criterion 9, the internal structure is measured in terms of the melting temperature of the single strand of siRNA, which is the temperature at which 50% of the molecules will become denatured. With respect to criteria 2-8 and 10-11, the positions refer to sequence positions on the sense strand, which is the strand that is identical to the mRNA.
In one preferred embodiment, at least criteria 1 and 8 are satisfied. In another preferred embodiment, at least criteria 7 and 8 are satisfied. In still another preferred embodiment, at least criteria 1, 8 and 9 are satisfied.
It should be noted that all of the aforementioned criteria regarding sequence position specifics are with respect to the 5′ end of the sense strand. Reference is made to the sense strand, because most databases contain information that describes the information of the mRNA. Because according to the present invention a chain can be from 18 to 30 bases in length, and the aforementioned criteria assumes a chain 19 base pairs in length, it is important to keep the aforementioned criteria applicable to the correct bases.
When there are only 18 bases, the base pair that is not present is the base pair that is located at the 3′ of the sense strand. When there are twenty to thirty bases present, then additional bases are added at the 5′ end of the sense chain and occupy positions −1 to −11. Accordingly, with respect to SEQ. ID NO. 0001 NNANANNNNUCNAANNNNA and SEQ. ID NO. 0028 GUCNNANANNNNUCNAANNNNA, both would have A at position 3, A at position 5, U at position 10, C at position 11, A and position 13, A and position 14 and A at position 19. However, SEQ. ID NO. 0028 would also have C at position −1, U at position −2 and G at position −3.
For a 19 base pair siRNA, an optimal sequence of one of the strands may be represented below, where N is any base, A, C, G, or U:
SEQ. ID NO. 0001. NNANANNNNUCNAANNNNA
SEQ. ID NO. 0002. NNANANNNNUGNAANNNNA
SEQ. ID NO. 0003. NNANANNNNUUNAANNNNA
SEQ. ID NO. 0004. NNANANNNNUCNCANNNNA
SEQ. ID NO. 0005. NNANANNNNUGNCANNNNA
SEQ. ID NO. 0006. NNANANNNNUUNCANNNNA
SEQ. ID NO. 0007. NNANANNNNUCNUANNNNA
SEQ. ID NO. 0008. NNANANNNNUGNUANNNNA
SEQ. ID NO. 0009. NNANANNNNUUNUANNNNA
SEQ. ID NO. 0010. NNANCNNNNUCNAANNNNA
SEQ. ID NO. 0011. NNANCNNNNUGNAANNNNA
SEQ. ID NO. 0012. NNANCNNNNUUNAANNNNA
SEQ. ID NO. 0013. NNANCNNNNUCNCANNNNA
SEQ. ID NO. 0014. NNANCNNNNUGNCANNNNA
SEQ. ID NO. 0015. NNANCNNNNUUNCANNNNA
SEQ. ID NO. 0016. NNANCNNNNUCNUANNNNA
SEQ. ID NO. 0017. NNANCNNNNUGNUANNNNA
SEQ. ID NO. 0018. NNANCNNNNUUNUANNNNA
SEQ. ID NO. 0019. NNANGNNNNUCNAANNNNA
SEQ. ID NO. 0020. NNANGNNNNUGNAANNNNA
SEQ. ID NO. 0021. NNANGNNNNUUNAANNNNA
SEQ. ID NO. 0022. NNANGNNNNUCNCANNNNA
SEQ. ID NO. 0023. NNANGNNNNUGNCANNNNA
SEQ. ID NO. 0024. NNANGNNNNUUNCANNNNA
SEQ. ID NO. 0025. NNANGNNNNUCNUANNNNA
SEQ. ID NO. 0026. NNANGNNNNUGNUANNNNA
SEQ. ID NO. 0027. NNANGNNNNNUNUANNNNA
In one embodiment, the sequence used as an siRNA is selected by choosing the siRNA that score highest according to one of the following seven algorithms that are represented by Formulas I-VII:
Relative functionality of siRNA=−(GC/3)+(AU15-19)−(Tm20° C.)*3−(G13)*3−(C19)+(A19)*2+(A3)+(U10)+(A14)−(U5)−(A11) Formula I
Relative functionality of siRNA=−(GC/3)−(AU15-19)*3−(G13)*3−(C19)+(A19)*2+(A3) Formula II
Relative functionality of siRNA=−(GC/3)+(AU15-19)−(Tm20° C.)*3 Formula III
Relative functionality of siRNA=−GC/2+(AU15-19)/2−(Tm20° C.)*2−(G13)*3−(C19)+(A19)*2+(A3)+(U10)+(A14)−(U5)−(A11) Formula IV
Relative functionality of siRNA=−(G13)*3−(C19)+(A19)*2+(A3)+(U10)+(A14)−(U5)−(A11) Formula V
Relative functionality of siRNA=−(G13)*3−(C19)+(A19)*2+(A3) Formula VI
Relative functionality of siRNA=−(GC/2)+(AU15-19)/2−(Tm20° C.)*1−(G13)*3−(C19)+(A19)*3+(A3)*3+(U10)/2+(A14)/2−(U5)/2−(A11)/2 Formula VII
In Formulas I-VII:
wherein A19=1 if A is the base at position 19 on the sense strand, otherwise its value is 0,
AU15-19=0-5 depending on the number of A or U bases on the sense strand at positions 15-19;
G13=1 if G is the base at position 13 on the sense strand, otherwise its value is 0;
C19=1 if C is the base at position 19 of the sense strand, otherwise its value is 0;
GC=the number of G and C bases in the entire sense strand;
Tm20° C.=1 if the Tm is greater than 20° C.;
A3=1 if A is the base at position 3 on the sense strand, otherwise its value is 0;
U10=1 if U is the base at position 10 on the sense strand, otherwise its value is 0;
A14=1 if A is the base at position 14 on the sense strand, otherwise its value is 0;
U5=1 if U is the base at position 5 on the sense strand, otherwise its value is 0; and
A11=1 if A is the base at position 11 of the sense strand, otherwise its value is 0.
Formulas I-VII provide relative information regarding functionality. When the values for two sequences are compared for a given formula, the relative functionality is ascertained; a higher positive number indicates a greater functionality. For example, in many applications a value of 5 or greater is beneficial.
Additionally, in many applications, more than one of these formulas would provide useful information as to the relative functionality of potential siRNA sequences. However, it is beneficial to have more than one type of formula, because not every formula will be able to help to differentiate among potential siRNA sequences. For example, in particularly high GC mRNAs, formulas that take that parameter into account would not be useful and application of formulas that lack GC elements (e.g., formulas V and VI) might provide greater insights into duplex functionality. Similarly, formula II might by used in situations where hairpin structures are not observed in duplexes, and formula IV might be applicable for sequences that have higher AU content. Thus, one may consider a particular sequence in light of more than one or even all of these algorithms to obtain the best differentiation among sequences. In some instances, application of a given algorithm may identify an unusually large number of potential siRNA sequences, and in those cases, it may be appropriate to re-analyze that sequence with a second algorithm that is, for instance, more stringent. Alternatively, it is conceivable that analysis of a sequence with a given formula yields no acceptable siRNA sequences (i.e. low SMARTSCORES™, or siRNA ranking). In this instance, it may be appropriate to re-analyze that sequences with a second algorithm that is, for instance, less stringent. In still other instances, analysis of a single sequence with two separate formulas may give rise to conflicting results (i.e. one formula generates a set of siRNA with high SMARTSCORES™, or siRNA ranking, while the other formula identifies a set of siRNA with low SMARTSCORES™, or siRNA ranking). In these instances, it may be necessary to determine which weighted factor(s) (e.g. GC content) are contributing to the discrepancy and assessing the sequence to decide whether these factors should or should not be included. Alternatively, the sequence could be analyzed by a third, fourth, or fifth algorithm to identify a set of rationally designed siRNA.
The above-referenced criteria are particularly advantageous when used in combination with pooling techniques as depicted in Table I: TABLE I
FUNCTIONAL PROBABILITY
OLIGOS POOLS
CRITERIA >95% >80% <70% >95% >80% <70%
CURRENT 33.0 50.0 23.0 79.5 97.3 0.3
NEW 50.0 88.5 8.0 93.8 99.98 0.005
(GC) 28.0 58.9 36.0 72.8 97.1 1.6
The term “current” used in Table I refers to Tuschl's conventional siRNA parameters (Elbashir, S. M. et al. (2002) “Analysis of gene function in somatic mammalian cells using small interfering RNAs” Methods 26: 199-213). “New” refers to the design parameters described in Formulas I-VII. “GC” refers to criteria that select siRNA solely on the basis of GC content.
As Table I indicates, when more functional siRNA duplexes are chosen, siRNAs that produce <70% silencing drops from 23% to 8% and the number of siRNA duplexes that produce >80% silencing rises from 50% to 88.5%. Further, of the siRNA duplexes with >80% silencing, a larger portion of these siRNAs actually silence >95% of the target expression (the new criteria increases the portion from 33% to 50%). Using this new criteria in pooled siRNAs, shows that, with pooling, the amount of silencing >95% increases from 79.5% to 93.8% and essentially eliminates any siRNA pool from silencing less than 70%.
Table II similarly shows the particularly beneficial results of pooling in combination with the aforementioned criteria. However, Table II, which takes into account each of the aforementioned variables, demonstrates even a greater degree of improvement in functionality. TABLE II
FUNCTIONAL PROBABILITY
OLIGOS POOLS
NON- NON-
FUNCTIONAL AVERAGE FUNCTIONAL FUNCTIONAL AVERAGE FUNCTIONAL
RANDOM 20 40 50 67 97 3
CRITERIA 1 52 99 0.1 97 93 0.0040
CRITERIA 4 89 99 0.1 99 99 0.0000
The terms “functional,” “Average,” and “Non-functional” used in Table II, refer to siRNA that exhibit >80%, >50%, and <50% functionality, respectively. Criteria 1 and 4 refer to specific criteria described above.
The above-described algorithms may be used with or without a computer program that allows for the inputting of the sequence of the mRNA and automatically outputs the optimal siRNA. The computer program may, for example, be accessible from a local terminal or personal computer, over an internal network or over the Internet.
In addition to the formulas above, more detailed algorithms may be used for selecting siRNA. Preferably, at least one RNA duplex of 18-30 base pairs is selected such that it is optimized according a formula selected from:
(−14)*G13−13*A1−12*U7−11*U2−10*A11−10*U4−10*C3−10*C5−10*C6−9*A10−9*U9−9*C18−8*G10−7*U1−7*U16−7*C17−7*C19+7*U17+8*A2+8*A4+8*A5+8*C4+9*G8+10*A7+10*U18+11*A19+11*C9+15*G1+18*A3+19*U10−Tm−3*(GCtotal)−6*(GC15-19)−30*X; and Formula VIII
(14.1)*A3+(14.9)*A6+(17.6)*A13+(24.7)*A19+(14.2)*U10+(10.5)*C9+(23.9)*G1+(16.3)*G2+(−12.3)*A11+(−19.3)*U1+(−12.1)*U2+(−11)*U3+(−15.2)*U15+(−11.3)*U16+(−11.8)*C3+(−17.4)*C6+(−10.5)*C7+(−13.7)*G13+(−25.9)*G19−Tm−3*(GCtotal)−6*(GC15-19)−30*X; and Formula IX
(−8)*A1+(−1)*A2+(12)*A3+(7)*A4+(18)*A5+(12)*A6+(19)*A7+(6)*A8+(−4)*A9+(−5)*A10+(−2)*A11+(−5)*A12+(17)*A13+(−3)*A14+(4)*A15+(2)*A16+(8)*A17+(11)*A18+(30)*A19+(−13)*U1+(−10)*U2+(2)*U3+(−2)*U4+(−5)*U5+(5)*U6+(−2)*U7+(−10)*U8+(−5)*U9+(15)*U10+(−1)*U11+(0)*U12+(10)*U13+(−9)*U14+(−13)*U15+(−10)*U16+(3)*U17+(9)*U18+(9)*U19+(7)*C1+(3)*C2+(−21)*C3+(5)*C4+(−9)*C5+(−20)*C6+(−18)*C7+(−5)*C8+(5)*C9+(1)*C10+(2)*C11+(−5)*C12+(−3)*C13+(−6)*C14+(−2)*C15+(−5)*C16+(−3)*C17+(−12)*C18+(−18)*C19+(14)*G1+(8)*G2+(7)*G3+(−10)*G4+(−4)*G5+(2)*G6+(1)*G7+(9)*G8+(5)*G9+(−11)*G10+(1)*G11+(9)*G12+(−24)*G13+(18)*G14+(11)*G15+(13)*G16+(−7)*G17+(−9)*G18+(−22)*G19+6*(number of A+U in position 15-19)−3*(number of G+C in whole siRNA). Formula X
wherein
A1=1 if A is the base at position 1 of the sense strand, otherwise its value is 0;
A2=1 if A is the base at position 2 of the sense strand, otherwise its value is 0;
A3=1 if A is the base at position 3 of the sense strand, otherwise its value is 0;
A4=1 if A is the base at position 4 of the sense strand, otherwise its value is 0;
A5=1 if A is the base at position 5 of the sense strand, otherwise its value is 0;
A6=1 if A is the base at position 6 of the sense strand, otherwise its value is 0;
A7=1 if A is the base at position 7 of the sense strand, otherwise its value is 0;
A10=1 if A is the base at position 10 of the sense strand, otherwise its value is 0;
A11=1 if A is the base at position 11 of the sense strand, otherwise its value is 0;
A13=1 if A is the base at position 13 of the sense strand, otherwise its value is 0;
A19=1 if A is the base at position 19 of the sense strand, otherwise if another base is present or the sense strand is only 18 base pairs in length, its value is 0;
C3=1 if C is the base at position 3 of the sense strand, otherwise its value is 0;
C4=1 if C is the base at position 4 of the sense strand, otherwise its value is 0;
C5=1 if C is the base at position 5 of the sense strand, otherwise its value is 0;
C6=1 if C is the base at position 6 of the sense strand, otherwise its value is 0;
C7=1 if C is the base at position 7 of the sense strand, otherwise its value is 0;
C9=1 if C is the base at position 9 of the sense strand, otherwise its value is 0;
C17=1 if C is the base at position 17 of the sense strand, otherwise its value is 0;
C18=1 if C is the base at position 18 of the sense strand, otherwise its value is 0;
C19=1 if C is the base at position 19 of the sense strand, otherwise if another base is present or the sense strand is only 18 base pairs in length, its value is 0;
G1=1 if G is the base at position 1 on the sense strand, otherwise its value is 0;
G2=1 if G is the base at position 2 of the sense strand, otherwise its value is 0;
G8=1 if G is the base at position 8 on the sense strand, otherwise its value is 0;
G10=1 if G is the base at position 10 on the sense strand, otherwise its value is 0;
G13=1 if G is the base at position 13 on the sense strand, otherwise its value is 0;
G19=1 if G is the base at position 19 of the sense strand, otherwise if another base is present or the sense strand is only 18 base pairs in length, its value is 0;
U1=1 if U is the base at position 1 on the sense strand, otherwise its value is 0;
U2=1 if U is the base at position 2 on the sense strand, otherwise its value is 0;
U3=1 if U is the base at position 3 on the sense strand, otherwise its value is 0;
U4=1 if U is the base at position 4 on the sense strand, otherwise its value is 0;
U7=1 if U is the base at position 7 on the sense strand, otherwise its value is 0;
U9=1 if U is the base at position 9 on the sense strand, otherwise its value is 0;
U10=1 if U is the base at position 10 on the sense strand, otherwise its value is 0;
U15=1 if U is the base at position 15 on the sense strand, otherwise its value is 0;
U16=1 if U is the base at position 16 on the sense strand, otherwise its value is 0;
U17=1 if U is the base at position 17 on the sense strand, otherwise its value is 0;
U18=1 if U is the base at position 18 on the sense strand, otherwise its value is 0;
GC15-19=the number of G and C bases within positions 15-19 of the sense strand, or within positions 15-18 if the sense strand is only 18 base pairs in length;
GCtotal=the number of G and C bases in the sense strand;
Tm=100 if the siRNA oligo has the internal repeat longer then 4 base pairs, otherwise its value is 0; and
X=the number of times that the same nucleotide repeats four or more times in a row.
The above formulas VIII, IX, and X, as well as formulas I-VII, provide methods for selecting siRNA in order to increase the efficiency of gene silencing. A subset of variables of any of the formulas may be used, though when fewer variables are used, the optimization hierarchy becomes less reliable.
With respect to the variables of the above-referenced formulas, a single letter of A or C or G or U followed by a subscript refers to a binary condition. The binary condition is that either the particular base is present at that particular position (wherein the value is “1”) or the base is not present (wherein the value is “0”). Because position 19 is optional, i.e., there might be only 18 base pairs, when there are only 18 base pairs, any base with a subscript of 19 in the formulas above would have a zero value for that parameter. Before or after each variable is a number followed by *, which indicates that the value of the variable is to be multiplied or weighed by that number.
The numbers preceding the variables A, or G, or C, or U in Formulas VIII, IX, and X (or after the variables in Formula I-VII) were determined by comparing the difference in the frequency of individual bases at different positions in functional siRNA and total siRNA. Specifically, the frequency in which a given base was observed at a particular position in functional groups was compared with the frequency that that same base was observed in the total, randomly selected siRNA set. If the absolute value of the difference between the functional and total values was found to be greater than 6%, that parameter was included in the equation. Thus, for instance, if the frequency of finding a “G” at position 13 (G13) is found to be 6% in a given functional group, and the frequency of G13 in the total population of siRNAs is 20%, the difference between the two values is 6%-20%=−14%. As the absolute value is greater than six (6), this factor (−14) is included in the equation. Thus, in Formula VIII, in cases where the siRNA under study has a G in position 13, the accrued value is (−14)*(1)=−14. In contrast, when a base other than G is found at position 13, the accrued value is (−14)*(0)=0.
When developing a means to optimize siRNAs, the inventors observed that a bias toward low internal thermodynamic stability of the duplex at the 5′-antisense (AS) end is characteristic of naturally occurring miRNA precursors. The inventors extended this observation to siRNAs for which functionality had been assessed in tissue culture.
With respect to the parameter GC15-19, a value of 0-5 will be ascribed depending on the number of G or C bases at positions 15 to 19. If there are only 18 base pairs, the value is between 0 and 4.
With respect to the criterion GCtotal content, a number from 0-30 will be ascribed, which correlates to the total number of G and C nucleotides on the sense strand, excluding overhangs. Without wishing to be bound by any one theory, it is postulated that the significance of the GC content (as well as AU content at positions 15-19, which is a parameter for formulas III-VII) relates to the easement of the unwinding of a double-stranded siRNA duplex. Duplex unwinding is believed to be crucial for siRNA functionality in vivo and overall low internal stability, especially low internal stability of the first unwound base pair is believed to be important to maintain sufficient processivity of RISC complex-induced duplex unwinding. If the duplex has 19 base pairs, those at positions 15-19 on the sense strand will unwind first if the molecule exhibits a sufficiently low internal stability at that position. As persons skilled in the art are aware, RISC is a complex of approximately twelve proteins; Dicer is one, but not the only, helicase within this complex. Accordingly, although the GC parameters are believed to relate to activity with Dicer, they are also important for activity with other RISC proteins.
The value of the parameter Tm is 0 when there are no internal repeats longer than (or equal to) four base pairs present in the siRNA duplex; otherwise the value is 1. Thus for example, if the sequence ACGUACGU, or any other four nucleotide (or more) palindrome exists within the structure, the value will be one (1). Alternatively if the structure ACGGACG, or any other 3 nucleotide (or less) palindrome exists, the value will be zero (0).
The variable “X” refers to the number of times that the same nucleotide occurs contiguously in a stretch of four or more units. If there are, for example, four contiguous As in one part of the sequence and elsewhere in the sequence four contiguous Cs, X=2. Further, if there are two separate contiguous stretches of four of the same nucleotides or eight or more of the same nucleotides in a row, then X=2. However, X does not increase for five, six or seven contiguous nucleotides.
Again, when applying Formula VIII, Formula IX, or Formula X, to a given mRNA, (the “target RNA” or “target molecule”), one may use a computer program to evaluate the criteria for every sequence of 18-30 base pairs or only sequences of a fixed length, e.g., 19 base pairs. Preferably the computer program is designed such that it provides a report ranking of all of the potential siRNAs 18-30 base pairs, ranked according to which sequences generate the highest value. A higher value refers to a more efficient siRNA for a particular target gene. The computer program that may be used may be developed in any computer language that is known to be useful for scoring nucleotide sequences, or it may be developed with the assistance of commercially available product such as Microsoft's PRODUCT.NET. Additionally, rather than run every sequence through one and/or another formula, one may compare a subset of the sequences, which may be desirable if for example only a subset are available. For instance, it may be desirable to first perform a BLAST (Basic Local Alignment Search Tool) search and to identify sequences that have no homology to other targets. Alternatively, it may be desirable to scan the sequence and to identify regions of moderate GC context, then perform relevant calculations using one of the above-described formulas on these regions. These calculations can be done manually or with the aid of a computer.
As with Formulas I-VII, either Formula VIII, Formula IX, or Formula X may be used for a given mRNA target sequence. However, it is possible that according to one or the other formula more than one siRNA will have the same value. Accordingly, it is beneficial to have a second formula by which to differentiate sequences. Formulas IX and X were derived in a similar fashion as Formula VIII, yet used a larger data set and thus yields sequences with higher statistical correlations to highly functional duplexes. The sequence that has the highest value ascribed to it may be referred to as a “first optimized duplex.” The sequence that has the second highest value ascribed to it may be referred to as a “second optimized duplex.” Similarly, the sequences that have the third and fourth highest values ascribed to them may be referred to as a third optimized duplex and a fourth optimized duplex, respectively. When more than one sequence has the same value, each of them may, for example, be referred to as first optimized duplex sequences or co-first optimized duplexes. Formula X is similar to Formula IX, yet uses a greater numbers of variables and for that reason, identifies sequences on the basis of slightly different criteria.
It should also be noted that the output of a particular algorithm will depend on several of variables including: (1) the size of the data base(s) being analyzed by the algorithm, and (2) the number and stringency of the parameters being applied to screen each sequence. Thus, for example, in U.S. patent application Ser. No. 10/714,333, entitled “Functional and Hyperfunctional siRNA,” filed Nov. 14, 2003, Formula VIII was applied to the known human genome (NCBI REFSEQ database) through ENTREZ (EFETCH). As a result of these procedures, roughly 1.6 million siRNA sequences were identified. Application of Formula VIII to the same database in March of 2004 yielded roughly 2.2 million sequences, a difference of approximately 600,000 sequences resulting from the growth of the database over the course of the months that span this period of time. Application of other formulas (e.g., Formula X) that change the emphasis of, include, or eliminate different variables can yield unequal numbers of siRNAs. Alternatively, in cases where application of one formula to one or more genes fails to yield sufficient numbers of siRNAs with scores that would be indicative of strong silencing, said genes can be reassessed with a second algorithm that is, for instance, less stringent.
siRNA sequences identified using Formula VIII and Formula X (minus sequences generated by Formula VIII) are contained within the sequence listing. The data included in the sequence listing is described more fully below. The sequences identified by Formula VIII and Formula X that are disclosed in the sequence listing may be used in gene silencing applications.
It should be noted that for Formulas VIII, IX, and X all of the aforementioned criteria are identified as positions on the sense strand when oriented in the 5′ to 3′ direction as they are identified in connection with Formulas I-VII unless otherwise specified.
Formulas I-X, may be used to select or to evaluate one, or more than one, siRNA in order to optimize silencing. Preferably, at least two optimized siRNAs that have been selected according to at least one of these formulas are used to silence a gene, more preferably at least three and most preferably at least four. The siRNAs may be used individually or together in a pool or kit. Further, they may be applied to a cell simultaneously or separately. Preferably, the at least two siRNAs are applied simultaneously. Pools are particularly beneficial for many research applications. However, for therapeutics, it may be more desirable to employ a single hyperfunctional siRNA as described elsewhere in this application.
When planning to conduct gene silencing, and it is necessary to choose between two or more siRNAs, one should do so by comparing the relative values when the siRNA are subjected to one of the formulas above. In general a higher scored siRNA should be used.
Useful applications include, but are not limited to, target validation, gene functional analysis, research and drug discovery, gene therapy and therapeutics. Methods for using siRNA in these applications are well known to persons of skill in the art.
Because the ability of siRNA to function is dependent on the sequence of the RNA and not the species into which it is introduced, the present invention is applicable across a broad range of species, including but not limited to all mammalian species, such as humans, dogs, horses, cats, cows, mice, hamsters, chimpanzees and gorillas, as well as other species and organisms such as bacteria, viruses, insects, plants and C. elegans.
The present invention is also applicable for use for silencing a broad range of genes, including but not limited to the roughly 45,000 genes of a human genome, and has particular relevance in cases where those genes are associated with diseases such as diabetes, Alzheimer's, cancer, as well as all genes in the genomes of the aforementioned organisms.
The siRNA selected according to the aforementioned criteria or one of the aforementioned algorithms are also, for example, useful in the simultaneous screening and functional analysis of multiple genes and gene families using high throughput strategies, as well as in direct gene suppression or silencing.
Development of the Algorithms
To identify siRNA sequence features that promote functionality and to quantify the importance of certain currently accepted conventional factors—such as G/C content and target site accessibility—the inventors synthesized an siRNA panel consisting of 270 siRNAs targeting three genes, Human Cyclophilin, Firefly Luciferase, and Human DBI. In all three cases, siRNAs were directed against specific regions of each gene. For Human Cyclophilin and Firefly Luciferase, ninety siRNAs were directed against a 199 bp segment of each respective mRNA. For DBI, 90 siRNAs were directed against a smaller, 109 base pair region of the mRNA. The sequences to which the siRNAs were directed are provided below.
It should be noted that in certain sequences, “t” is present. This is because many databases contain information in this manner. However, the t denotes a uracil residue in mRNA and siRNA. Any algorithm will, unless otherwise specified, process at in a sequence as a u.
Human Cyclophilin: 193-390, M60857
SEQ. ID NO. 29:
gttccaaaaa cagtggataa ttttgtggcc ttagctacag
gagagaaagg atttggctac aaaaacagca aattccatcg
tgtaatcaag gacttcatga tccagggcgg agacttcacc
aggggagatg gcacaggagg aaagagcatc tacggtgagc
gcttccccga tgagaacttc aaactgaagc actacgggcc
tggctggg
Firefly Luciferase: 1434-1631, U47298 (pGL3, Promega)
SEQ. ID NO. 30:
tgaacttccc gccgccgttq ttgttttgga gcacggaaag
acgatgacgg aaaaagagat cgtggattac gtcgccagtc
aagtaacaac cgcgaaaaag ttgcgcggag gagttgtgtt
tgtggacgaa gtaccgaaag gtcttaccgg aaaactcgac
gcaagaaaaa toagagagat cctcataaag gccaagaagg
DBI, NM—020548 (202-310) (Every Position)
SEQ. ID NO. 0031:
acgggcaagg ccaagtggga tgcctggaat gagctgaaag
ggacttccaa ggaagatgcc atgaaagctt acatcaacaa
agtagaagag ctaaagaaaa aatacggg
A list of the siRNAs appears in Table III (see Examples Section, Example II)
The set of duplexes was analyzed to identify correlations between siRNA functionality and other biophysical or thermodynamic properties. When the siRNA panel was analyzed in functional and non-functional subgroups, certain nucleotides were much more abundant at certain positions in functional or non-functional groups. More specifically, the frequency of each nucleotide at each position in highly functional siRNA duplexes was compared with that of nonfunctional duplexes in order to assess the preference for or against any given nucleotide at every position. These analyses were used to determine important criteria to be included in the siRNA algorithms (Formulas VIII, IX, and X).
The data set was also analyzed for distinguishing biophysical properties of siRNAs in the functional group, such as optimal percent of GC content, propensity for internal structures and regional thermodynamic stability. Of the presented criteria, several are involved in duplex recognition, RISC activation/duplex unwinding, and target cleavage catalysis.
The original data set that was the source of the statistically derived criteria is shown in FIG. 2. Additionally, this figure shows that random selection yields siRNA duplexes with unpredictable and widely varying silencing potencies as measured in tissue culture using HEK293 cells. In the figure, duplexes are plotted such that each x-axis tick-mark represents an individual siRNA, with each subsequent siRNA differing in target position by two nucleotides for Human Cyclophilin B and Firefly Luciferase, and by one nucleotide for Human DBI. Furthermore, the y-axis denotes the level of target expression remaining after transfection of the duplex into cells and subsequent silencing of the target.
siRNA identified and optimized in this document work equally well in a wide range of cell types. FIG. 3a shows the evaluation of thirty siRNAs targeting the DBI gene in three cell lines derived from different tissues. Each DBI siRNA displays very similar functionality in HEK293 (ATCC, CRL-1573, human embryonic kidney), HeLa (ATCC, CCL-2, cervical epithelial adenocarcinoma) and DU145 (HTB-81, prostate) cells as determined by the B-DNA assay. Thus, siRNA functionality is determined by the primary sequence of the siRNA and not by the intracellular environment. Additionally, it should be noted that although the present invention provides for a determination of the functionality of siRNA for a given target, the same siRNA may silence more than one gene. For example, the complementary sequence of the silencing siRNA may be present in more than one gene. Accordingly, in these circumstances, it may be desirable not to use the siRNA with highest SMARTSCORE™, or siRNA ranking. In such circumstances, it may be desirable to use the siRNA with the next highest SMARTSCORE™, or siRNA ranking.
To determine the relevance of G/C content in siRNA function, the G/C content of each duplex in the panel was calculated and the functional classes of siRNAs (<F50, ≧F50, ≧F80, ≧F95 where F refers to the percent gene silencing) were sorted accordingly. The majority of the highly-functional siRNAs (≧F95) fell within the G/C content range of 36%-52% (FIG. 3B). Twice as many non-functional (<F50) duplexes fell within the high G/C content groups (>57% GC content) compared to the 36%-52% group. The group with extremely low GC content (26% or less) contained a higher proportion of non-functional siRNAs and no highly-functional siRNAs. The G/C content range of 30%-52% was therefore selected as Criterion I for siRNA functionality, consistent with the observation that a G/C range 30%-70% promotes efficient RNAi targeting. Application of this criterion alone provided only a marginal increase in the probability of selecting functional siRNAs from the panel: selection of F50 and F95 siRNAs was improved by 3.6% and 2.2%, respectively. The siRNA panel presented here permitted a more systematic analysis and quantification of the importance of this criterion than that used previously.
A relative measure of local internal stability is the A/U base pair (bp) content; therefore, the frequency of A/U bp was determined for each of the five terminal positions of the duplex (5′ sense (S)/5′ antisense (AS)) of all siRNAs in the panel. Duplexes were then categorized by the number of A/U bp in positions 1-5 and 15-19 of the sense strand. The thermodynamic flexibility of the duplex 5′-end (positions 1-5; S) did not appear to correlate appreciably with silencing potency, while that of the 3′-end (positions 15-19; S) correlated with efficient silencing. No duplexes lacking A/U bp in positions 15-19 were functional. The presence of one A/U bp in this region conferred some degree of functionality, but the presence of three or more A/Us was preferable and therefore defined as Criterion II. When applied to the test panel, only a marginal increase in the probability of functional siRNA selection was achieved: a 1.8% and 2.3% increase for F50 and F95 duplexes, respectively (Table IV).
The complementary strands of siRNAs that contain internal repeats or palindromes may form internal fold-back structures. These hairpin-like structures exist in equilibrium with the duplexed form effectively reducing the concentration of functional duplexes. The propensity to form internal hairpins and their relative stability can be estimated by predicted melting temperatures. High Tm reflects a tendency to form hairpin structures. Lower Tm values indicate a lesser tendency to form hairpins. When the functional classes of siRNAs were sorted by Tm (FIG. 3c), the following trends were identified: duplexes lacking stable internal repeats were the most potent silencers (no F95 duplex with predicted hairpin structure Tm>60° C.). In contrast, about 60% of the duplexes in the groups having internal hairpins with calculated Tm values less than 20° C. were F80. Thus, the stability of internal repeats is inversely proportional to the silencing effect and defines Criterion III (predicted hairpin structure Tm≦20° C.).
Sequence-Based Determinants of siRNA Functionality
When the siRNA panel was sorted into functional and non-functional groups, the frequency of a specific nucleotide at each position in a functional siRNA duplex was compared with that of a nonfunctional duplex in order to assess the preference for or against a certain nucleotide. FIG. 4 shows the results of these queries and the subsequent resorting of the data set (from FIG. 2). The data is separated into two sets: those duplexes that meet the criteria, a specific nucleotide in a certain position—grouped on the left (Selected) and those that do not—grouped on the right (Eliminated). The duplexes are further sorted from most functional to least functional with the y-axis of FIG. 4a-e representing the % expression i.e., the amount of silencing that is elicited by the duplex (Note: each position on the X-axis represents a different duplex). Statistical analysis revealed correlations between silencing and several sequence-related properties of siRNAs. FIG. 4 and Table IV show quantitative analysis for the following five sequence-related properties of siRNA: (A) an A at position 19 of the sense strand; (B) an A at position 3 of the sense strand; (C) a U at position 10 of the sense strand; (D) a base other than G at position 13 of the sense strand; and (E) a base other than C at position 19 of the sense strand.
When the siRNAs in the panel were evaluated for the presence of an A at position 19 of the sense strand, the percentage of non-functional duplexes decreased from 20% to 11.8%, and the percentage of F95 duplexes increased from 21.7% to 29.4% (Table IV). Thus, the presence of an A in this position defined Criterion IV.
Another sequence-related property correlated with silencing was the presence of an A in position 3 of the sense strand (FIG. 4b). Of the siRNAs with A3, 34.4% were F95, compared with 21.7% randomly selected siRNAs. The presence of a U base in position 10 of the sense strand exhibited an even greater impact (FIG. 4c). Of the duplexes in this group, 41.7% were F95. These properties became criteria V and VI, respectively.
Two negative sequence-related criteria that were identified also appear on FIG. 4. The absence of a G at position 13 of the sense strand, conferred a marginal increase in selecting functional duplexes (FIG. 4d). Similarly, lack of a C at position 19 of the sense strand also correlated with functionality (FIG. 4e). Thus, among functional duplexes, position 19 was most likely occupied by A, and rarely occupied by C. These rules were defined as criteria VII and VIII, respectively.
Application of each criterion individually provided marginal but statistically significant increases in the probability of selecting a potent siRNA. Although the results were informative, the inventors sought to maximize potency and therefore consider multiple criteria or parameters. Optimization is particularly important when developing therapeutics. Interestingly, the probability of selecting a functional siRNA based on each thermodynamic criteria was 2%-4% higher than random, but 4%-8% higher for the sequence-related determinates. Presumably, these sequence-related increases reflect the complexity of the RNAi mechanism and the multitude of protein-RNA interactions that are involved in RNAi-mediated silencing. TABLE IV
PERCENT IMPROVEMENT
CRITERION FUNCTIONAL OVER RANDOM (%)
I. 30%-52% G/C Content <F50 16.4 −3.6
≧F50 83.6 3.6
≧F80 60.4 4.3
≧F95 23.9 2.2
II. At least 3 A/U bases at <F50 18.2 −1.8
positions 15-19 of the sense ≧F50 81.8 1.8
strand ≧F80 59.7 3.6
≧F95 24.0 2.3
III. Absence of internal <F50 16.7 −3.3
repeats, as measured by Tm of ≧F50 83.3 3.3
secondary structure ≦20° C. ≧F80 61.1 5.0
≧F95 24.6 2.9
IV. An A base at position 19 <F50 11.8 −8.2
of the sense strand ≧F50 88.2 8.2
≧F80 75.0 18.9
≧F95 29.4 7.7
V. An A base at position 3 of <F50 17.2 −2.8
the sense strand ≧F50 82.8 2.8
≧F80 62.5 6.4
≧F95 34.4 12.7
VI. A U base at position 10 <F50 13.9 −6.1
of the sense strand ≧F50 86.1 6.1
≧F80 69.4 13.3
≧F95 41.7 20
VII. A base other than C at <F50 18.8 −1.2
position 19 of the sense strand ≧F50 81.2 1.2
≧F80 59.7 3.6
≧F95 24.2 2.5
VIII. A base other than G at <F50 15.2 −4.8
position 13 of the sense strand ≧F50 84.8 4.8
≧F80 61.4 5.3
≧F95 26.5 4.8
The siRNA Selection Algorithm
In an effort to improve selection further, all identified criteria, including but not limited to those listed in Table IV were combined into the algorithms embodied in Formula VIII, Formula IX, and Formula X. Each siRNA was then assigned a score (referred to as a SMARTSCORE™, or siRNA ranking) according to the values derived from the formulas. Duplexes that scored higher than 0 or −20 (unadjusted), for Formulas VIII and IX, respectively, effectively selected a set of functional siRNAs and excluded all non-functional siRNAs. Conversely, all duplexes scoring lower than 0 and −20 (minus 20) according to formulas VIII and IX, respectively, contained some functional siRNAs but included all non-functional siRNAs. A graphical representation of this selection is shown in FIG. 5. It should be noted that the scores derived from the algorithm can also be provided as “adjusted” scores. To convert Formula VIII unadjusted scores into adjusted scores it is necessary to use the following equation:
(160+unadjusted score)/2.25
When this takes place, an unadjusted score of “0” (zero) is converted to 75. Similarly, unadjusted scores for Formula X can be converted to adjusted scores. In this instance, the following equation is applied:
(228+unadjusted score)/3.56
When these manipulations take place, an unadjusted score of 38 is converted to an adjusted score of 75.
The methods for obtaining the seven criteria embodied in Table IV are illustrative of the results of the process used to develop the information for Formulas VIII, IX, and X. Thus similar techniques were used to establish the other variables and their multipliers. As described above, basic statistical methods were use to determine the relative values for these multipliers.
To determine the value for “Improvement over Random” the difference in the frequency of a given attribute (e.g., GC content, base preference) at a particular position is determined between individual functional groups (e.g., <F50) and the total siRNA population studied (e.g., 270 siRNA molecules selected randomly). Thus, for instance, in Criterion I (30%-52% GC content) members of the <F50 group were observed to have GC contents between 30-52% in 16.4% of the cases. In contrast, the total group of 270 siRNAs had GC contents in this range, 20% of the time. Thus for this particular attribute, there is a small negative correlation between 30%-52% GC content and this functional group (i.e., 16.4%-20%=−3.6%). Similarly, for Criterion VI, (a “U” at position 10 of the sense strand), the >F95 group contained a “U” at this position 41.7% of the time. In contrast, the total group of 270 siRNAs had a “U” at this position 21.7% of the time, thus the improvement over random is calculated to be 20% (or 41.7%-21.7%).
Identifying the Average Internal Stability Profile of Strong siRNA
In order to identify an internal stability profile that is characteristic of strong siRNA, 270 different siRNAs derived from the cyclophilin B, the diazepam binding inhibitor (DBI), and the luciferase gene were individually transfected into HEK293 cells and tested for their ability to induce RNAi of the respective gene. Based on their performance in the in vivo assay, the sequences were then subdivided into three groups, (i) >95% silencing; (ii) 80-95% silencing; and (iii) less than 50% silencing. Sequences exhibiting 51-84% silencing were eliminated from further consideration to reduce the difficulties in identifying relevant thermodynamic patterns.
Following the division of siRNA into three groups, a statistical analysis was performed on each member of each group to determine the average internal stability profile (AISP) of the siRNA. To accomplish this the Oligo 5.0 Primer Analysis Software and other related statistical packages (e.g., Excel) were exploited to determine the internal stability of pentamers using the nearest neighbor method described by Freier et al., (1986) Improved free-energy parameters for predictions of RNA duplex stability, Proc Natl. Acad. Sci. USA 83(24): 9373-7. Values for each group at each position were then averaged, and the resulting data were graphed on a linear coordinate system with the Y-axis expressing the AG (free energy) values in kcal/mole and the X-axis identifying the position of the base relative to the 5′ end.
The results of the analysis identified multiple key regions in siRNA molecules that were critical for successful gene silencing. At the 3′-most end of the sense strand (5′antisense), highly functional siRNA (>95% gene silencing, see FIG. 6a, >F95) have a low internal stability (AISP of position 19=˜−7.6 kcal/mol). In contrast low-efficiency siRNA (i.e., those exhibiting less than 50% silencing, <F50) display a distinctly different profile, having high ΔG values (˜−8.4 kcal/mol) for the same position. Moving in a 5′ (sense strand) direction, the internal stability of highly efficient siRNA rises (position 12=˜−8.3 kcal/mole) and then drops again (position 7=˜−7.7 kcal/mol) before leveling off at a value of approximately −8.1 kcal/mol for the 5′ terminus. siRNA with poor silencing capabilities show a distinctly different profile. While the AISP value at position 12 is nearly identical with that of strong siRNAs, the values at positions 7 and 8 rise considerably, peaking at a high of ˜−9.0 kcal/mol. In addition, at the 5′ end of the molecule the AISP profile of strong and weak siRNA differ dramatically. Unlike the relatively strong values exhibited by siRNA in the >95% silencing group, siRNAs that exhibit poor silencing activity have weak AISP values (−7.6, −7.5, and −7.5 kcal/mol for positions 1, 2 and 3 respectively).
Overall the profiles of both strong and weak siRNAs form distinct sinusoidal shapes that are roughly 180° out-of-phase with each other. While these thermodynamic descriptions define the archetypal profile of a strong siRNA, it will likely be the case that neither the ΔG values given for key positions in the profile or the absolute position of the profile along the Y-axis (i.e., the ΔG-axis) are absolutes. Profiles that are shifted upward or downward (i.e., having on an average, higher or lower values at every position) but retain the relative shape and position of the profile along the X-axis can be foreseen as being equally effective as the model profile described here. Moreover, it is likely that siRNA that have strong or even stronger gene-specific silencing effects might have exaggerated ΔG values (either higher or lower) at key positions. Thus, for instance, it is possible that the 5′-most position of the sense strand (position 19) could have ΔG values of 7.4 kcal/mol or lower and still be a strong siRNA if, for instance, a G-C→G-T/U mismatch were substituted at position 19 and altered duplex stability. Similarly, position 12 and position 7 could have values above 8.3 kcal/mol and below 7.7 kcal/mole, respectively, without abating the silencing effectiveness of the molecule. Thus, for instance, at position 12, a stabilizing chemical modification (e.g., a chemical modification of the 2′ position of the sugar backbone) could be added that increases the average internal stability at that position. Similarly, at position 7, mismatches similar to those described previously could be introduced that would lower the AG values at that position.
Lastly, it is important to note that while functional and non-functional siRNA were originally defined as those molecules having specific silencing properties, both broader or more limiting parameters can be used to define these molecules. As used herein, unless otherwise specified, “non-functional siRNA” are defined as those siRNA that induce less than 50% (<50%) target silencing, “semi-functional siRNA” induce 50-79% target silencing, “functional siRNA” are molecules that induce 80-95% gene silencing, and “highly-functional siRNA” are molecules that induce great than 95% gene silencing. These definitions are not intended to be rigid and can vary depending upon the design and needs of the application. For instance, it is possible that a researcher attempting to map a gene to a chromosome using a functional assay, may identify an siRNA that reduces gene activity by only 30%. While this level of gene silencing may be “non-functional” for, e.g., therapeutic needs, it is sufficient for gene mapping purposes and is, under these uses and conditions, “functional.” For these reasons, functional siRNA can be defined as those molecules having greater than 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% silencing capabilities at 100 nM transfection conditions. Similarly, depending upon the needs of the study and/or application, non-functional and semi-functional siRNA can be defined as having different parameters. For instance, semi-functional siRNA can be defined as being those molecules that induce 20%, 30%, 40%, 50%, 60%, or 70% silencing at 100 nM transfection conditions. Similarly, non-functional siRNA can be defined as being those molecules that silence gene expression by less than 70%, 60%, 50%, 40%, 30%, or less. Nonetheless, unless otherwise stated, the descriptions stated in the “Definitions” section of this text should be applied.
Functional attributes can be assigned to each of the key positions in the AISP of strong siRNA. The low 5′ (sense strand) AISP values of strong siRNAs may be necessary for determining which end of the molecule enters the RISC complex. In contrast, the high and low AISP values observed in the central regions of the molecule may be critical for siRNA-target mRNA interactions and product release, respectively.
If the AISP values described above accurately define the thermodynamic parameters of strong siRNA, it would be expected that similar patterns would be observed in strong siRNA isolated from nature. Natural siRNAs exist in a harsh, RNase-rich environment and it can be hypothesized that only those siRNA that exhibit heightened affinity for RISC (i.e., siRNA that exhibit an average internal stability profile similar to those observed in strong siRNA) would survive in an intracellular environment. This hypothesis was tested using GFP-specific siRNA isolated from N. benthamiana. Llave et al. (2002) Endogenous and Silencing-Associated Small RNAs in Plants, The Plant Cell 14, 1605-1619, introduced long double-stranded GFP-encoding RNA into plants and subsequently re-isolated GFP-specific siRNA from the tissues. The AISP of fifty-nine of these GFP-siRNA were determined, averaged, and subsequently plotted alongside the AISP profile obtained from the cyclophilin B/DBI/luciferase siRNA having >90% silencing properties (FIG. 6b). Comparison of the two groups show that profiles are nearly identical. This finding validates the information provided by the internal stability profiles and demonstrates that: (1) the profile identified by analysis of the cyclophilin B/DBI/luciferase siRNAs are not gene specific; and (2) AISP values can be used to search for strong siRNAs in a variety of species.
Both chemical modifications and base-pair mismatches can be incorporated into siRNA to alter the duplex's AISP and functionality. For instance, introduction of mismatches at positions 1 or 2 of the sense strand destabilized the 5′ end of the sense strand and increases the functionality of the molecule (see Luc, FIG. 7). Similarly, addition of 2′-O-methyl groups to positions 1 and 2 of the sense strand can also alter the AISP and (as a result) increase both the functionality of the molecule and eliminate off-target effects that results from sense strand homology with the unrelated targets (FIG. 8).
Rationale for Criteria in a Biological Context
The fate of siRNA in the RNAi pathway may be described in 5 major steps: (1) duplex recognition and pre-RISC complex formation; (2) ATP-dependent duplex unwinding/strand selection and RISC activation; (3) mRNA target identification; (4) mRNA cleavage, and (5) product release (FIG. 1). Given the level of nucleic acid-protein interactions at each step, siRNA functionality is likely influenced by specific biophysical and molecular properties that promote efficient interactions within the context of the multi-component complexes. Indeed, the systematic analysis of the siRNA test set identified multiple factors that correlate well with functionality. When combined into a single algorithm, they proved to be very effective in selecting active siRNAs.
The factors described here may also be predictive of key functional associations important for each step in RNAi. For example, the potential formation of internal hairpin structures correlated negatively with siRNA functionality. Complementary strands with stable internal repeats are more likely to exist as stable hairpins thus decreasing the effective concentration of the functional duplex form. This suggests that the duplex is the preferred conformation for initial pre-RISC association. Indeed, although single complementary strands can induce gene silencing, the effective concentration required is at least two orders of magnitude higher than that of the duplex form.
siRNA-pre-RISC complex formation is followed by an ATP-dependent duplex unwinding step and “activation” of the RISC. The siRNA functionality was shown to correlate with overall low internal stability of the duplex and low internal stability of the 3′ sense end (or differential internal stability of the 3′ sense compare to the 5′ sense strand), which may reflect strand selection and entry into the RISC. Overall duplex stability and low internal stability at the 3′ end of the sense strand were also correlated with siRNA functionality. Interestingly, siRNAs with very high and very low overall stability profiles correlate strongly with non-functional duplexes. One interpretation is that high internal stability prevents efficient unwinding while very low stability reduces siRNA target affinity and subsequent mRNA cleavage by the RISC.
Several criteria describe base preferences at specific positions of the sense strand and are even more intriguing when considering their potential mechanistic roles in target recognition and mRNA cleavage. Base preferences for A at position 19 of the sense strand but not C, are particularly interesting because they reflect the same base preferences observed for naturally occurring miRNA precursors. That is, among the reported miRNA precursor sequences 75% contain a U at position 1 which corresponds to an A in position 19 of the sense strand of siRNAs, while G was under-represented in this same position for miRNA precursors. These observations support the hypothesis that both miRNA precursors and siRNA duplexes are processed by very similar if not identical protein machinery. The functional interpretation of the predominance of a U/A base pair is that it promotes flexibility at the 5′antisense ends of both siRNA duplexes and miRNA precursors and facilitates efficient unwinding and selective strand entrance into an activated RISC.
Among the criteria associated with base preferences that are likely to influence mRNA cleavage or possibly product release, the preference for U at position 10 of the sense strand exhibited the greatest impact, enhancing the probability of selecting an F80 sequence by 13.3%. Activated RISC preferentially cleaves target mRNA between nucleotides 10 and 11 relative to the 5′ end of the complementary targeting strand. Therefore, it may be that U, the preferred base for most endoribonucleases, at this position supports more efficient cleavage. Alternatively, a U/A bp between the targeting siRNA strand and its cognate target mRNA may create an optimal conformation for the RISC-associated “slicing” activity.
Post Algorithm Filters
According to another embodiment, the output of any one of the formulas previously listed can be filtered to remove or select for siRNAs containing undesirable or desirable motifs or properties, respectively. In one example, sequences identified by any of the formulas can be filtered to remove any and all sequences that induce toxicity or cellular stress. Introduction of an siRNA containing a toxic motif into a cell can induce cellular stress and/or cell death (apoptosis) which in turn can mislead researchers into associating a particular (e.g., nonessential) gene with, e.g., an essential function. Alternatively, sequences generated by any of the before mentioned formulas can be filtered to identify and retain duplexes that contain toxic motifs. Such duplexes may be valuable from a variety of perspectives including, for instance, uses as therapeutic molecules. A variety of toxic motifs exist and can exert their influence on the cell through RNAi and non-RNAi pathways. Examples of toxic motifs are explained more fully in commonly assigned U.S. Provisional Patent Application Ser. No. 60/538,874, entitled “Identification of Toxic Sequences,” filed Jan. 23, 2004. Briefly, toxic motifs include A/G UUU A/G/U, G/C AAA G/C, and GCCA, or a complement of any of the foregoing.
In another instance, sequences identified by any of the before mentioned formulas can be filtered to identify duplexes that contain motifs (or general properties) that provide serum stability or induce serum instability. In one envisioned application of siRNA as therapeutic molecules, duplexes targeting disease-associated genes will be introduced into patients intravenously. As the half-life of single and double stranded RNA in serum is short, post-algorithm filters designed to select molecules that contain motifs that enhance duplex stability in the presence of serum and/or (conversely) eliminate duplexes that contain motifs that destabilize siRNA in the presence of serum, would be beneficial.
In another instance, sequences identified by any of the before mentioned formulas can be filtered to identify duplexes that are hyperfunctional. Hyperfunctional sequences are defined as those sequences that (1) induce greater than 95% silencing of a specific target when they are transfected at subnanomolar concentrations (i.e., less than one nanomolar); and/or (2) induce functional (or better) levels of silencing for greater than 96 hours. Filters that identify hyperfunctional molecules can vary widely. In one example, the top ten, twenty, thirty, or forty siRNA can be assessed for the ability to silence a given target at, e.g., concentrations of 1 nM and 0.5 nM to identify hyperfunctional molecules.
Pooling
According to another embodiment, the present invention provides a pool of at least two siRNAs, preferably in the form of a kit or therapeutic reagent, wherein one strand of each of the siRNAs, the sense strand comprises a sequence that is substantially similar to a sequence within a target mRNA. The opposite strand, the antisense strand, will preferably comprise a sequence that is substantially complementary to that of the target mRNA. More preferably, one strand of each siRNA will comprise a sequence that is identical to a sequence that is contained in the target mRNA. Most preferably, each siRNA will be 19 base pairs in length, and one strand of each of the siRNAs will be 100% complementary to a portion of the target mRNA.
By increasing the number of siRNAs directed to a particular target using a pool or kit, one is able both to increase the likelihood that at least one siRNA with satisfactory functionality will be included, as well as to benefit from additive or synergistic effects. Further, when two or more siRNAs directed against a single gene do not have satisfactory levels of functionality alone, if combined, they may satisfactorily promote degradation of the target messenger RNA and successfully inhibit translation. By including multiple siRNAs in the system, not only is the probability of silencing increased, but the economics of operation are also improved when compared to adding different siRNAs sequentially. This effect is contrary to the conventional wisdom that the concurrent use of multiple siRNA will negatively impact gene silencing (e.g., Holen, T. et al. (2003) Similar behavior of single strand and double strand siRNAs suggests they act through a common RNAi pathway. NAR 31: 2401-21407).
In fact, when two siRNAs were pooled together, 54% of the pools of two siRNAs induced more than 95% gene silencing. Thus, a 2.5-fold increase in the percentage of functionality was achieved by randomly combining two siRNAs. Further, over 84% of pools containing two siRNAs induced more than 80% gene silencing.
More preferably, the kit is comprised of at least three siRNAs, wherein one strand of each siRNA comprises a sequence that is substantially similar to a sequence of the target mRNA and the other strand comprises a sequence that is substantially complementary to the region of the target mRNA. As with the kit that comprises at least two siRNAs, more preferably one strand will comprise a sequence that is identical to a sequence that is contained in the mRNA and another strand that is 100% complementary to a sequence that is contained in the mRNA. During experiments, when three siRNAs were combined together, 60% of the pools induced more than 95% gene silencing and 92% of the pools induced more than 80% gene silencing.
Further, even more preferably, the kit is comprised of at least four siRNAs, wherein one strand of each siRNA comprises a sequence that is substantially similar to a region of the sequence of the target mRNA, and the other strand comprises a sequence that is substantially complementary to the region of the target mRNA. As with the kit or pool that comprises at least two siRNAs, more preferably one strand of each of the siRNA duplexes will comprise a sequence that is identical to a sequence that is contained in the mRNA, and another strand that is 100% complementary to a sequence that is contained in the mRNA.
Additionally, kits and pools with at least five, at least six, and at least seven siRNAs may also be useful with the present invention. For example, pools of five siRNA induced 95% gene silencing with 77% probability and 80% silencing with 98.8% probability. Thus, pooling of siRNAs together can result in the creation of a target-specific silencing reagent with almost a 99% probability of being functional. The fact that such high levels of success are achievable using such pools of siRNA, enables one to dispense with costly and time-consuming target-specific validation procedures.
For this embodiment, as well as the other aforementioned embodiments, each of the siRNAs within a pool will preferably comprise 18-30 base pairs, more preferably 18-25 base pairs, and most preferably 19 base pairs. Within each siRNA, preferably at least 18 contiguous bases of the antisense strand will be 100% complementary to the target mRNA. More preferably, at least 19 contiguous bases of the antisense strand will be 100% complementary to the target mRNA. Additionally, there may be overhangs on either the sense strand or the antisense strand, and these overhangs may be at either the 5′ end or the 3′ end of either of the strands, for example there may be one or more overhangs of 1-6 bases. When overhangs are present, they are not included in the calculation of the number of base pairs. The two nucleotide 3′ overhangs mimic natural siRNAs and are commonly used but are not essential. Preferably, the overhangs should consist of two nucleotides, most often dTdT or UU at the 3′ end of the sense and antisense strand that are not complementary to the target sequence. The siRNAs may be produced by any method that is now known or that comes to be known for synthesizing double stranded RNA that one skilled in the art would appreciate would be useful in the present invention. Preferably, the siRNAs will be produced by Dharmacon's proprietary ACE® technology. However, other methods for synthesizing siRNAs are well known to persons skilled in the art and include, but are not limited to, any chemical synthesis of RNA oligonucleotides, ligation of shorter oligonucleotides, in vitro transcription of RNA oligonucleotides, the use of vectors for expression within cells, recombinant Dicer products and PCR products.
The siRNA duplexes within the aforementioned pools of siRNAs may correspond to overlapping sequences within a particular mRNA, or non-overlapping sequences of the mRNA. However, preferably they correspond to non-overlapping sequences. Further, each siRNA may be selected randomly, or one or more of the siRNA may be selected according to the criteria discussed above for maximizing the effectiveness of siRNA.
Included in the definition of siRNAs are siRNAs that contain substituted and/or labeled nucleotides that may, for example, be labeled by radioactivity, fluorescence or mass. The most common substitutions are at the 2′ position of the ribose sugar, where moieties such as H (hydrogen) F, NH3, OCH3 and other O— alkyl, alkenyl, alkynyl, and orthoesters, may be substituted, or in the phosphorous backbone, where sulfur, amines or hydrocarbons may be substituted for the bridging of non-bridging atoms in the phosphodiester bond. Examples of modified siRNAs are explained more fully in commonly assigned U.S. patent application Ser. No. 10/613,077, filed Jul. 1, 2003.
Additionally, as noted above, the cell type into which the siRNA is introduced may affect the ability of the siRNA to enter the cell; however, it does not appear to affect the ability of the siRNA to function once it enters the cell. Methods for introducing double-stranded RNA into various cell types are well known to persons skilled in the art.
As persons skilled in the art are aware, in certain species, the presence of proteins such as RdRP, the RNA-dependent RNA polymerase, may catalytically enhance the activity of the siRNA. For example, RdRP propagates the RNAi effect in C. elegans and other non-mammalian organisms. In fact, in organisms that contain these proteins, the siRNA may be inherited. Two other proteins that are well studied and known to be a part of the machinery are members of the Argonaute family and Dicer, as well as their homologues. There is also initial evidence that the RISC complex might be associated with the ribosome so the more efficiently translated mRNAs will be more susceptible to silencing than others.
Another very important factor in the efficacy of siRNA is mRNA localization. In general, only cytoplasmic mRNAs are considered to be accessible to RNAi to any appreciable degree. However, appropriately designed siRNAs, for example, siRNAs modified with internucleotide linkages or 2′-O-methyl groups, may be able to cause silencing by acting in the nucleus. Examples of these types of modifications are described in commonly assigned U.S. patent application Ser. Nos. 10/431,027 and 10/613,077.
As described above, even when one selects at least two siRNAs at random, the effectiveness of the two may be greater than one would predict based on the effectiveness of two individual siRNAs. This additive or synergistic effect is particularly noticeable as one increases to at least three siRNAs, and even more noticeable as one moves to at least four siRNAs. Surprisingly, the pooling of the non-functional and semi-functional siRNAs, particularly more than five siRNAs, can lead to a silencing mixture that is as effective if not more effective than any one particular functional siRNA.
Within the kits of the present invention, preferably each siRNA will be present in a concentration of between 0.001 and 200 μM, more preferably between 0.01 and 200 nM, and most preferably between 0.1 and 10 nM.
In addition to preferably comprising at least four or five siRNAs, the kits of the present invention will also preferably comprise a buffer to keep the siRNA duplex stable. Persons skilled in the art are aware of buffers suitable for keeping siRNA stable. For example, the buffer may be comprised of 100 mM KCl, 30 mM HEPES-pH 7.5, and 1 mM MgCl2. Alternatively, kits might contain complementary strands that contain any one of a number of chemical modifications (e.g., a 2′-O-ACE) that protect the agents from degradation by nucleases. In this instance, the user may (or may not) remove the modifying protective group (e.g., deprotect) before annealing the two complementary strands together.
By way of example, the kits may be organized such that pools of siRNA duplexes are provided on an array or microarray of wells or drops for a particular gene set or for unrelated genes. The array may, for example, be in 96 wells, 384 wells or 1284 wells arrayed in a plastic plate or on a glass slide using techniques now known or that come to be known to persons skilled in the art. Within an array, preferably there will be controls such as functional anti-lamin A/C, cyclophilin and two siRNA duplexes that are not specific to the gene of interest.
In order to ensure stability of the siRNA pools prior to usage, they may be retained in lyophilized form at minus twenty degrees (−20° C.) until they are ready for use. Prior to usage, they should be resuspended; however, even once resuspended, for example, in the aforementioned buffer, they should be kept at minus twenty degrees, (−20° C.) until used. The aforementioned buffer, prior to use, may be stored at approximately 4° C. or room temperature. Effective temperatures at which to conduct transfections are well known to persons skilled in the art and include for example, room temperature.
The kits may be applied either in vivo or in vitro. Preferably, the siRNA of the pools or kits is applied to a cell through transfection, employing standard transfection protocols. These methods are well known to persons skilled in the art and include the use of lipid-based carriers, electroporation, cationic carriers, and microinjection. Further, one could apply the present invention by synthesizing equivalent DNA sequences (either as two separate, complementary strands, or as hairpin molecules) instead of siRNA sequences and introducing them into cells through vectors. Once in the cells, the cloned DNA could be transcribed, thereby forcing the cells to generate the siRNA. Examples of vectors suitable for use with the present application include but are not limited to the standard transient expression vectors, adenoviruses, retroviruses, lentivirus-based vectors, as well as other traditional expression vectors. Any vector that has an adequate siRNA expression and procession module may be used. Furthermore, certain chemical modifications to siRNAs, including but not limited to conjugations to other molecules, may be used to facilitate delivery. For certain applications it may be preferable to deliver molecules without transfection by simply formulating in a physiological acceptable solution.
This embodiment may be used in connection with any of the aforementioned embodiments. Accordingly, the sequences within any pool may be selected by rational design.
Multigene Silencing
In addition to developing kits that contain multiple siRNA directed against a single gene, another embodiment includes the use of multiple siRNA targeting multiple genes. Multiple genes may be targeted through the use of high- or hyper-functional siRNA. High- or hyper-functional siRNA that exhibit increased potency, require lower concentrations to induce desired phenotypic (and thus therapeutic) effects. This circumvents RISC saturation. It therefore reasons that if lower concentrations of a single siRNA are needed for knockout or knockdown expression of one gene, then the remaining (uncomplexed) RISC will be free and available to interact with siRNA directed against two, three, four, or more, genes. Thus in this embodiment, the authors describe the use of highly functional or hyper-functional siRNA to knock out three separate genes. More preferably, such reagents could be combined to knockout four distinct genes. Even more preferably, highly functional or hyperfunctional siRNA could be used to knock out five distinct genes. Most preferably, siRNA of this type could be used to knockout or knockdown the expression of six or more genes.
Hyperfunctional siRNA
The term hyperfunctional siRNA (hf-siRNA) describes a subset of the siRNA population that induces RNAi in cells at low- or sub-nanomolar concentrations for extended periods of time. These traits, heightened potency and extended longevity of the RNAi phenotype, are highly attractive from a therapeutic standpoint. Agents having higher potency require lesser amounts of the molecule to achieve the desired physiological response, thus reducing the probability of side effects due to “off-target” interference. In addition to the potential therapeutic benefits associated with hyperfunctional siRNA, hf-siRNA are also desirable from an economic perspective. Hyperfunctional siRNA may cost less on a per-treatment basis, thus reducing overall expenditures to both the manufacturer and the consumer.
Identification of hyperfunctional siRNA involves multiple steps that are designed to examine an individual siRNA agent's concentration- and/or longevity-profiles. In one non-limiting example, a population of siRNA directed against a single gene are first analyzed using the previously described algorithm (Formula VIII). Individual siRNA are then introduced into a test cell line and assessed for the ability to degrade the target mRNA. It is important to note that when performing this step it is not necessary to test all of the siRNA. Instead, it is sufficient to test only those siRNA having the highest SMARTSCORES™, or siRNA ranking (i.e., SMARTSCORES™, or siRNA ranking >−10). Subsequently, the gene silencing data is plotted against the SMARTSCORES™, or siRNA rankings (see FIG. 9). siRNA that (1) induce a high degree of gene silencing (i.e., they induce greater than 80% gene knockdown) and (2) have superior SMARTSCORES™ (i.e., a SMARTSCORE™, or siRNA ranking, of >−10, suggesting a desirable average internal stability profile) are selected for further investigations designed to better understand the molecule's potency and longevity. In one, non-limiting study dedicated to understanding a molecule's potency, an siRNA is introduced into one (or more) cell types in increasingly diminishing concentrations (e.g., 3.0→0.3 nM). Subsequently, the level of gene silencing induced by each concentration is examined and siRNA that exhibit hyperfunctional potency (i.e., those that induce 80% silencing or greater at, e.g., picomolar concentrations) are identified. In a second study, the longevity profiles of siRNA having high (>−10) SMARTSCORES™, or siRNA rankings and greater than 80% silencing are examined. In one non-limiting example of how this is achieved, siRNA are introduced into a test cell line and the levels of RNAi are measured over an extended period of time (e.g., 24-168 hrs). siRNAs that exhibit strong RNA interference patterns (i.e., >80% interference) for periods of time greater than, e.g., 120 hours, are thus identified. Studies similar to those described above can be performed on any and all of the >106 siRNA included in this document to further define the most functional molecule for any given gene. Molecules possessing one or both properties (extended longevity and heightened potency) are labeled “hyperfunctional siRNA,” and earmarked as candidates for future therapeutic studies.
While the example(s) given above describe one means by which hyperfunctional siRNA can be isolated, neither the assays themselves nor the selection parameters used are rigid and can vary with each family of siRNA. Families of siRNA include siRNAs directed against a single gene, or directed against a related family of genes.
The highest quality siRNA achievable for any given gene may vary considerably. Thus, for example, in the case of one gene (gene X), rigorous studies such as those described above may enable the identification of an siRNA that, at picomolar concentrations, induces 99+% silencing for a period of 10 days. Yet identical studies of a second gene (gene Y) may yield an siRNA that at high nanomolar concentrations (e.g., 100 nM) induces only 75% silencing for a period of 2 days. Both molecules represent the very optimum siRNA for their respective gene targets and therefore are designated “hyperfunctional.” Yet due to a variety of factors including but not limited to target concentration, siRNA stability, cell type, off-target interference, and others, equivalent levels of potency and longevity are not achievable. Thus, for these reasons, the parameters described in the before mentioned assays can vary. While the initial screen selected siRNA that had SMARTSCORES™ above −10 and a gene silencing capability of greater than 80%, selections that have stronger (or weaker) parameters can be implemented. Similarly, in the subsequent studies designed to identify molecules with high potency and longevity, the desired cutoff criteria (i.e., the lowest concentration that induces a desirable level of interference, or the longest period of time that interference can be observed) can vary. The experimentation subsequent to application of the rational criteria of this application is significantly reduced where one is trying to obtain a suitable hyperfunctional siRNA for, for example, therapeutic use. When, for example, the additional experimentation of the type described herein is applied by one skilled in the art with this disclosure in hand, a hyperfunctional siRNA is readily identified.
The siRNA may be introduced into a cell by any method that is now known or that comes to be known and that from reading this disclosure, persons skilled in the art would determine would be useful in connection with the present invention in enabling siRNA to cross the cellular membrane. These methods include, but are not limited to, any manner of transfection, such as, for example, transfection employing DEAE-Dextran, calcium phosphate, cationic lipids/liposomes, micelles, manipulation of pressure, microinjection, electroporation, immunoporation, use of vectors such as viruses, plasmids, cosmids, bacteriophages, cell fusions, and coupling of the polynucleotides to specific conjugates or ligands such as antibodies, antigens, or receptors, passive introduction, adding moieties to the siRNA that facilitate its uptake, and the like.
Having described the invention with a degree of particularity, examples will now be provided. These examples are not intended to and should not be construed to limit the scope of the claims in any way.
EXAMPLES General Techniques and Nomenclatures siRNA nomenclature. All siRNA duplexes are referred to by sense strand. The first nucleotide of the 5′-end of the sense strand is position 1, which corresponds to position 19 of the antisense strand for a 19-mer. In most cases, to compare results from different experiments, silencing was determined by measuring specific transcript mRNA levels or enzymatic activity associated with specific transcript levels, 24 hours post-transfection, with siRNA concentrations held constant at 100 nM. For all experiments, unless otherwise specified, transfection efficiency was ensured to be over 95%, and no detectable cellular toxicity was observed. The following system of nomenclature was used to compare and report siRNA-silencing functionality: “F” followed by the degree of minimal knockdown. For example, F50 signifies at least 50% knockdown, F80 means at least 80%, and so forth. For this study, all sub-F50 siRNAs were considered non-functional.
Cell culture and transfection. 96-well plates are coated with 50 μl of 50 mg/ml poly-L-lysine (Sigma) for 1 hr, and then washed 3× with distilled water before being dried for 20 min. HEK293 cells or HEK293Lucs or any other cell type of interest are released from their solid support by trypsinization, diluted to 3.5×105 cells/ml, followed by the addition of 100 μL of cells/well. Plates are then incubated overnight at 37° C., 5% CO2. Transfection procedures can vary widely depending on the cell type and transfection reagents. In one non-limiting example, a transfection mixture consisting of 2 mL Opti-MEM I (Gibco-BRL), 80 μl Lipofectamine 2000 (Invitrogen), 15 μL SUPERNasin at 20 U/R1 (Ambion), and 1.5 μl of reporter gene plasmid at 1 μg/μl is prepared in 5-ml polystyrene round bottom tubes. One hundred μl of transfection reagent is then combined with 100 μl of siRNAs in polystyrene deep-well titer plates (Beckman) and incubated for 20 to 30 min at room temperature. Five hundred and fifty microliters of Opti-MEM is then added to each well to bring the final siRNA concentration to 100 nM. Plates are then sealed with parafilm and mixed. Media is removed from HEK293 cells and replaced with 95 μl of transfection mixture. Cells are incubated overnight at 37° C., 5% CO2.
Quantification of gene knockdown. A variety of quantification procedures can be used to measure the level of silencing induced by siRNA or siRNA pools. In one non-limiting example: to measure mRNA levels 24 hrs post-transfection, QuantiGene branched-DNA (bDNA) kits (Bayer) (Wang, et al, Regulation of insulin preRNA splicing by glucose. Proc. Natl. Acad. Sci. USA 1997, 94:4360.) are used according to manufacturer instructions. To measure luciferase activity, media is removed from HEK293 cells 24 hrs post-transfection, and 50 μl of Steady-GLO reagent (Promega) is added. After 5 minutes, plates are analyzed on a plate reader.
Example I Sequences Used to Develop the Algorithm Anti-Firefly and anti-Cyclophilin siRNAs panels (FIG. 5a, b) sorted according to using Formula VIII predicted values. All siRNAs scoring more than 0 (formula VIII) and more then 20 (formula IX) are fully functional. All ninety sequences for each gene (and DBI) appear below in Table III. TABLE III
Cyclo 1 SEQ. ID 0032 GUUCCAAAAACAGUGGAUA
Cyclo 2 SEQ. ID 0033 UCCAAAAACAGUGGAUAAU
Cyclo 3 SEQ. ID 0034 CAAAAACAGUGGAUAAUUU
Cyclo 4 SEQ. ID 0035 AAAACAGUGGAUAAUUUUG
Cyclo 5 SEQ. ID 0036 AACAGUGGAUAAUUUUGUG
Cyclo 6 SEQ. ID 0037 CAGUGGAUAAUUUUGUGGC
Cyclo 7 SEQ. ID 0038 GUGGAUAAUUUUGUGGCCU
Cyclo 8 SEQ. ID 0039 GGAUAAUUUUGUGGCCUUA
Cyclo 9 SEQ. ID 0040 AUAAUUUUGUGGCCUUAGC
Cyclo 10 SEQ. ID 0041 AAUUUUGUGGCCUUAGCUA
Cyclo 11 SEQ. ID 0042 UUUUGUGGCCUUAGCUACA
Cyclo 12 SEQ. ID 0043 UUGUGGCCUUAGCUACAGG
Cyclo 13 SEQ. ID 0044 GUGGCCUUAGCUACAGGAG
Cyclo 14 SEQ. ID 0045 GGCCUUAGCUACAGGAGAG
Cyclo 15 SEQ. ID 0046 CCUUAGCUACAGGAGAGAA
Cyclo 16 SEQ. ID 0047 UUAGCUACAGGAGAGAAAG
Cyclo 17 SEQ. ID 0048 AGCUACAGGAGAGAAAGGA
Cyclo 18 SEQ. ID 0049 CUACAGGAGAGAAAGGAUU
Cyclo 19 SEQ. ID 0050 ACAGGAGAGAAAGGAUUUG
Cyclo 20 SEQ. ID 0051 AGGAGAGAAAGGAUUUGGC
Cyclo 21 SEQ. ID 0052 GAGAGAAAGGAUUUGGCUA
Cyclo 22 SEQ. ID 0053 GAGAAAGGAUUUGGCUACA
Cyclo 23 SEQ. ID 0054 GAAAGGAUUUGGCUACAAA
Cyclo 24 SEQ. ID 0055 AAGGAUUUGGCUACAAAAA
Cyclo 25 SEQ. ID 0056 GGAUUUGGCUACAAAAACA
Cyclo 26 SEQ. ID 0057 AUUUGGCUACAAAAACAGC
Cyclo 27 SEQ. ID 0058 UUGGCUACAAAAACAGCAA
Cyclo 28 SEQ. ID 0059 GGCUACAAAAACAGCAAAU
Cyclo 29 SEQ. ID 0060 CUACAAAAACAGCAAAUUC
Cyclo 30 SEQ. ID 0061 ACAAAAACAGCAAAUUCCA
Cyclo 31 SEQ. ID 0062 AAAAACAGCAAAUUCCAUC
Cyclo 32 SEQ. ID 0063 AAACAGCAAAUUCCAUCGU
Cyclo 33 SEQ. ID 0064 ACAGCAAAUUCCAUCGUGU
Cyclo 34 SEQ. ID 0065 AGCAAAUUCCAUCGUGUAA
Cyclo 35 SEQ. ID 0066 CAAAUUCCAUCGUGUAAUC
Cyclo 36 SEQ. ID 0067 AAUUCCAUCGUGUAAUCAA
Cyclo 37 SEQ. ID 0068 UUCCAUCGUGUAAUCAAGG
Cyclo 38 SEQ. ID 0069 CCAUCGUGUAAUCAAGGAC
Cyclo 39 SEQ. ID 0070 AUCGUGUAAUCAAGGACUU
Cyclo 40 SEQ. ID 0071 CGUGUAAUCAAGGACUUCA
Cyclo 41 SEQ. ID 0072 UGUAAUCAAGGACUUCAUG
Cyclo 42 SEQ. ID 0073 UAAUCAAGGACUUCAUGAU
Cyclo 43 SEQ. ID 0074 AUCAAGGACUUCAUGAUCC
Cyclo 44 SEQ. ID 0075 CAAGGACUUCAUGAUCCAG
Cyclo 45 SEQ. ID 0076 AGGACUUCAUGAUCCAGGG
Cyclo 46 SEQ. ID 0077 GACUUCAUGAUCCAGGGCG
Cyclo 47 SEQ. ID 0078 CUUCAUGAUCCAGGGCGGA
Cyclo 48 SEQ. ID 0079 UCAUGAUCCAGGGCGGAGA
Cyclo 49 SEQ. ID 0080 AUGAUCCAGGGCGGAGACU
Cyclo 50 SEQ. ID 0081 GAUCCAGGGCGGAGACUUC
Cyclo 51 SEQ. ID 0082 UCCAGGGCGGAGACUUCAC
Cyclo 52 SEQ. ID 0083 CAGGGCGGAGACUUCACCA
Cyclo 53 SEQ. ID 0084 GGGCGGAGACUUCACCAGG
Cyclo 54 SEQ. ID 0085 GCGGAGACUUCACCAGGGG
Cyclo 55 SEQ. ID 0086 GGAGACUUCACCAGGGGAG
Cyclo 56 SEQ. ID 0087 AGACUUCACCAGGGGAGAU
Cyclo 57 SEQ. ID 0088 ACUUCACCAGGGGAGAUGG
Cyclo 58 SEQ. ID 0089 UUCACCAGGGGAGAUGGCA
Cyclo 59 SEQ. ID 0090 CACCAGGGGAGAUGGCACA
Cyclo 60 SEQ. ID 0091 CCAGGGGAGAUGGCACAGG
Cyclo 61 SEQ. ID 0092 AGGGGAGAUGGCACAGGAG
Cyclo 62 SEQ. ID 0093 GGGAGAUGGCACAGGAGGA
Cyclo 63 SEQ. ID 0094 GAGAUGGCACAGGAGGAAA
Cyclo 64 SEQ. ID 0095 GAUGGCACAGGAGGAAAGA
Cyclo 65 SEQ. ID 0096 UGGCACAGGAGGAAAGAGC
Cyclo 66 SEQ. ID 0097 GCACAGGAGGAAAGAGCAU
Cyclo 67 SEQ. ID 0098 ACAGGAGGAAAGAGCAUCU
Cyclo 68 SEQ. ID 0099 AGGAGGAAAGAGCAUCUAC
Cyclo 69 SEQ. ID 0100 GAGGAAAGAGCAUCUACGG
Cyclo 70 SEQ. ID 0101 GGAAAGAGCAUCUACGGUG
Cyclo 71 SEQ. ID 0102 AAAGAGCAUCUACGGUGAG
Cyclo 72 SEQ. ID 0103 AGAGCAUCUACGGUGAGCG
Cyclo 73 SEQ. ID 0104 AGCAUCUACGGUGAGCGCU
Cyclo 74 SEQ. ID 0105 CAUCUACGGUGAGCGCUUC
Cyclo 75 SEQ. ID 0106 UCUACGGUGAGCGCUUCCC
Cyclo 76 SEQ. ID 0107 UACGGUGAGCGCUUCCCCG
Cyclo 77 SEQ. ID 0108 CGGUGAGCGCUUCCCCGAU
Cyclo 78 SEQ. ID 0109 GUGAGCGCUUCCCCGAUGA
Cyclo 79 SEQ. ID 0110 GAGCGCUUCCCCGAUGAGA
Cyclo 80 SEQ. ID 0111 GCGCUUCCCCGAUGAGAAC
Cyclo 81 SEQ. ID 0112 GCUUCCCCGAUGAGAACUU
Cyclo 82 SEQ. ID 0113 UUCCCCGAUGAGAACUUCA
Cyclo 83 SEQ. ID 0114 CCCCGAUGAGAACUUCAAA
Cyclo 84 SEQ. ID 0115 CCGAUGAGAACUUCAAACU
Cyclo 85 SEQ. ID 0116 GAUGAGAACUUCAAACUGA
Cyclo 86 SEQ. ID 0117 UGAGAACUUCAAACUGAAG
Cyclo 87 SEQ. ID 0118 AGAACUUCAAACUGAAGCA
Cyclo 88 SEQ. ID 0119 AACUUCAAACUGAAGCACU
Cyclo 89 SEQ. ID 0120 CUUCAAACUGAAGCACUAC
Cyclo 90 SEQ. ID 0121 UCAAACUGAAGCACUACGG
DB 1 SEQ. ID 0122 ACGGGCAAGGCCAAGUGGG
DB 2 SEQ. ID 0123 CGGGCAAGGCCAAGUGGGA
DB 3 SEQ. ID 0124 GGGCAAGGCCAAGUGGGAU
DB 4 SEQ. ID 0125 GGCAAGGCCAAGUGGGAUG
DB 5 SEQ. ID 0126 GCAAGGCCAAGUGGGAUGC
DB 6 SEQ. ID 0127 CAAGGCCAAGUGGGAUGCC
DB 7 SEQ. ID 0128 AAGGCCAAGUGGGAUGCCU
DB 8 SEQ. ID 0129 AGGCCAAGUGGGAUGCCUG
DB 9 SEQ. ID 0130 GGCCAAGUGGGAUGCCUGG
DB 10 SEQ. ID 0131 GCCAAGUGGGAUGCCUGGA
DB 11 SEQ. ID 0132 CCAAGUGGGAUGCCUGGAA
DB 12 SEQ. ID 0133 CAAGUGGGAUGCCUGGAAU
DB 13 SEQ. ID 0134 AAGUGGGAUGCCUGGAAUG
DB 14 SEQ. ID 0135 AGUGGGAUGCCUGGAAUGA
DB 15 SEQ. ID 0136 GUGGGAUGCCUGGAAUGAG
DB 16 SEQ. ID 0137 UGGGAUGCCUGGAAUGAGC
DB 17 SEQ. ID 0138 GGGAUGCCUGGAAUGAGCU
DB 18 SEQ. ID 0139 GGAUGCCUGGAAUGAGCUG
DB 19 SEQ. ID 0140 GAUGCCUGGAAUGAGCUGA
DB 20 SEQ. ID 0141 AUGCCUGGAAUGAGCUGAA
DB 21 SEQ. ID 0142 UGCCUGGAAUGAGCUGAAA
DB 22 SEQ. ID 0143 GCCUGGAAUGAGCUGAAAG
DB 23 SEQ. ID 0144 CCUGGAAUGAGCUGAAAGG
DB 24 SEQ. ID 0145 CUGGAAUGAGCUGAAAGGG
DB 25 SEQ. ID 0146 UGGAAUGAGCUGAAAGGGA
DB 26 SEQ. ID 0147 GGAAUGAGCUGAAAGGGAC
DB 27 SEQ. ID 0148 GAAUGAGCUGAAAGGGACU
DB 28 SEQ. ID 0149 AAUGAGCUGAAAGGGACUU
DB 29 SEQ. ID 0150 AUGAGCUGAAAGGGACUUC
DB 30 SEQ. ID 0151 UGAGCUGAAAGGGACUUCC
DB 31 SEQ. ID 0152 GAGCUGAAAGGGACUUCCA
DB 32 SEQ. ID 0153 AGCUGAAAGGGACUUCCAA
DB 33 SEQ. ID 0154 GCUGAAAGGGACUUCCAAG
DB 34 SEQ. ID 0155 CUGAAAGGGACUUCCAAGG
DB 35 SEQ. ID 0156 UGAAAGGGACUUCCAAGGA
DB 36 SEQ. ID 0157 GAAAGGGACUUCCAAGGAA
DB 37 SEQ. ID 0158 AAAGGGACUUCCAAGGAAG
DB 38 SEQ. ID 0159 AAGGGACUUCCAAGGAAGA
DB 39 SEQ. ID 0160 AGGGACUUCCAAGGAAGAU
DB 40 SEQ. ID 0161 GGGACUUCCAAGGAAGAUG
DB 41 SEQ. ID 0162 GGACUUCCAAGGAAGAUGC
DB 42 SEQ. ID 0163 GACUUCCAAGGAAGAUGCC
DB 43 SEQ. ID 0164 ACUUCCAAGGAAGAUGCCA
DB 44 SEQ. ID 0165 CUUCCAAGGAAGAUGCCAU
DB 45 SEQ. ID 0166 UUCCAAGGAAGAUGCCAUG
DB 46 SEQ. ID 0167 UCCAAGGAAGAUGCCAUGA
DB 47 SEQ. ID 0168 CCAAGGAAGAUGCCAUGAA
DB 48 SEQ. ID 0169 CAAGGAAGAUGCCAUGAAA
DB 49 SEQ. ID 0170 AAGGAAGAUGCCAUGAAAG
DB 50 SEQ. ID 0171 AGGAAGAUGCCAUGAAAGC
DB 51 SEQ. ID 0172 CGAAGAUGCCAUGAAAGCU
DB 52 SEQ. ID 0173 GAAGAUGCCAUGAAAGCUU
DB 53 SEQ. ID 0174 AAGAUGCCAUGAAAGCUUA
DB 54 SEQ. ID 0175 AGAUGCCAUGAAAGCUUAC
DB 55 SEQ. ID 0176 GAUGCCAUGAAAGCUUACA
DB 56 SEQ. ID 0177 AUGCCAUGAAAGCUUACAU
DB 57 SEQ. ID 0178 UGCCAUGAAAGCUUACAUC
DB 58 SEQ. ID 0179 GCCAUGAAAGCUUACAUCA
DB 59 SEQ. ID 0180 CCAUGAAAGCUUACAUCAA
DB 60 SEQ. ID 0181 CAUGAAAGCUUACAUCAAC
DB 61 SEQ. ID 0182 AUGAAAGCUUACAUCAACA
DB 62 SEQ. ID 0183 UGAAAGCUUACAUCAACAA
DB 63 SEQ. ID 0184 GAAAGCUUACAUCAACAAA
DB 64 SEQ. ID 0185 AAAGCUUACAUCAACAAAG
DB 65 SEQ. ID 0186 AAGCUUACAUCAACAAAGU
DB 66 SEQ. ID 0187 AGCUUACAUCAACAAAGUA
DB 67 SEQ. ID 0188 GCUUACAUCAACAAAGUAG
DB 68 SEQ. ID 0189 CUUACAUCAACAAAGUAGA
DB 69 SEQ. ID 0190 UUACAUCAACAAAGUAGAA
DB 70 SEQ. ID 0191 UACAUCAACAAAGUAGAAG
DB 71 SEQ. ID 0192 ACAUCAACAAAGUAGAAGA
DB 72 SEQ. ID 0193 CAUCAACAAAGUAGAAGAG
DB 73 SEQ. ID 0194 AUCAACAAAGUAGAAGAGC
DB 74 SEQ. ID 0195 UCAACAAAGUAGAAGAGCU
DB 75 SEQ. ID 0196 CAACAAAGUAGAAGAGCUA
DB 76 SEQ. ID 0197 AACAAAGUAGAAGAGCUAA
DB 77 SEQ. ID 0198 ACAAAGUAGAAGAGCUAAA
DB 78 SEQ. ID 0199 CAAAGUAGAAGAGCUAAAG
DB 79 SEQ. ID 0200 AAAGUAGAAGAGCUAAAGA
DB 80 SEQ. ID 0201 AAGUAGAAGAGCUAAAGAA
DB 81 SEQ. ID 0202 AGUAGAAGAGCUAAAGAAA
DB 82 SEQ. ID 0203 GUAGAAGAGCUAAAGAAAA
DB 83 SEQ. ID 0204 UAGAAGAGCUAAAGAAAAA
DB 84 SEQ. ID 0205 AGAAGAGCUAAAGAAAAAA
DB 85 SEQ. ID 0206 GAAGAGCUAAAGAAAAAAU
DB 86 SEQ. ID 0207 AAGAGCUAAAGAAAAAAUA
DB 87 SEQ. ID 0208 AGAGCUAAAGAAAAAAUAC
DB 88 SEQ. ID 0209 GAGCUAAAGAAAAAAUACG
DB 89 SEQ. ID 0210 AGCUAAAGAAAAAAUACGG
DB 90 SEQ. ID 0211 GCUAAAGAAAAAAUACGGG
Luc 1 SEQ. ID 0212 AUCCUCAUAAAGGCCAAGA
Luc 2 SEQ. ID 0213 AGAUCCUCAUAAAGGCCAA
Luc 3 SEQ. ID 0214 AGAGAUCCUCAUAAAGGCC
Luc 4 SEQ. ID 0215 AGAGAGAUCCUCAUAAAGG
Luc 5 SEQ. ID 0216 UCAGAGAGAUCCUCAUAAA
Luc 6 SEQ. ID 0217 AAUCAGAGAGAUCCUCAUA
Luc 7 SEQ. ID 0218 AAAAUCAGAGAGAUCCUCA
Luc 8 SEQ. ID 0219 GAAAAAUCAGAGAGAUCCU
Luc 9 SEQ. ID 0220 AAGAAAAAUCAGAGAGAUC
Luc 10 SEQ. ID 0221 GCAAGAAAAAUCAGAGAGA
Luc 11 SEQ. ID 0222 ACGCAAGAAAAAUCAGAGA
Luc 12 SEQ. ID 0223 CGACGCAAGAAAAAUCAGA
Luc 13 SEQ. ID 0224 CUCGACGCAAGAAAAAUCA
Luc 14 SEQ. ID 0225 AACUCGACGCAAGAAAAAU
Luc 15 SEQ. ID 0226 AAAACUCGACGCAAGAAAA
Luc 16 SEQ. ID 0227 GGAAAACUCGACGCAAGAA
Luc 17 SEQ. ID 0228 CCGGAAAACUCGACGCAAG
Luc 18 SEQ. ID 0229 UACCGGAAAACUCGACGCA
Luc 19 SEQ. ID 0230 CUUACCGGAAAACUCGACG
Luc 20 SEQ. ID 0231 GUCUUACCGGAAAACUCGA
Luc 21 SEQ. ID 0232 AGGUCUUACCGGAAAACUC
Luc 22 SEQ. ID 0233 AAAGGUCUUACCGGAAAAC
Luc 23 SEQ. ID 0234 CGAAAGGUCUUACCGGAAA
Luc 24 SEQ. ID 0235 ACCGAAAGGUCUUACCGGA
Luc 25 SEQ. ID 0236 GUACCGAAAGGUCUUACCG
Luc 26 SEQ. ID 0237 AAGUACCGAAAGGUCUUAC
Luc 27 SEQ. ID 0238 CGAAGUACCGAAAGGUCUU
Luc 28 SEQ. ID 0239 GACGAAGUACCGAAAGGUC
Luc 29 SEQ. ID 0240 UGGACGAAGUACCGAAAGG
Luc 30 SEQ. ID 0241 UGUGGACGAAGUACCGAAA
Luc 31 SEQ. ID 0242 UUUGUGGACGAAGUACCGA
Luc 32 SEQ. ID 0243 UGUUUGUGGACGAAGUACC
Luc 33 SEQ. ID 0244 UGUGUUUGUGGACGAAGUA
Luc 34 SEQ. ID 0245 GUUGUGUUUGUGGACGAAG
Luc 35 SEQ. ID 0246 GAGUUGUGUUUGUGGACGA
Luc 36 SEQ. ID 0247 AGGAGUUGUGUUUGUGGAC
Luc 37 SEQ. ID 0248 GGAGGAGUUGUGUUUGUGG
Luc 38 SEQ. ID 0249 GCGGAGGAGUUGUGUUUGU
Luc 39 SEQ. ID 0250 GCGCGGAGGAGUUGUGUUU
Luc 40 SEQ. ID 0251 UUGCGCGGAGGAGUUGUGU
Luc 41 SEQ. ID 0252 AGUUGCGCGGAGGAGUUGU
Luc 42 SEQ. ID 0253 AAAGUUGCGCGGAGGAGUU
Luc 43 SEQ. ID 0254 AAAAAGUUGCGCGGAGGAG
Luc 44 SEQ. ID 0255 CGAAAAAGUUGCGCGGAGG
Luc 45 SEQ. ID 0256 CGCGAAAAAGUUGCGCGGA
Luc 46 SEQ. ID 0257 ACCGCGAAAAAGUUGCGCG
Luc 47 SEQ. ID 0258 CAACCGCGAAAAAGUUGCG
Luc 48 SEQ. ID 0259 AACAACCGCGAAAAAGUUG
Luc 49 SEQ. ID 0260 GUAACAACCGCGAAAAAGU
Luc 50 SEQ. ID 0261 AAGUAACAACCGCGAAAAA
Luc 51 SEQ. ID 0262 UCAAGUAACAACCGCGAAA
Luc 52 SEQ. ID 0263 AGUCAAGUAACAACCGCGA
Luc 53 SEQ. ID 0264 CCAGUCAAGUAACAACCGC
Luc 54 SEQ. ID 0265 CGCCAGUCAAGUAACAACC
Luc 55 SEQ. ID 0266 GUCGCCAGUCAAGUAACAA
Luc 56 SEQ. ID 0267 ACGUCGCCAGUCAAGUAAC
Luc 57 SEQ. ID 0268 UUACGUCGCCAGUCAAGUA
Luc 58 SEQ. ID 0269 GAUUACGUCGCCAGUCAAG
Luc 59 SEQ. ID 0270 UGGAUUACGUCGCCAGUCA
Luc 60 SEQ. ID 0271 CGUGGAUUACGUCGCCAGU
Luc 61 SEQ. ID 0272 AUCGUGGAUUACGUCGCCA
Luc 62 SEQ. ID 0273 AGAUCGUGGAUUACGUCGC
Luc 63 SEQ. ID 0274 AGAGAUCGUGGAUUACGUC
Luc 64 SEQ. ID 0275 AAAGAGAUCGUGGAUUACG
Luc 65 SEQ. ID 0276 AAAAAGAGAUCGUGGAUUA
Luc 66 SEQ. ID 0277 GGAAAAAGAGAUCGUGGAU
Luc 67 SEQ. ID 0278 ACGGAAAAAGAGAUCGUGG
Luc 68 SEQ. ID 0279 UGACGGAAAAAGAGAUCGU
Luc 69 SEQ. ID 0280 GAUGACGGAAAAAGAGAUC
Luc 70 SEQ. ID 0281 ACGAUGACGGAAAAAGAGA
Luc 71 SEQ. ID 0282 AGACGAUGACGGAAAAAGA
Luc 72 SEQ. ID 0283 AAAGACGAUGACGGAAAAA
Luc 73 SEQ. ID 0284 GGAAAGACGAUGACGGAAA
Luc 74 SEQ. ID 0285 ACGGAAAGACGAUGACGGA
Luc 75 SEQ. ID 0286 GCACGGAAAGACGAUGACG
Luc 76 SEQ. ID 0287 GAGCACGGAAAGACGAUGA
Luc 77 SEQ. ID 0288 UGGAGCACGGAAAGACGAU
Luc 78 SEQ. ID 0289 UUUGGAGCACGGAAAGACG
Luc 79 SEQ. ID 0290 GUUUUGGAGCACGGAAAGA
Luc 80 SEQ. ID 0291 UUGUUUUGGAGCACGGAAA
Luc 81 SEQ. ID 0292 UGUUGUUUUGGAGCACGGA
Luc 82 SEQ. ID 0293 GUUGUUGUUUUGGAGCACG
Luc 83 SEQ. ID 0294 CCGUUGUUGUUUUGGAGCA
Luc 84 SEQ. ID 0295 CGCCGUUGUUGUUUUGGAG
Luc 85 SEQ. ID 0296 GCCGCCGUUGUUGUUUUGG
Luc 86 SEQ. ID 0297 CCGCCGCCGUUGUUGUUUU
Luc 87 SEQ. ID 0298 UCCCGCCGCCGUUGUUGUU
Luc 88 SEQ. ID 0299 CUUCCCGCCGCCGUUGUUG
Luc 89 SEQ. ID 0300 AACUUCCCGCCGCCGUUGU
Luc 90 SEQ. ID 0301 UGAACUUCCCGCCGCCGUU
Example II Validation of the Algorithm Using DBI, Luciferase, PLK, EGFR, and SEAP The algorithm (Formula VIII) identified siRNAs for five genes, human DBI, firefly luciferase (fLuc), renilla luciferase (rLuc), human PLK, and human secreted alkaline phosphatase (SEAP). Four individual siRNAs were selected on the basis of their SMARTSCORES™ derived by analysis of their sequence using Formula VIII (all of the siRNAs would be selected with Formula IX as well) and analyzed for their ability to silence their targets' expression. In addition to the scoring, a BLAST search was conducted for each siRNA. To minimize the potential for off-target silencing effects, only those target sequences with more than three mismatches against un-related sequences were selected. Semizarov, et al. (2003)
Specificity of short interfering RNA determined through gene expression signatures, Proc. Natl. Acad. Sci. USA, 100:6347. These duplexes were analyzed individually and in pools of 4 and compared with several siRNAs that were randomly selected. The functionality was measured as a percentage of targeted gene knockdown as compared to controls. All siRNAs were transfected as described by the methods above at 100 nM concentration into HEK293 using Lipofectamine 2000. The level of the targeted gene expression was evaluated by B-DNA as described above and normalized to the non-specific control. FIG. 10 shows that the siRNAs selected by the algorithm disclosed herein were significantly more potent than randomly selected siRNAs. The algorithm increased the chances of identifying an F50 siRNA from 48% to 91%, and an F80 siRNA from 13% to 57%. In addition, pools of SMART siRNA silence the selected target better than randomly selected pools (see FIG. 10F).
Example III Validation of the Algorithm Using Genes Involved in Clathrin-Dependent Endocytosis Components of clathrin-mediated endocytosis pathway are key to modulating intracellular signaling and play important roles in disease. Chromosomal rearrangements that result in fusion transcripts between the Mixed-Lineage Leukemia gene (MLL) and CALM (clathrin assembly lymphoid myeloid leukemia gene) are believed to play a role in leukemogenesis. Similarly, disruptions in Rab7 and Rab9, as well as HIP1 (Huntingtin-interacting protein), genes that are believed to be involved in endocytosis, are potentially responsible for ailments resulting in lipid storage, and neuronal diseases, respectively. For these reasons, siRNA directed against clathrin and other genes involved in the clathrin-mediated endocytotic pathway are potentially important research and therapeutic tools.
siRNAs directed against genes involved in the clathrin-mediated endocytosis pathways were selected using Formula VIII. The targeted genes were clathrin heavy chain (CHC, accession # NM 004859), clathrin light chain A (CLCa, NM—001833), clathrin light chain B (CLCb, NM—001834), CALM (U45976), β2 subunit of AP-2 (β2, NM—001282), Eps15 (NM—001981), Eps15R(NM—021235), dynamin II (DYNII, NM—004945), Rab5a (BC001267), Rab5b (NM-002868), Rab5c (AF141304), and EEA.1 (XM—018197).
For each gene, four siRNAs duplexes with the highest scores were selected and a BLAST search was conducted for each of them using the Human EST database. In order to minimize the potential for off-target silencing effects, only those sequences with more than three mismatches against un-related sequences were used. All duplexes were synthesized at Dharmacon, Inc. as 21-mers with 3′-UU overhangs using a modified method of 2′-ACE chemistry, Scaringe (2000) Advanced 5′-silyl-2′-orthoester approach to RNA oligonucleotide synthesis, Methods Enzymol. 317:3, and the antisense strand was chemically phosphorylated to insure maximized activity.
HeLa cells were grown in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal bovine serum, antibiotics and glutamine. siRNA duplexes were resuspended in 1× siRNA Universal buffer (Dharmacon, Inc.) to 20CM prior to transfection. HeLa cells in 12-well plates were transfected twice with 4 μl of 20 μM siRNA duplex in 3 μl Lipofectamine 2000 reagent (Invitrogen, Carlsbad, Calif., USA) at 24-hour intervals. For the transfections in which 2 or 3 siRNA duplexes were included, the amount of each duplex was decreased, so that the total amount was the same as in transfections with single siRNAs. Cells were plated into normal culture medium 12 hours prior to experiments, and protein levels were measured 2 or 4 days after the first transfection.
Equal amounts of lysates were resolved by electrophoresis, blotted, and stained with the antibody specific to targeted protein, as well as antibodies specific to unrelated proteins, PP1 phosphatase and Tsg101 (not shown). The cells were lysed in Triton X-100/glycerol solubilization buffer as described previously. Tebar, Bohlander, & Sorkin (1999) Clathrin Assembly Lymphoid Myeloid Leukemia (CALM) Protein: Localization in Endocytic-coated Pits, Interactions with Clathrin, and the Impact of Overexpression on Clathrin-mediated Traffic, Mol. Biol. Cell, 10:2687. Cell lysates were electrophoresed, transferred to nitrocellulose membranes, and Western blotting was performed with several antibodies followed by detection using enhanced chemiluminescence system (Pierce, Inc). Several x-ray films were analyzed to determine the linear range of the chemiluminescence signals, and the quantifications were performed using densitometry and AlphaImager v5.5 software (Alpha Innotech Corporation). In experiments with Eps15R-targeted siRNAs, cell lysates were subjected to immunoprecipitation with Ab860, and Eps15R was detected in immunoprecipitates by Western blotting as described above.
The antibodies to assess the levels of each protein by Western blot were obtained from the following sources: monoclonal antibody to clathrin heavy chain (TD. 1) was obtained from American Type Culture Collection (Rockville, Md., USA); polyclonal antibody to dynamin II was obtained from Affinity Bioreagents, Inc. (Golden, Colo., USA); monoclonal antibodies to EEA. 1 and Rab5a were purchased from BD Transduction Laboratories (Los Angeles, Calif., USA); the monoclonal antibody to Tsg101 was purchased from Santa Cruz Biotechnology, Inc. (Santa Cruz, Calif., USA); the monoclonal antibody to GFP was from ZYMED Laboratories Inc. (South San Francisco, Calif., USA); the rabbit polyclonal antibodies Ab32 specific to α-adaptins and Ab20 to CALM were described previously (Sorkin et al. (1995) Stoichiometric Interaction of the Epidermal Growth Factor Receptor with the Clathrin-associated Protein Complex AP-2, J. Biol. Chem., 270:619), the polyclonal antibodies to clathrin light chains A and B were kindly provided by Dr. F. Brodsky (UCSF); monoclonal antibodies to PP1 (BD Transduction Laboratories) and α-Actinin (Chemicon) were kindly provided by Dr. M. Dell'Acqua (University of Colorado); Eps15 Ab577 and Eps15R Ab860 were kindly provided by Dr. P. P. Di Fiore (European Cancer Institute).
FIG. 11 demonstrates the in vivo functionality of 48 individual siRNAs, selected using Formula VIII (most of them will meet the criteria incorporated by Formula IX as well) targeting 12 genes. Various cell lines were transfected with siRNA duplexes (Dup1-4) or pools of siRNA duplexes (Pool), and the cells were lysed 3 days after transfection with the exception of CALM (2 days) and β2 (4 days).
Note a β1-adaptin band (part of AP-1 Golgi adaptor complex) that runs slightly slower than β2 adaptin. CALM has two splice variants, 66 and 72 kD. The full-length Eps15R (a doublet of ˜130 kD) and several truncated spliced forms of ˜100 kD and ˜70 kD were detected in Eps15R immunoprecipitates (shown by arrows). The cells were lysed 3 days after transfection. Equal amounts of lysates were resolved by electrophoresis and blotted with the antibody specific to a targeted protein (GFP antibody for YFP fusion proteins) and the antibody specific to unrelated proteins PP1 phosphatase or α-actinin, and TSG1101. The amount of protein in each specific band was normalized to the amount of non-specific proteins in each lane of the gel. Nearly all of them appear to be functional, which establishes that Formula VIII and IX can be used to predict siRNAs' functionality in general in a genome wide manner.
To generate the fusion of yellow fluorescent protein (YFP) with Rab5b or Rab5c (YFP-Rab5b or YFP-Rab5c), a DNA fragment encoding the full-length human Rab5b or Rab5c was obtained by PCR using Pfu polymerase (Stratagene) with a SacI restriction site introduced into the 5′ end and a KpnI site into the 3′ end and cloned into pEYFP-C1 vector (CLONTECH, Palo Alto, Calif., USA). GFP-CALM and YFP-Rab5a were described previously (Tebar, Bohlander, & Sorkin (1999) Clathrin Assembly Lymphoid Myeloid Leukemia (CALM) Protein: Localization in Endocytic-coated Pits, Interactions with Clathrin, and the Impact of Overexpression on Clathrin-mediated Traffic, Mol. Biol. Cell 10:2687).
Example IV Validation of the Algorithm Using Eg5, GADPH, ATE1, MEK2, MEK1, QB, LaminA/C, C-myc, Human Cyclophilin, and Mouse Cyclophilin A number of genes have been identified as playing potentially important roles in disease etiology. Expression profiles of normal and diseased kidneys has implicated Edg5 in immunoglobulin A neuropathy, a common renal glomerular disease. Myc1, MEK1/2 and other related kinases have been associated with one or more cancers, while lamins have been implicated in muscular dystrophy and other diseases. For these reasons, siRNA directed against the genes encoding these classes of molecules would be important research and therapeutic tools.
FIG. 12 illustrates four siRNAs targeting 10 different genes (Table V for sequence and accession number information) that were selected according to the Formula VIII and assayed as individuals and pools in HEK293 cells. The level of siRNA induced silencing was measured using the B-DNA assay. These studies demonstrated that thirty-six out of the forty individual SMART-selected siRNA tested are functional (90%) and all 10 pools are fully functional.
Example V Validation of the Algorithm Using Bcl2 Bcl-2 is a ˜25 kD, 205-239 amino acid, anti-apoptotic protein that contains considerable homology with other members of the BCL family including BCLX, MCL1, BAX, BAD, and BIK. The protein exists in at least two forms (Bcl2a, which has a hydrophobic tail for membrane anchorage, and Bcl2b, which lacks the hydrophobic tail) and is predominantly localized to the mitochondrial membrane. While Bcl2 expression is widely distributed, particular interest has focused on the expression of this molecule in B and T cells. Bcl2 expression is down-regulated in normal germinal center B cells yet in a high percentage of follicular lymphomas, Bcl2 expression has been observed to be elevated. Cytological studies have identified a common translocation ((14; 18)(q32; q32)) amongst a high percentage (>70%) of these lymphomas. This genetic lesion places the Bcl2 gene in juxtaposition to immunoglobulin heavy chain gene (IgH) encoding sequences and is believed to enforce inappropriate levels of gene expression, and resistance to programmed cell death in the follicle center B cells. In other cases, hypomethylation of the Bcl2 promoter leads to enhanced expression and again, inhibition of apoptosis. In addition to cancer, dysregulated expression of Bcl-2 has been correlated with multiple sclerosis and various neurological diseases.
The correlation between Bcl-2 translocation and cancer makes this gene an attractive target for RNAi. Identification of siRNA directed against the bcl2 transcript (or Bcl2-IgH fusions) would further our understanding Bcl2 gene function and possibly provide a future therapeutic agent to battle diseases that result from altered expression or function of this gene.
In Silico Identification of Functional siRNA
To identify functional and hyperfunctional siRNA against the Bcl2 gene, the sequence for Bcl-2 was downloaded from the NCBI Unigene database and analyzed using the Formula VIII algorithm. As a result of these procedures, both the sequence and SMARTSCORES™, or siRNA rankings of the Bcl2 siRNA were obtained and ranked according to their functionality. Subsequently, these sequences were BLAST'ed (database) to insure that the selected sequences were specific and contained minimal overlap with unrealated genes. The SMARTSCORES™, or siRNA rankings for the top 10 Bcl-2 siRNA are identified in FIG. 13.
In Vivo Testing of Bcl-2 SiRNA
Bcl-2 siRNAs having the top ten SMARTSCORES™, or siRNA rankings were selected and tested in a functional assay to determine silencing efficiency. To accomplish this, each of the ten duplexes were synthesized using 2′-O-ACE chemistry and transfected at 100 nM concentrations into cells. Twenty-four hours later assays were performed on cell extracts to assess the degree of target silencing. Controls used in these experiments included mock transfected cells, and cells that were transfected with a non-specific siRNA duplex.
The results of these experiments are presented below (and in FIG. 14) and show that all ten of the selected siRNA induce 80% or better silencing of the Bcl2 message at 100 nM concentrations. These data verify that the algorithm successfully identified functional Bcl2 siRNA and provide a set of functional agents that can be used in experimental and therapeutic environments.
siRNA 1 GGGAGAUAGUGAUGAAGUA SEQ. ID NO. 302
siRNA 2 GAAGUACAUCCAUUAUAAG SEQ. ID NO. 303
siRNA 3 GUACGACAACCGGGAGAUA SEQ. ID NO. 304
siRNA 4 AGAUAGUGAUGAAGUACAU SEQ. ID NO. 305
siRNA 5 UGAAGACUCUGCUCAGUUU SEQ. ID NO. 306
sIRNA 6 GCAUGCGGCCUCUGUUUGA SEQ. ID NO. 307
siRNA 7 UGCGGCCUCUGUUUGAUUU SEQ. ID NO. 308
siRNA 8 GAGAUAGUGAUGAAGUACA SEQ. ID NO. 309
siRNA 9 GGAGAUAGUGAUGAAGUAC SEQ. ID NO. 310
siRNA 10 GAAGACUCUGCUCAGUUUG SEQ. ID NO. 311
Bcl2 siRNA: Sense Strand, 5′→3′
Example VI Sequences Selected by the Algorithm Sequences of the siRNAs selected using Formulas (Algorithms) VIII and IX with their corresponding ranking, which have been evaluated for the silencing activity in vivo in the present study (Formula VIII and IX, respectively) are shown in Table V. It should be noted that the “t” residues in Table V, and elsewhere, when referring to siRNA, should be replaced by “u” residues. TABLE V
SEQ.
ID FORMULA FORMULA
GENE Name NO. FTLLSEQTENCE VIII IX
CLTC NM_004859 0312 GAAAGAATCTGTAGAGAAA 76 94.2
CLTC NM_004859 0313 GCAATGAGCTGTTTGAAGA 65 39.9
CLTC NM_004859 0314 TGACAAAGGTGGATAAATT 57 38.2
CLTC NM_004859 0315 GGAAATGGATCTCTTTGAA 54 49.4
CLTA NM_001833 0316 GGAAAGTAATGGTCCAACA 22 55.5
CLTA NM_001833 0317 AGACAGTTATGCAGCTATT 4 22.9
CLTA NM_001833 0318 CCAATTCTCGGAAGCAAGA 1 17
CLTA NM_001833 0319 GAAAGTAATGGTCCAACAG −1 −13
CLTB NM_001834 0320 GCGCCAGAGTGAACAAGTA 17 57.5
CLTB NM_001834 0321 GAAGGTGGCCCAGCTATGT 15 −8.6
CLTB NM_001834 0322 GGAACCAGCGCCAGAGTGA 13 40.5
CLTB NM_001834 0323 GAGCGAGATTGCAGGCATA 20 61.7
CALM U45976 0324 GTTAGTATCTGATGACTTG 36 −34.6
CALM U45976 0325 GAAATGGAACCACTAAGAA 33 46.1
CALM U45976 0326 GGAAATGGAACCACTAAGA 30 61.2
CALM U45976 0327 CAACTACACTTTCCAATGC 28 6.8
EPS15 NM_001981 0328 CCACCAAGATTTCATGATA 48 25.2
EPS15 NM_001981 0329 GATCGGAACTCCAACAAGA 43 49.3
EPS15 NM_001981 0330 AAACGGAGCTACAGATTAT 39 11.5
EPS15 NM_001981 0331 CCACACAGCATTCTTGTAA 33 −23.6
EPS15R NM_021235 0332 GAAGTTACCTTGAGCAATC 48 33
EPS15R NM_021235 0333 GGACTTGGCCGATCCAGAA 27 33
EPS15R NM_021235 0334 GCACTTGGATCGAGATGAG 20 1.3
EPS15R NM_021235 0335 CAAAGACCAATTCGCGTTA 17 27.7
DNM2 NM_004945 0336 CCGAATCAATCGCATCTTC 6 −29.6
DNM2 NM_004945 0337 GACATGATCCTGCAGTTCA 5 −14
DNM2 NM_004945 0338 GAGCGAATCGTCACCACTT 5 24
DNM2 NM_004945 0339 CCTCCGAGCTGGCGTCTAC −4 −63.6
ARF6 AF93885 0340 TCACATGGTTAACCTCTAA 27 −21.1
ARF6 AF93885 0341 GATGAGGGACGCCATAATC 7 −38.4
ARF6 AF93885 0342 CCTCTAACTACAAATCTTA 4 16.9
ARF6 AF93885 0343 GGAAGGTGCTATCCAAAAT 4 11.5
RAB5A BC001267 0344 GCAAGCAAGTCCTAACATT 40 25.1
RAB5A BC001267 0345 GGAAGAGGAGTAGACCTTA 17 50.1
RAB5A BC001267 0346 AGGAATCAGTGTTGTAGTA 16 11.5
RAB5A BC001267 0347 GAAGAGGAGTAGACCTTAC 12 7
RAB5B NM_002868 0348 GAAAGTCAAGCCTGGTATT 14 18.1
RAB5B NM_002868 0349 AAAGTCAAGCCTGGTATTA 6 −17.8
RAB5B NM_002868 0350 GCTATGAACGTGAATGATC 3 −21.1
RAB5B NM_002868 0351 CAAGCCTGGTATTACGTTT −7 −37.5
RAB5C AF141304 0352 GGAACAAGATCTGTCAATT 38 51.9
RAB5C AF141304 0353 GCAATGAACGTGAACGAAA 29 43.7
RAB5C AF141304 0354 CAATGAACGTGAACGAAAT 18 43.3
RAB5C AF141304 0355 GGACAGGAGCGGTATCACA 6 18.2
EEA1 XM_018197 0356 AGACAGAGCTTGAGAATAA 67 64.1
EEA1 XM_018197 0357 GAGAAGATCTTTATGCAAA 60 48.7
EEA1 XM_018197 0358 GAAGAGAAATCAGCAGATA 58 45.7
EEA1 XM_018197 0359 GCAAGTAACTCAACTAACA 56 72.3
AP2B1 NM_001282 0360 GAGCTAATCTGCCACATTG 49 −12.4
AP2B1 NM_001282 0361 GCAGATGAGTTACTAGAAA 44 48.9
AP2B1 NM_001282 0362 CAACTTAATTGTCCAGAAA 41 28.2
AP2B1 NM_001282 0363 CAACACAGGATTCTGATAA 33 −5.8
PLK NM_005030 0364 AGATTGTGCCTAAGTCTCT −35 −3.4
PLK NM_005030 0365 ATGAAGATCTGGAGGTGAA 0 −4.3
PLK NM_005030 0366 TTTGAGACTTCTTGCCTAA −5 −27.7
PLK NM_005030 0367 AGATCACCCTCCTTAAATA 15 72.3
GAPDH NM_002046 0368 CAACGGATTTGGTCGTATT 27 −2.8
GAPDH NM_002046 0369 GAAATCCCATCACCATCTT 24 3.9
GAPDH NM_002046 0370 GACCTCAACTACATGGTTT 22 −22.9
GAPDH NM_002046 0371 TGGTTTACATGTTCCAATA 9 9.8
c-Myc 0372 GAAGAAATCGATGTTGTTT 31 −11.7
c-Myc 0373 ACACAAACTTGAACAGCTA 22 51.3
c-Myc 0374 GGAAGAAATCGATGTTGTT 18 26
c-Myc 0375 GAAACGACGAGAACAGTTG 18 −8.9
MAP2K1 NM_002755 0376 GCACATGGATGGAGGTTCT 26 16
MAP2K1 NM_002755 0377 GCAGAGAGAGCAGATTTGA 16 0.4
MAP2K1 NM_002755 0378 GAGGTTCTCTGGATCAAGT 14 15.5
MAP2K1 NM_002755 0379 GAGCAGATTTGAAGCAACT 14 18.5
MAP2K2 NM_030662 0380 CAAAGACGATGACTTCGAA 37 26.4
MAP2K2 NM_030662 0381 GATCAGCATTTGCATGGAA 24 −0.7
MAP2K2 NM_030662 0382 TCCAGGAGTTTGTCAATAA 17 −4.5
MAP2K2 NM_030662 0383 GGAAGCTGATCCACCTTGA 16 59.2
KNSL1(EG5) NM_004523 0384 GCAGAAATCTAAGGATATA 53 35.8
KNSL1(EG5) NM_004523 0385 CAACAAGGATGAAGTCTAT 50 18.3
KNSL1(EG5) NM_004523 0386 CAGCAGAAATCTAAGGATA 41 32.7
KNSL1(EG5) NM_004523 0387 CTAGATGGCTTTCTCAGTA 39 3.9
CyclophilinA NM_021130 0388 AGACAAGGTCCCAAAGACA −16 58.1
CyclophilinA NM_021130 0389 GGAATGGCAAGACCAGCAA −6 36
CyclophilinA NM_021130 0390 AGAATTATTCCAGGGTTTA −3 16.1
CyclophilinA NM_021130 0391 GCAGACAAGGTCCCAAAGA 8 8.9
LAMIN A/C NM_170707 0392 AGAAGCAGCTTCAGGATGA 31 38.8
LAMIN A/C NM_170707 0393 GAGCTTGACTTCCAGAAGA 33 22.4
LAMIN A/C NM_170707 0394 CCACCGAAGTTCACCCTAA 21 27.5
LAMIN A/C NM_170707 0395 GAGAAGAGCTCCTCCATCA 55 30.1
CyclophilinB M60857 0396 GAAAGAGCATCTACGGTGA 41 83.9
CyclophilinB M60857 0397 GAAAGGATTTGGCTACAAA 53 59.1
CyclophilinB M60857 0398 ACAGCAAATTCCATCGTGT −20 28.8
CyclophilinB M60857 0399 GGAAAGACTGTTCCAAAAA 2 27
DBI1 NM_020548 0400 CAACACGCCTCATCCTCTA 27 −7.6
DBI2 NM_020548 0401 CATGAAAGCTTACATCAAC 25 −30.8
DBI3 NM_020548 0402 AAGATGCCATGAAAGCTTA 17 22
DBI4 NM_020548 0403 GCACATACCGCCTGAGTCT 15 3.9
rLUC1 0404 GATCAAATCTGAAGAAGGA 57 49.2
rLUC2 0405 GCCAAGAAGTTTCCTAATA 50 13.7
rLUC3 0406 CAGCATATCTTGAACCATT 41 −2.2
rLUC4 0407 GAACAAAGGAAACGGATGA 39 29.2
SeAP1 NM_031313 0408 CGGAAACGGTCCAGGCTAT 6 26.9
SeAP2 NM_031313 0409 GCTTCGAGCAGACATGATA 4 −11.2
SeAP3 NM_031313 0410 CCTACACGGTCCTCCTATA 4 4.9
SeAP4 NM_031313 0411 GCCAAGAACCTCATCATCT 1 −9.9
fLUC1 0412 GATATGGGCTGAATACAAA 54 40.4
fLUC2 0413 GCACTCTGATTGACAAATA 47 54.7
fLUC3 0414 TGAAGTCTCTGATTAAGTA 46 34.5
fLUC4 0415 TCAGAGAGATCCTCATAAA 40 11.4
mCyclo_1 NM_008907 0416 GCAAGAAGATCACCATTTC 52 46.4
mCyclo_2 NM_008907 0417 GAGAGAAATTTGAGGATGA 36 70.7
mCyclo_3 NM_008907 0418 GAAAGGATTTGGCTATAAG 35 −1.5
mCyclo_4 NM_008907 0419 GAAAGAAGGCATGAACATT 27 10.3
BCL2_1 NM_000633 0420 GGGAGATAGTGATGAAGTA 21 72
BCL2_2 NM_000633 0421 GAAGTACATCCATTATAAG 1 3.3
BCL2_3 NM_000633 0422 GTACGACAACCGGGAGATA 1 35.9
BCL2_4 NM_000633 0423 AGATAGTGATGAAGTACAT −12 22.1
BCL2_5 NM_000633 0424 TGAAGACTCTGCTCAGTTT 36 19.1
BCL2_6 NM_000633 0425 GCATGCGGCCTCTGTTTGA 5 −9.7
QB1 NM_003365.1 0426 GCACACAGCUUACUACAUC 52 −4.8
QB2 NM_003365.1 0427 GAAAUGCCCUGGUAUCUCA 49 22.1
QB3 NM_003365.1 0428 GAAGGAACGUGAUGUGAUC 34 22.9
QB4 NM_003365.1 0429 GCACUACUCCUGUGUGUGA 28 20.4
ATE1-1 NM_007041 0430 GAACCCAGCUGGAGAACUU 45 15.5
ATE1-2 NM_007041 0431 GAUAUACAGUGUGAUCUUA 40 12.2
ATE1-3 NM_007041 0432 GUACUACGAUCCUGAUUAU 37 32.9
ATE1-4 NM_007041 0433 GUGCCGACCUUUACAAUUU 35 18.2
EGFR-1 NM_005228 0434 GAAGGAAACTGAATTCAAA 68 79.4
EGFR-1 NM_005228 0435 GGAAATATGTACTACGAAA 49 49.5
EGFR-1 NM_005228 0436 CCACAAAGCAGTGAATTTA 41 7.6
EGFR-1 NM_005228 0437 GTAACAAGCTCACGCAGTT 40 25.9
Many of the genes to which the described siRNA are directed play critical roles in disease etiology. For this reason, the siRNAs listed in the sequence listing may potentially act as therapeutic agents. A number of prophetic examples follow and should be understood in view of the siRNA that are identified in the sequence listing. To isolate these siRNAs, the appropriate message sequence for each gene is analyzed using one of the before mentioned formulas (preferably formula VIII) to identify potential siRNA targets. Subsequently these targets are BLAST'ed to eliminate homology with potential off-targets.
Example VII Evidence for the Benefits of Pooling Evidence for the benefits of pooling have been demonstrated using the reporter gene, luciferase. Ninety siRNA duplexes were synthesized using Dharmacon proprietary ACE® chemistry against one of the standard reporter genes: firefly luciferase. The duplexes were designed to start two base pairs apart and to cover approximately 180 base pairs of the luciferase gene (see sequences in Table III). Subsequently, the siRNA duplexes were co-transfected with a luciferase expression reporter plasmid into HEK293 cells using standard transfection protocols and luciferase activity was assayed at 24 and 48 hours.
Transfection of individual siRNAs showed standard distribution of inhibitory effect. Some duplexes were active, while others were not. FIG. 15 represents a typical screen of ninety siRNA duplexes (SEQ. ID NO. 0032-0120) positioned two base pairs apart. As the figure suggests, the functionality of the siRNA duplex is determined more by a particular sequence of the oligonucleotide than by the relative oligonucleotide position within a gene or excessively sensitive part of the mRNA, which is important for traditional anti-sense technology.
When two continuous oligonucleotides were pooled together, a significant increase in gene silencing activity was observed (see FIGS. 16A and B). A gradual increase in efficacy and the frequency of pools functionality was observed when the number of siRNAs increased to 3 and 4 (FIGS. 16A, 16B, 17A, and 17B). Further, the relative positioning of the oligonucleotides within a pool did not determine whether a particular pool was functional (see FIGS. 18A and 18B, in which 100% of pools of oligonucleotides distanced by 2, 10 and 20 base pairs were functional).
However, relative positioning may nonetheless have an impact. An increased functionality may exist when the siRNA are positioned continuously head to toe (5′ end of one directly adjacent to the 3′ end of the others).
Additionally, siRNA pools that were tested performed at least as well as the best oligonucleotide in the pool, under the experimental conditions whose results are depicted in FIG. 19. Moreover, when previously identified non-functional and marginally (semi) functional siRNA duplexes were pooled together in groups of five at a time, a significant functional cooperative action was observed (see FIG. 20). In fact, pools of semi-active oligonucleotides were 5 to 25 times more functional than the most potent oligonucleotide in the pool. Therefore, pooling several siRNA duplexes together does not interfere with the functionality of the most potent siRNAs within a pool, and pooling provides an unexpected significant increase in overall functionality
Example VIII Additional Evidence of the Benefits of Pooling Experiments were performed on the following genes: P-galactosidase, Renilla luciferase, and Secreted alkaline phosphatase, which demonstrates the benefits of pooling. (see FIGS. 21A, 21B and 21C). Individual and pools of siRNA (described in Figure legends 21A-C) were transfected into cells and tested for silencing efficiency. Approximately 50% of individual siRNAs designed to silence the above-specified genes were functional, while 100% of the pools that contain the same siRNA duplexes were functional.
Example IX Highly Functional siRNA Pools of five siRNAs in which each two siRNAs overlap to 10-90% resulted in 98% functional entities (>80% silencing). Pools of siRNAs distributed throughout the mRNA that were evenly spaced, covering an approximate 20-2000 base pair range, were also functional. When the pools of siRNA were positioned continuously head to tail relative to mRNA sequences and mimicked the natural products of Dicer cleaved long double stranded RNA, 98% of the pools evidenced highly functional activity (>95% silencing).
Example X Human Cyclophilin B Table III above lists the siRNA sequences for the human cyclophilin B protein. A particularly functional siRNA may be selected by applying these sequences to any of Formula I to VII above.
Alternatively, one could pool 2, 3, 4, 5 or more of these sequences to create a kit for silencing a gene. Preferably, within the kit there would be at least one sequence that has a relatively high predicted functionality when any of Formulas I-VII is applied.
Example XI Sample Pools of siRNAs and Their Application to Human Disease The genetic basis behind human disease is well documented and siRNA may be used as both research or diagnostic tools and therapeutic agents, either individually or in pools. Genes involved in signal transduction, the immune response, apoptosis, DNA repair, cell cycle control, and a variety of other physiological functions have clinical relevance and therapeutic agents that can modulate expression of these genes may alleviate some or all of the associated symptoms. In some instances, these genes can be described as a member of a family or class of genes and siRNA (randomly, conventionally, or rationally designed) can be directed against one or multiple members of the family to induce a desired result.
To identify rationally designed siRNA to each gene, the sequence was analyzed using Formula VIII or Formula X to identify rationally designed siRNA. To confirm the activity of these sequences, the siRNA are introduced into a cell type of choice (e.g., HeLa cells, HEK293 cells) and the levels of the appropriate message are analyzed using one of several art proven techniques. siRNA having heightened levels of potency can be identified by testing each of the before mentioned duplexes at increasingly limiting concentrations. Similarly, siRNA having increased levels of longevity can be identified by introducing each duplex into cells and testing functionality at 24, 48, 72, 96, 120, 144, 168, and 192 hours after transfection. Agents that induce >95% silencing at sub-nanomolar concentrations and/or induce functional levels of silencing for >96 hours are considered hyperfunctional.
Example XII Validation of Multigene Knockout Using Rab5 and Eps Two or more genes having similar, overlapping functions often leads to genetic redundancy. Mutations that knockout only one of, e.g., a pair of such genes (also referred to as homologs) results in little or no phenotype due to the fact that the remaining intact gene is capable of fulfilling the role of the disrupted counterpart. To fully understand the function of such genes in cellular physiology, it is often necessary to knockout or knockdown both homologs simultaneously. Unfortunately, concomitant knockdown of two or more genes is frequently difficult to achieve in higher organisms (e.g., mice) thus it is necessary to introduce new technologies dissect gene function. One such approach to knocking down multiple genes simultaneously is by using siRNA. For example, FIG. 11 showed that rationally designed siRNA directed against a number of genes involved in the clathrin-mediated endocytosis pathway resulted in significant levels of protein reduction (e.g., >80%). To determine the effects of gene knockdown on clathrin-related endocytosis, internalization assays were performed using epidermal growth factor and transferrin. Specifically, mouse receptor-grade EGF (Collaborative Research Inc.) and iron-saturated human transferrin (Sigma) were iodinated as described previously (Jiang, X., Huang, F., Marusyk, A. & Sorkin, A. (2003) Mol Biol Cell 14, 858-70). HeLa cells grown in 12-well dishes were incubated with 125I-EGF (1 ng/ml) or 125I-transferrin (1 μg/ml) in binding medium (DMEM, 0.1% bovine serum albumin) at 37° C., and the ratio of internalized and surface radioactivity was determined during 5-min time course to calculate specific internalization rate constant kc as described previously (Jiang, X et al.). The measurements of the uptakes of radiolabeled transferrin and EGF were performed using short time-course assays to avoid influence of the recycling on the uptake kinetics, and using low ligand concentration to avoid saturation of the clathrin-dependent pathway (for EGF Lund, K. A., Opresko, L. K., Strarbuck, C., Walsh, B. J. & Wiley, H. S. (1990) J. Biol. Chem. 265, 15713-13723).
The effects of knocking down Rab5a, 5b, 5c, Eps, or Eps 15R (individually) are shown in FIG. 22 and demonstrate that disruption of single genes has little or no effect on EGF or Tfn internalization. In contrast, simultaneous knock down of Rab5a, 5b, and 5c, or Eps and Eps 15R, leads to a distinct phenotype (note: total concentration of siRNA in these experiments remained constant with that in experiments in which a single siRNA was introduced, see FIG. 23). These experiments demonstrate the effectiveness of using rationally designed siRNA to knockdown multiple genes and validates the utility of these reagents to override genetic redundancy.
Example XIII Validation of Multigene Targeting Using G6PD, GAPDH, PLK, and UQC Further demonstration of the ability to knock down expression of multiple genes using rationally designed siRNA was performed using pools of siRNA directed against four separate genes. To achieve this, siRNA were transfected into cells (total siRNA concentration of 100 nM) and assayed twenty-four hours later by B-DNA. Results shown in FIG. 24 show that pools of rationally designed molecules are capable of simultaneously silencing four different genes.
Example XIV Validation of Multigene Knockouts as Demonstrated by Gene Expression Profiling, a Prophetic Example To further demonstrate the ability to concomitantly knockdown the expression of multiple gene targets, single siRNA or siRNA pools directed against a collection of genes (e.g., 4, 8, 16, or 23 different targets) are simultaneously transfected into cells and cultured for twenty-four hours. Subsequently, mRNA is harvested from treated (and untreated) cells and labeled with one of two fluorescent probes dyes (e.g., a red fluorescent probe for the treated cells, a green fluorescent probe for the control cells.). Equivalent amounts of labeled RNA from each sample is then mixed together and hybridized to sequences that have been linked to a solid support (e.g., a slide, “DNA CHIP”). Following hybridization, the slides are washed and analyzed to assess changes in the levels of target genes induced by siRNA.
Example XV Identifying Hyperfunctional siRNA Identification of Hyperfunctional Bcl-2 siRNA
The ten rationally designed Bcl2 siRNA (identified in FIGS. 13, 14) were tested to identify hyperpotent reagents. To accomplish this, each of the ten Bcl-2 siRNA were individually transfected into cells at a 300 pM (0.3 nM) concentrations. Twenty-four hours later, transcript levels were assessed by B-DNA assays and compared with relevant controls. As shown in FIG. 25, while the majority of Bcl-2 siRNA failed to induce functional levels of silencing at this concentration, siRNA 1 and 8 induced >80% silencing, and siRNA 6 exhibited greater than 90% silencing at this subnanomolar concentration.
By way of prophetic examples, similar assays could be performed with any of the groups of rationally designed genes described in the Examples. Thus for instance, rationally designed siRNA sequences directed against a gene of interest could be introduced into cells at increasingly limiting concentrations to determine whether any of the duplexes are hyperfunctional.
Example XVI Gene Silencing: Prophetic Example Below is an example of how one might transfect a cell.
Select a cell line. The selection of a cell line is usually determined by the desired application. The most important feature to RNAi is the level of expression of the gene of interest. It is highly recommended to use cell lines for which siRNA transfection conditions have been specified and validated.
Plate the cells. Approximately 24 hours prior to transfection, plate the cells at the appropriate density so that they will be approximately 70-90% confluent, or approximately 1×105 cells/ml at the time of transfection. Cell densities that are too low may lead to toxicity due to excess exposure and uptake of transfection reagent-siRNA complexes. Cell densities that are too high may lead to low transfection efficiencies and little or no silencing. Incubate the cells overnight. Standard incubation conditions for mammalian cells are 37° C. in 5% CO2. Other cell types, such as insect cells, require different temperatures and CO2 concentrations that are readily ascertainable by persons skilled in the art. Use conditions appropriate for the cell type of interest.
siRNA re-suspension. Add 20 μl siRNA universal buffer to each siRNA to generate a final concentration of 50 μM.
siRNA-lipid complex formation. Use RNase-free solutions and tubes. Using the following table, Table XI: TABLE XI
96-WELL 24-WELL
MIXTURE 1 (TRANSIT-TKO-PLASMID DILUTION MIXTURE)
Opti-MEM 9.3 μl 46.5 μl
TransIT-TKO (1 μg/μl) 0.5 μl 2.5 μl
MIXTURE 1 FINAL VOLUME 10.0 μl 50.0 μl
MIXTURE 2 (SIRNA DILUTION MIXTURE)
Opti-MEM 9.0 μl 45.0 μl
siRNA (1 μM) 1.0 μl 5.0 μl
MIXTURE 2 FINAL VOLUME 10.0 μl 50.0 μl
MIXTURE 3 (SIRNA-TRANSFECTION REAGENT MIXTURE)
Mixture 1 10 μl 50 μl
Mixture 2 10 μl 50 μl
MIXTURE 3 FINAL VOLUME 20 μl 100 μl
Incubate 20 minutes at room temperature
MIXTURE 4 (MEDIA-SIRNA/TRANSFECTION REAGENT
MIXTURE)
Mixture 3 20 μl 100 μl
Complete media 80 μl 400 μl
MIXTURE 4 FINAL VOLUME 100 μl 500 μl
Incubate 48 hours at 37° C.
Transfection. Create a Mixture 1 by combining the specified amounts of OPTI-MEM serum free media and transfection reagent in a sterile polystyrene tube. Create a Mixture 2 by combining specified amounts of each siRNA with OPTI-MEM media in sterile 1 ml tubes. Create a Mixture 3 by combining specified amounts of Mixture 1 and Mixture 2. Mix gently (do not vortex) and incubate at room temperature for 20 minutes. Create a Mixture 4 by combining specified amounts of Mixture 3 to complete media. Add appropriate volume to each cell culture well. Incubate cells with transfection reagent mixture for 24-72 hours at 37° C. This incubation time is flexible. The ratio of silencing will remain consistent at any point in the time period. Assay for gene silencing using an appropriate detection method such as RT-PCR, Western blot analysis, immunohistochemistry, phenotypic analysis, mass spectrometry, fluorescence, radioactive decay, or any other method that is now known or that comes to be known to persons skilled in the art and that from reading this disclosure would useful with the present invention. The optimal window for observing a knockdown phenotype is related to the mRNA turnover of the gene of interest, although 24-72 hours is standard. Final Volume reflects amount needed in each well for the desired cell culture format. When adjusting volumes for a Stock Mix, an additional 10% should be used to accommodate variability in pipetting, etc. Duplicate or triplicate assays should be carried out when possible.
Example XVII siRNAs That Target Deubiquitination Enzymes siRNAs that target nucleotide sequences for deubiquitination enzymes with the NCBI accession numbers denoted below and having sequences generated in silico by the algorithms herein, are provided. In various embodiments, the siRNAs are rationally designed. In various embodiments, the siRNAs are functional or hyperfunctional. These siRNA that have been generated by the algorithms of the present invention include:
SEQ +HL,26
ID
NO Name siRNASense Accession
438 AMSH AGAAGGAAGCAGAGGAAUU NM_006463
439 AMSH CGGUAGAGGUGAAUGAAGA NM_006463
440 AMSH GGGCAUCACCUGAGAAAGA NM_006463
441 AMSH GAAGAAGGAAGCAGAGGAA NM_006463
442 AMSH CAAUAUGAAUGGAGCUUAU NM_006463
443 AMSH GCUCUGGAGUUGAGAUUAU NM_006463
444 AMSH GUGGAAAACUGAUGAGGAA NM_006463
445 AMSH GAAAGACACAGUAAAGAAA NM_006463
446 AMSH ACACAGAGAACGAAGAAGA NM_006463
447 AMSH AGAAAGACACAGUAAAGAA NM_006463
448 AMSH GAAAAGAAAGACACAGUAA NM_006463
449 AMSH GAAAUUAAGUAGCUCAGAA NM_006463
450 AMSH CAACAGAAGCAGCAGCAAU NM_006463
451 AMSH GAACAUGGCCAUCCAGCAA NM_006463
452 AMSH GCUAACACAUCCCGAAGAA NM_006463
453 AMSH GGAGAUUGCAUUUCCCAAA NM_006463
454 AMSH CAACUGUAACUCAGAAAUU NM_006463
455 AMSH UUACAAAUCUGCUGUCAUU NM_006463
456 AMSH CUAGAAAGCUUUGGAAGUU NM_006463
457 AMSH GAGUUGAGAUUAUCCGAAU NM_006463
458 AMSH CAACACAGAGAACGAAGAA NM_006463
459 AMSH-LP GAGUAGAGAUGGAGAGGAU NM_020799
460 AMSH-LP AAUAGAAACCUGUGGAAUA NM_020799
461 AMSH-LP UGGAGAAUGUAGAGGAAUU NM_020799
462 AMSH-LP UGAUAGAGGCAGAAAGGAA NM_020799
463 AMSH-LP UGAAGAAACUGAAGGAGAU NM_020799
464 AMSH-LP GAAGAAGGAAAUUUGGAAA NM_020799
465 AMSH-LP UAAUACAGUGAGAGGAAUA NM_020799
466 AMSH-LP GAAUGUAUUUGCAGAUCAA NM_020799
467 AMSH-LP UGGAAUACUCUGUGGAAAA NM_020799
468 AMSH-LP GGACCAGACUAUUGUGACA NM_020799
469 AMSH-LP UCUAAUACAGUGAGAGGAA NM_020799
470 AMSH-LP ACGUAGAAUACCAAGAAUA NM_020799
471 AMSH-LP CGUAGAAUACCAAGAAUAU NM_020799
472 AMSH-LP AGAGUUAGCCCGAGGUCAA NM_020799
473 AMSH-LP AGAGAUUGAUAGAGGCAGA NM_020799
474 AMSH-LP UGUAUUUGGAAGAAGGAAA NM_020799
475 AMSH-LP CAUGGAGAAUGUAGAGGAA NM_020799
476 AMSH-LP AUGAAGAAACUGAAGGAGA NM_020799
477 AMSH-LP GGAAGAAGGAAAUUUGGAA NM_020799
478 AMSH-LP GGAAUAGAAACCUGUGGAA NM_020799
479 AMSH-LP UCUAAGUGCUGUUCAGAAU NM_020799
480 AMSH-LP GGAGAAUGUAGAGGAAUUA NM_020799
481 AMSH-LP UCACCAAAGCAUAAAGACA NM_020799
482 AMSH-LP GCAUAAAGACACUGGCAUC NM_020799
483 AMSH-LP GUGGAAUACUCUGUGGAAA NM_020799
484 AMSH-LP AAUUGGAGCAUCAGAGAUU NM_020799
485 AMSH-LP GCAGAAAGGAAGCGGAUUG NM_020799
486 AMSH-LP GGUCUGGAGUAGAGAUGGA NM_020799
487 AMSH-LP CUGAAAAGCAGGAUAUUAU NM_020799
488 AMSH-LP CUUCCUAACCAUCGAGAUU NM_020799
489 BAP1 GAGCAAAGGAUAUGCGAUU NM_004656
490 BAP1 CCACAAGUCUCAAGAGUCA NM_004656
491 BAP1 GAGAAGAGGAAGAAGUUCA NM_004656
492 BAP1 GGGUGCAAGUGGAGGAGAU NM_004656
493 BAP1 CGUGAUUGAUGAUGAUAUU NM_004656
494 BAP1 UCUACGACCUUCAGAGCAA NM_004656
495 BAP1 GGGUCAUCAUGGAGCGUAU NM_004656
496 BAP1 GAGGUAGAGAAGAGGAAGA NM_004656
497 BAP1 UCAAAGAGUCCCAGAAGGA NM_004656
498 BAP1 CCAUCAACGUCUUGGCUGA NM_004656
499 BAP1 AGGAUGACGAGGAGGAUGA NM_004656
500 BAP1 AGGAGGUAGAGAAGAGGAA NM_004656
501 BAP1 AGGCUGAGAUUGCAAACUA NM_004656
502 BAP1 UCAAGGAGGAGGUAGAGAA NM_004656
503 BAP1 UGGAUGGGCUGAAGGUCUA NM_004656
504 BAP1 UGUCAGUGCUGCAGCCCAA NM_004656
505 BAP1 CCAACCUAGUGGAGCAGAA NM_004656
506 BAP1 GUAGAGAAGAGGAAGAAGU NM_004656
507 BAP1 AGGAUGACUAUGAGGAUGA NM_004656
508 BAP1 CAGAUGAUGAGGAUGACUA NM_004656
509 BAP1 AGAGAAGGACCCACAACUA NM_004656
510 BAP1 CGGUUCUGCUGAUGGGCAA NM_004656
511 BAP1 AGGAAGAAGUUCAAGAUUG NM_004656
512 BAP1 AGGAAGGCAUGCUGGCCAA NM_004656
513 BAP1 CUGGAUCAAUGAAUGAAUA NM_004656
514 BAP1 AACCCAAGCUAGUGGUGAA NM_004656
515 BAP1 CCAAGGAGCUGCUGGCACU NM_004656
516 BAP1 AGGUAUAAGGGGAAGGGAA NM_004656
517 BAP1 GCAGAGACAGGGUUGCUUA NM_004656
518 BAP1 CCUACAAGGCCAAGCGCCA NM_004656
519 C10ORF29 GAUGAUGACUGGAGGCAAA NM_152586
520 C10ORF29 UAACCUAUCCAGAGAGAAA NM_152586
521 C10ORF29 GAUAGAAGUUUGUCAGGUA NM_152586
522 C10ORF29 GUGAGGAAGCCUUUGGAAA NM_152586
523 C10ORF29 AGUACAGGUUUCAAGGAUA NM_152586
524 C10ORF29 CAGGAAGGACUUUGAACUA NM_152586
525 C10ORF29 GCAGUACAGUGCAGAGAAU NM_152586
526 C10ORF29 GCAGCACAGUCAAUGGUAA NM_152586
527 C10ORF29 CCUCAGAAUUGGAGUCUCU NM_152586
528 C10ORF29 GAGCAGGAGACCUCAGAAU NM_152586
529 C10ORF29 AGACAUAUACCAAGAGAAG NM_152586
530 C10ORF29 CAGGGUGGACUGAGAAGAA NM_152586
531 C10ORF29 CCAAACAGGCUCUGCAGAU NM_152586
532 C10ORF29 UCAGGUAGUCUAAGGAAGA NM_152586
533 C12ORF6 UCACAAAGCAGAAGAAUUA NM_020367
534 C12orf6 CAAGAUAGACUUUGCAGAA NM_020367
535 C12ORF6 AGAUAGACUUUGCAGAAAU NM_020367
536 C12orf6 CAAACAAUGAAGUGGAUGA NM_020367
537 C12orf6 GUGAAUUUGUGGAAGCAAU NM_020367
538 C12ORF6 ACAAUGAAGUGGAUGACAU NM_020367
539 C12ORF6 GAGAUUACAUAAACGGAGA NM_020367
540 C12ORF6 GUUUCUUGCUCGAGUGCUA NM_020367
541 C12ORF6 GAUGAUACCUGGAACCCAA NM_020367
542 C12orf6 CAGAAAUGAAGCAAAUGAA NM_020367
543 C12ORF6 GCAGAAAUGAAGCAAAUGA NM_020367
544 C12ORF6 GGAGCUAUGUGAAUUUAUA NM_020367
545 C12orf6 CAGCAGUGAAUUUGUGGAA NM_020367
546 C12orf6 GGGAGAAUGUGAAUACUCA NM_020367
547 C12ORF6 CAACAAACAAUGAAGUGGA NM_020367
548 C12orf6 GAAGCAAUCUGCAUUCAUA NM_020367
549 C12ORF6 GCACAAUCAAACACAUGAA NM_020367
550 C12ORF6 UCUGCAAAGAUGACAUAAA NM_020367
551 C12ORF6 UGACAUAAAGCAUGGGAAC NM_020367
552 C12ORF6 CAAAGAUGACAUAAAGCAU NM_020367
553 C12orf6 GCAAAGAUGACAUAAAGCA NM_020367
554 C12ORF6 GAACCUAUUUUGCUAGAGA NM_020367
555 C12ORF6 GCCUCAGAUUAAUGAACAA NM_020367
556 C12orf6 AAGAUAGACUUUGCAGAAA NM_020367
557 C12orf6 CAAGGAAGCUUUAUUCUUU NM_020367
558 C12ORF6 GACAUGGACACGUCAGAUA NM_020367
559 C12ORF6 CCUGAGUACUUGAUAGACU NM_020367
560 C12ORF6 CUUCCAAAGACGGGAGCUA NM_020367
561 C12ORF6 GGAGUUCUUUUGCAGGAAA NM_020367
562 C12ORF6 UUGCUAAUCUCUUUGGGAA NM_020367
563 C14orf137 CAGACUGGCUGGAGAAAUU NM_023112
564 C14orf137 GGGAAAACAUAGUGGAUGA NM_023112
565 C14orf137 UGAGAUUCCUUGUGUGAAA NM_023112
566 C14orf137 GAACAAUUAGCAACAGAAA NM_023112
567 C14orf137 ACAAUUAGCAACAGAAAGA NM_023112
568 C14orf137 GAGGAAAAGCUCAAGGUUA NM_023112
569 C14orf137 GCCGAUAAACAUUGAUUAA NM_023112
570 C14orf137 CCACCAUGGUCUAUGAGAA NM_023112
571 C14orf137 AAACAUUCUCCUAGCAUUA NM_023112
572 C14orf137 CAACAAUACCUAUGUGUCA NM_023112
573 C14orf137 CCACCUGGACAGAGGCUUA NM_023112
574 C140RF137 AGGAUUUACCGGAGGAAAA NM_023112
575 C140RF137 UGGUGGAACUGGUAGAGAA NM_023112
576 C14orf137 UCACUGGAUUAUUGGUUAA NM_023112
577 C140RF137 GGGAGAUCUUCAAGUUCAA NM_023112
578 C140RF137 GGAGGAAAAUCGAGGAACU NM_023112
579 C14orf137 GGGAACAAUUAGCAACAGA NM_023112
580 C14orf137 CCAAUAGCACUCUCAGAUA NM_023112
581 C14orf137 UCUGGAUACUUCAAGGAUA NM_023112
582 C14or1137 CCGUUUACCUGCUCUAUAA NM_023112
583 C140RF137 UCUACAGGGCCUUGGGCUA NM_023112
584 C140RF137 UGGAACUGGUAGAGAAGGA NM_023112
585 C14orf137 GGACAAAUGCUUUCUAACU NM_023112
586 C14orf137 GGACAGAGGCUUACAAGAC NM_023112
587 C14orf137 GGCCAUACCCCUUAAAUAA NM_023112
588 C14orf137 CCUCAGGACCUUCAAGAUU NM_023112
589 C14orf137 CUGCAGGGAUUUACUGGAA NM_023112
590 C14orf137 GGAACAAUUAGCAACAGAA NM_023112
591 C14orf137 GGUUCUAACUUCAGCAUUC NM_023112
592 C14orf137 CAAUAGCACUCUCAGAUAU NM_023112
593 C15ORF16 GGAAAGACGACAACGAUAA NM_130901
594 C15ORF16 GGGAAAGACGACAACGAUA NM_130901
595 C15ORF16 AGGACAAGGAGAAGGAGAA NM_130901
596 C15ORF16 GCAAGGAGAAGAAGGCCAA NM_130901
597 C15ORF16 GGACCUGGUGUUACGGAAA NM_130901
598 C15ORF16 AGGCAACAAUGGUGGCUUU NM_130901
599 C15ORF16 GCGUGUACAGCGAGGAUUU NM_130901
600 C15ORF16 AGAAGGAGAAGCAGCGCAA NM_130901
601 C15ORF16 CCACGCAGCUGGUGCUCAA NM_130901
602 C15ORF16 CCAAGCAGCCAGAGCGAGA NM_130901
603 C15ORF16 GAACAGAGAGACCAGCAAA NM_130901
604 C15ORF16 AGACCAGCAAAGAGAACAA NM_130901
605 C15ORF16 CCACGUACCCGCAGCAGAA NM_130901
606 C15ORF16 ACGGCAAGGACAAGGAGAA NM_130901
607 C15ORF16 GAGACCUGCUGGAAGGCAA NM_130901
608 C15ORF16 GUUAAGAGACUCAGGUGGA NM_130901
609 C15ORF16 ACGAGGAGAUGAUCGGCUA NM_130901
610 C15ORF16 GGCAAGAACGGCAAGGACA NM_130901
611 C15ORF16 UGACGGAUUCUGAGCACAA NM_130901
612 C15ORF16 CGCUAGAAGCCAAGCUGAA NM_130901
613 C15ORF16 GGUUCUGGCCUAUGAUCAA NM_130901
614 C15ORF16 GAGAAGCAGCGCAAGGAGA NM_130901
615 C6.1A GAAUAAAUCAGGAGACAAA NM_024332
616 C6.1A CCACAAAACUCAACAAUAA NM_024332
617 C6.1A GGGAAAGAGUUUAUGAAUU NM_024332
618 C6.1A AGGAAAGGUAUGAGAGAAU NM_024332
619 C6.1A CAACAGAGGCAGAGAGGUU NM_024332
620 C6.1A GGAACUAACUGUUGAUACA NM_024332
621 C6.1A GAGAGAACCCAGAAAUAAA NM_024332
622 C6.1A GAAUAAAGUCUGUAGUCUA NM_024332
623 C6.1A AGGAAGAGCUUAUGCAAGA NM_024332
624 C6.1A GCACAGAGAAGGAGGAAGU NM_024332
625 C6.1A GCAAUUCAAUGGAGGAAGA NM_024332
626 C6.1A GAGGAAGGACCGAGUAGAA NM_024332
627 C6.1A GGACCUACAUACACACAAA NM_024332
628 C6.1A CGUCAGAAUUGUUCACAUU NM_024332
629 C6.1A AAGAUAAGCUACAGAUUGA NM_024332
630 C6.1A AGAAGGAAGAGGAAAGGUA NM_024332
631 C6.1A GAAGAUAAGAACACAAAGA NM_024332
632 C6.1A GCAUAUACUGGAACUGAAA NM_024332
633 C6.1A CAGAGAAGGAGGAAGUAAU NM_024332
634 C6.1A AGGACAGACUGGAGCAAAA NM_024332
635 C6.1A GCAGAGGAACAGACACAUA NM_024332
636 C6.1A GAAUAGCCUUUCUGACAAA NM_024332
637 C6.1A GAACAGACACAUACGUCAA NM_024332
638 C6.1A GAGGAAAGGUAUGAGAGAA NM_024332
639 C6.1A AGGUAUGAGAGAAUCGAAA NM_024332
640 C6.1A GACAUUCAUUCCAGAGAAA NM_024332
641 C6.1A GGAAGGACCGAGUAGAAAU NM_024332
642 C6.1A GUACAGCCACUCUGGGAAA NM_024332
643 C6.1A GGGCCAGAAGGAAGAGGAA NM_024332
644 C6.1A UAGAAUAAAUCAGGAGACA NM_024332
645 CEZANNE CAAAGAUGAUAGUGACAAU NM_020205
646 CEZANNE GCACUGAGACACUGGAGAA NM_020205
647 CEZANNE UGGCAGAACAGAAGCAGAA NM_020205
648 CEZANNE CAGCUGAGUCUGUUGGUAA NM_020205
649 CEZANNE CUGAGACACUGGAGAAGAA NM_020205
650 CEZANNE GGGCAAGGAGGCUAAACAA NM_020205
651 CEZANNE GCAGAGAGGAAGAUCAUGA NM_020205
652 CEZANNE GGAAAGAAUUGGGAUGUGA NM_020205
653 CEZANNE AGAAGGGAGUUGAGAAGGA NM_020205
654 CEZANNE CAAAGGAGGUUCUCAGUCA NM_020205
655 CEZANNE CCGAUUGGCCAGUGUAAUU NM_020205
656 CGI-77 CAUUAUAGUUGGUGAAGAA NM_016023
657 CGI-77 CAGAAGAAUUUCAGAAGUA NM_016023
658 CGI-77 ACAGAAACAUAGAGAGGAA NM_016023
659 CGI-77 GAGAGGAACUGGAGCAAUU NM_016023
660 CGI-77 ACAUAUGGAAAGUGAGAAA NM_016023
661 CGI-77 GCACAAAAGAGACGGGAAA NM_016023
662 CGI-77 ACAAACACCAAUAGAGAUA NM_016023
663 CGI-77 GUAUAAAGCCAUUGAAGAU NM_016023
664 CGI-77 GCAAAGAGAAGAAGGAGUU NM_016023
665 CGI-77 GGAAAAGGAGCGAGAAGAA NM_016023
666 CGI-77 CGAAGAGCUUGAUGAGGAA NM_016023
667 CGI-77 GCAGCUAGACAGUUAGAAA NM_016023
668 CGI-77 GAAGAUCAACUGAAAGAAA NM_016023
669 CG1-77 CCGAAGAGCUUGAUGAGGA NM_016023
670 CGI-77 AAGAAAUGGAACAGAAACA NM_016023
671 CGI-77 AAAGAAAGCUGCAUUGGAA NM_016023
672 CGI-77 CAGAAGUACUGUGAAGAUA NM_016023
673 CGI-77 GAAAUGGAACAGAAACAUA NM_016023
674 CGI-77 GGAGCGAGAAGAACGGAUA NM_016023
675 CGI-77 GAGACAUGCAUAUGGCUUA NM_016023
676 CGI-77 AGACAUAUGGAAAGUGAGA NM_016023
677 CGI-77 GCUCAAAUAUUGGCAGCUA NM_016023
678 CGI-77 GGUAUUGACCGAAGAGCUU NM_016023
679 CGI-77 AGAAGGAGUUGCAAGCCAA NM_016023
680 CGI-77 ACUUGGUGCUUGAGAAUCA NM_016023
681 CGI-77 CAAUUGAAGCUGACUACUA NM_016023
682 CGI-77 CCAGACAUAUGGAAAGUGA NM_016023
683 CGI-77 GCUGAGAAGGCAUCGCAAA NM_016023
684 CGI-77 UGACUACUAAGGAGAAUAA NM_016023
685 CGI-77 CUAAGGAGAAUAAGAUAGA NM_016023
686 COPS5 GGACAUACCCAAAGGGCUA NM_006837
687 COPS5 CUACAAACCUCCUGAUGAA NM_006837
688 COPS5 UGGAAUAAAUACUGGGUGA NM_006837
689 COPS5 UGAAAGACAGUAUGAGAAA NM_006837
690 COPS5 GGACUAAGGAUCACCAUUA NM_006837
691 COPS5 ACAAAUACGACAAGAAACA NM_006837
692 COPS5 GGUGAAACCAUGAUCAUUA NM_006837
693 COPS5 CCGAAAAUCAGAAGACAAA NM_006837
694 COPS5 GGAUUGAUGUCUCAGGUUA NM_006837
695 COPS5 AACAAUAUCCGCAGGGAAA NM_006837
696 COPS5 CUACAAAUACGACAAGAAA NM_006837
697 COPS5 GUGAAUACGUUGAGUUCUU NM_006837
698 COPS5 UAGGAAAGGUGGAUGGUGA NM_006837
699 COPS5 GAACAAUAUCCGCAGGGAA NM_006837
700 COPS5 AUACAUGGCUGCAUACAUA NM_006837
701 COPS5 ACAAGAAACAGCAGCAAGA NM_006837
702 COPS5 CUGAAAGACAGUAUGAGAA NM_006837
703 COPS5 GAGAAGUACUUUACCUGAA NM_006837
704 COPS5 AAGAAACAGCAGCAAGAAA NM_006837
705 COPS5 AGAAACAGCAGCAAGAAAU NM_006837
706 COPS5 CUUGAGCUGUUGUGGAAUA NM_006837
707 COPS5 GGAGUUUCAUGUUGGGUUU NM_006837
708 COPS5 CGGCGAAGCCCUGGACUAA NM_006837
709 COPS5 CCUUAGAAGUCUCAUAUUU NM_006837
710 COPS5 UAGAAACGCAUGACCGAAA NM_006837
711 COPS5 CCUGAAAGACAGUAUGAGA NM_006837
712 COPS5 GAAUAAAUACUGGGUGAAU NM_006837
713 COPS5 AUGAAUACAUGGCUGCAUA NM_006837
714 COPS5 GGAAUAAAUACUGGGUGAA NM_006837
715 COPS5 GGUGAUUGAUCCAACAAGA NM_006837
716 CYLD UGAAAGAAUUGGAGUGAUA NM_015247
717 CYLD GGAAGAAGGUCGUGGUCAA NM_015247
718 CYLD GGGUAGAACCUUUGCUAAA NM_015247
719 CYLD CUUCAAGAAUGCAGCGUUA NM_015247
720 CYLD CCGAAGAGGCUGAAUCAUA NM_015247
721 CYLD CAUAAUAAACCAAAGGCUA NM_015247
722 CYLD GCUCAUUGGCUGAAGUUAA NM_015247
723 CYLD AAAGGAUGUUGUAGAGAUA NM_015247
724 CYLD AUGUAUGAGUGUAGAGAAU NM_015247
725 CYLD CCGGAUAUGUGGAGGGCUU NM_015247
726 CYLD CUGUAAUGGAAGAGCUAAA NM_015247
727 CYLD GUGAAGUAGUAGAAGAAAA NM_015247
728 CYLD CGAAGAGGCUGAAUCAUAA NM_015247
729 CYLD UGGCUGAAGUUAAGGAGAA NM_015247
730 CYLD AAGUAAAGGCCUCCAAAUA NM_015247
731 CYLD AGGAUGUUGUAGAGAUAAA NM_015247
732 CYLD UGGGAGAGAUGGAUAUUUA NM_015247
733 CYLD CAGAAACAGACUAAGUAAA NM_015247
734 CYLD GAAAAGAAAGCUUAGGAUA NM_015247
735 CYLD GAGUUGAAUUGCUGGAAGA NM_015247
736 CYLD GGAUUUACCUCUGAAGAAA NM_015247
737 CYLD GGGAAGUAUAGGACAGUAU NM_015247
738 CYLD CACAAUGAGUUCAGGCUUA NM_015247
739 CYLD AGAGAUAUCUACAGACUUU NM_015247
740 CYLD UAGUGAAACCCAAGAGCUA NM_015247
741 CYLD AAGAAGGCUUGGAGAUAAU NM_015247
742 CYLD CAGAGUUACUUUUGGCAAU NM_015247
743 CYLD AAGUGAAGUAGUAGAAGAA NM_015247
744 CYLD AGAAAAUACUCCACCAAAA NM_015247
745 CYLD AGAUAAUGAUUGGGAAGAA NM_015247
746 DKFZP434D0127 GAAGGAUACUAAUGGGUAA NM_032147
747 DKFZP434D0127 CCAACGAGUUACUGAGAAU NM_032147
748 DKFZP434D0127 GGGACUGACCUCUGAGUUA NM_032147
749 DKFZP434D0127 UCACAGAAGCCCAGAAACA NM_032147
750 DKFZP434D0127 AAACGAAGGCCAAUAGUAA NM_032147
751 DKFZP434D0127 GUAGAAAGAUGGAACUUAU NM_032147
752 DKFZP434D0127 UGAAAGAGGUUGAUUUGUA NM_032147
753 DKFZP434D0127 GAAAGAGGUUGAUUUGUAA NM_032147
754 DKFZP434D0127 GGAAUUUCUUUGUGAACUU NM_032147
755 DKFZP434D0127 CCAGAAACAACUUAUGAUA NM_032147
756 DKFZP434D0127 GCAUUUGCCCUGAUGGAAA NM_032147
757 DKFZP434D0127 AAUAGUAACUCCUGGUGUA NM_032147
758 DKFZP434D0127 GUAAUAACCGAGAGAAGAU NM_032147
759 DKFZP761A052 CAACACAUUCCAUGGGAUA NM_017602
760 DKFZP761A052 UGUUUUAGCUCUUGCCAAA NM_017602
761 DKFZP761A052 UGCAUGAGGUUGUGCGAAA NM_017602
762 DKFZP761A052 UGGACUAUCUGAUGAAGAA NM_017602
763 DKFZP761A052 CCACCUACAUUAACAGGAA NM_017602
764 DKFZP761A052 CGGAAUAUCCACUAUAAUU NM_017602
765 DKFZP761A052 UGAUGAAGAAUGCCAUAAA NM_017602
766 DKFZP761A052 CAACAGUGAGGACGAGUAU NM_017602
767 DKFZP761A052 CAGCACGCAUCGAGGCUAU NM_017602
768 DKFZP761A052 GAGCAGUCUCUGAUGAAGA NM_017602
769 DKFZP761A052 GCUACAACAGUGAGGACGA NM_017602
770 DKFZP761A052 ACAGUGAGGACGAGUAUGA NM_017602
771 DKFZP761A052 CAACAGGAAUACCUAGACA NM_017602
772 DKFZP761A052 CAGCAAGCGGCGACGUCAA NM_017602
773 DKFZP761A052 CAGGAGCAUUGGUUUGAAA NM_017602
774 DKFZP761A052 AAAACAAAGUGCACAGAGA NM_017602
775 DKFZP761A052 CUGUGGAGGUGUACCAGUA NM_017602
776 DKFZP761A052 GCAUGGACUAUCUGAUGAA NM_017602
777 DKFZP761A052 CUGCAGUGGUUGCGGGAUC NM_017602
778 DKFZP761A052 GAUGCUAGAAGACAAGAAA NM_017602
779 DKFZP761A052 ACAUUAACAGGAAGCGGAA NM_017602
780 DKFZP761A052 CUAGACAGUAUGAAGAAAA NM_017602
781 DKFZP761A052 CCGACUACUUCUCCAACUA NM_017602
782 DKFZP761A052 CCUAGACAGUAUGAAGAAA NM_017602
783 DKFZP761A052 AUUAACAGGAAGCGGAAAA NM_017602
784 DKFZP761A052 GUUAGCUACCAUCGGAAUA NM_017602
785 DKFZP761A052 CUGACCAGGUGUAUGGAGA NM_017602
786 DKFZP761A052 AGUCAUGGAUUGAACAGCA NM_017602
787 DKFZP761A052 UGAUGAAGAAUGCCGACUA NM_017602
788 DKFZP761A052 GCAACCACAUUGAGAUGCA NM_017602
789 E2-EPF CCUCCAACUCUGUCUCUAA NM_014501
790 E2-EPF GGCACUGGGACCUGGAUUU NM_014501
791 E2-EPF ACAAGGAGGUGACGACACU NM_014501
792 E2-EPF GGAGAACUACGAGGAGUAU NM_014501
793 E2-EPF UCAAGUGCCUGCUGAUCCA NM_014501
794 E2-EPF GACACGUACUGCUGACCAU NM_014501
795 E2-EPF CCGCAGCCAUGAACUCCAA NM_014501
796 E2-EPF GCUACUUCCUGACCAAGAU NM_014501
797 E2-EPF GGAGGUCUGUUCCGCAUGA NM_014501
798 E2-EPF ACUGGGACCUGGAUUUGUU NM_014501
799 E2-EPF UCAAGGUCUUUCCCAACGA NM_014501
800 E2-EPF GCACUGGGACCUGGAUUUG NM_014501
801 E2-EPF GUACUGCUGACCAUCAAGU NM_014501
802 FBXO7 GGAAAGAACUGUACAGGAA NM_012179
803 FBXO7 GUGCUGAUCUCGAGUGUUA NM_012179
804 FBXO7 CCAGAAACCUUUUAAGAGA NM_012179
805 FBXO7 GAAUAUGACCAAAGACCAA NM_012179
806 FBXO7 AGGAAGAGGCACAUACAAA NM_012179
807 FBXO7 UGAGAUUAGAAGUGUGAAA NM_012179
808 FBXO7 ACAAAGAUCUUCAGAAACU NM_012179
809 FBXO7 CCGGAGAAGUGGAAGUUGA NM_012179
810 FBXO7 GCGUGAUUUUCGAGACAAU NM_012179
811 FBXO7 CCUGUGUGCCUUUGGGAAA NM_012179
812 FBXO7 ACUCCAGAAUAAUGAGCAA NM_012179
813 FBXO7 GCACAUACAAAGAAAAGAA NM_012179
814 FBXO7 CCUUGAUAGUGUUGAUACA NM_012179
815 FBXO7 CAUUAGAGACCUUGUAUCA NM_012179
816 FBXO7 CCGAAAGGGCGGUUUGUGA NM_012179
817 FBXO7 AGACUAGCAUACAGGAUGA NM_012179
818 FBXO7 UAGCAUACAGGAUGAACAA NM_012179
819 FBXO7 GAAACCUGAUUGUUGUAAA NM_012179
820 FBXO7 CAAAGAGAAACUAGGGGAA NM_012179
821 FBXO7 GAACCUACCAGAUGUAUUU NM_012179
822 FBXO7 AAAGAACUGUACAGGAAGA NM_012179
823 FBXO7 CUGAGUCAAUUCAAGAUAA NM_012179
824 FBXO7 CUGUACAGGAAGAGGCACA NM_012179
825 FBXO7 GUGAAUCGGUGGAAGGGCA NM_012179
826 FBXO7 CCACAGAUUCAGAGCAUUC NM_012179
827 FBXO7 GAAUGACGACAGUAUGUUA NM_012179
828 FBXO7 GAUGAACAACCAAGUGAUU NM_012179
829 FBXO7 AGACACAGAUUGGAAAGAA NM_012179
830 FBXO7 AGAGGCACAUACAAAGAAA NM_012179
831 FBXO7 GGGUGUAUAAGCUGCAGUA NM_012179
832 FBXO8 CGAAAGAACAGGAAGGAUU NM_012180
833 FBXO8 CCAAAUGCACUGAGAGAAU NM_012180
834 FBXO8 UGGCAAGGGUUGUGCAAAU NM_012180
835 FBXO8 GGAGAAUGGCUGCGAGCAA NM_012180
836 FBXO8 GGAGAGAUGUCUUGGAUGA NM_012180
837 FBXO8 CCAAGGAGGCAUUGACAUA NM_012180
838 FBXO8 UGAAGAGCGUGGAGAGUAU NM_012180
839 FBXO8 GAAAUCAGUUCUUGCCAAA NM_012180
840 FBXO8 CAGAUGAGGGAGUGAACUA NM_012180
841 FBXO8 GCAAGGAAAUCGAAAGAAC NM_012180
842 FBXO8 GAACCCACCUUUAGGAUUU NM_012180
843 FBXO8 CGCCAAAGGAAAUAGCAAA NM_012180
844 FBXO8 GAUGAUUCGCCAAAGGAAA NM_012180
845 FBXO8 GCUGUUAACGAAUGAUAAA NM_012180
846 FBXO8 AAGCAGAGCCACUGUCUAA NM_012180
847 FBXO8 GCAUUAGAUUUGCCUGAAA NM_012180
848 FBXO8 GAAGAGUGUUGAUUUGUUA NM_012180
849 FBXO8 GAGAAUCUAUCUUGAUGAA NM_012180
850 FBXO8 UGUGGAGAGUGGUCAGAAA NM_012180
851 FBXO8 GGUCAAGGGUUGUGGAGAG NM_012180
852 FBXO8 GGACAAGUAAAGUUUGAAU NM_012180
853 FBXO8 AGGCAAGGAAAUCGAAAGA NM_012180
854 FBXO8 CACCAAUCAUCGUAAACAA NM_012180
855 FBXO8 CAAUAAGAACCCACCUUUA NM_012180
856 FBXO8 GCCCUCAUGUGAAGAAUAA NM_012180
857 FBXO8 GGUAAGUCCUUUAAACCAU NM_012180
858 FBXO8 UGAUUUAAUGCGAGAACUU NM_012180
859 FBXO8 CCAAGGACUUAGCAGAUAU NM_012180
860 FBXO8 CAGGAAGGAUUCAUUAAUU NM_012180
861 FBXO8 GAACAGGAAGGAUUCAUUA NM_012180
862 FBXW3 GGGAAGAGUACAAGGACAA NM_012165
863 FBXW3 GGGCAAGGCGGAAGAGGAA NM_012165
864 FBXW3 GGAUGCAGCUAGAGGAUGA NM_012165
865 FBXW3 GAAAGAGGCACAAGGAAGA NM_012165
866 FBXW3 CAUCCAGACUGAAGACCAA NM_012165
867 FBXW3 GGCACAAGGAAGAAAGUAU NM_012165
868 FBXW3 GGGAAAGAGGCACAAGGAA NM_012165
869 FBXW3 UGACACACUUGGACAGAGA NM_012165
870 FBXW3 GGACAAGGAGGUCAGGUUU NM_012165
871 FBXW3 GGAAGAUUGGCCUUGGUAA NM_012165
872 FBXW3 GGAUGAUGCUUUGUACAUA NM_012165
873 FBXW3 GAAGGAAGGGGAAGAGGAA NM_012165
874 FBXW3 ACACUUGGACAGAGACUUU NM_012165
875 FBXW3 CAGUGAAGGUGUCUCAGAA NM_012165
876 FBXW3 GAUGAUGCUUUGUACAUAU NM_012165
877 FBXW3 GAAGAAAGUAUGGGAAGGA NM_012165
878 FBXW3 CCGCACCAGUGUCCGGAAA NM_012165
879 FBXW3 AGGAGGAGAUGGGAAGAUU NM_012165
880 FBXW3 UGAACUGUGUGGAUUGCAA NM_012165
881 FBXW3 GAAGAUUGGCCUUGGUAAG NM_012165
882 FBXW3 AAGUGGAGAUGCAGUCAGA NM_012165
883 FBXW3 GAACUGUGUGGAUUGCAAA NM_012165
884 FBXW3 GCACAAGGAAGAAAGUAUG NM_012165
885 FBXW3 GGAGGUGAACUGUGUGGAU NM_012165
886 FBXW3 GUACAUAUCCCAGGCUAAU NM_012165
887 FBXW3 CGGGAAAGAGGCACAAGGA NM_012165
888 FBXW3 GAGGUGAACUGUGUGGAUU NM_012165
889 FBXW3 GGCGAGAGGCAUCAUCAAA NM_012165
890 FBXW3 CCAGAUGGUGCCAGCUUGA NM_012165
891 FBXW3 GAUUGGCCUUGGUAAGAUU NM_012165
892 FLJ11807 AGACCAAGAUCCAGAAAGA NM_024954
893 FLJ11807 CGGGAUGAGUUCUGGGACA NM_024954
894 FLJ11807 CUGAAGAAAGAGCGGCUUA NM_024954
895 FLJ11807 GCAAUGAGCCCCUGAAGAA NM_024954
896 FLJ11807 GCUACGAUGAGCUGGGCAA NM_024954
897 FLJ11807 GAGCAAACGGGAUGAGUUC NM_024954
898 FLJ11807 CCAGAAAGAUUUUGUCAUC NM_024954
899 FLJ11807 ACCAAGAUCCAGAAAGAUU NM_024954
900 FLJ11807 CCAAGAUCCAGAAAGAUUU NM_024954
901 FLJ11807 CUUGCAACCUUGUCAGAGA NM_024954
902 FLJ11807 CUUAAGUGGAAGAGCGACU NM_024954
903 FLJ11807 GGAGCAAACGGGAUGAGUU NM_024954
904 FLJ11807 CAGCACAAUUGGCAGAGAU NM_024954
905 FLJ11807 CCGGGAAGCUGCUCACAGA NM_024954
906 FLJ11807 CAAGCGAGCAGGACGCAAU NM_024954
907 FLJ11807 UGAAGAAAGAGCGGCUUAA NM_024954
908 FLJ11807 ACACGGAGGAGGAGAGCCU NM_024954
909 FLJ11807 AAGAGCGGCUUAAGUGGAA NM_024954
910 FLJ11807 GCUACCAGCUGCCCAUCUA NM_024954
911 FLJ11807 UCAUCCAGGUCAUCAUCAA NM_024954
912 FLJ11807 GGAGACCAAGAUCCAGAAA NM_024954
913 FLJ11807 AAGAAAGAGCGGCUUAAGU NM_024954
914 FLJ11807 GCACAAUUGGCAGAGAUGA NM_024954
915 FLJ11807 UUGCAACCUUGUCAGAGAA NM_024954
916 FLJ11807 GCCGUGAGUUCCCGCUGAA NM_024954
917 FLJ11807 CAUGGCACCCUCUGUGAAU NM_024954
918 FLJ11807 GCAAACGGGAUGAGUUCUG NM_024954
919 FLJ11807 CCACACACGGGCCUUGCAA NM_024954
920 FLJ11807 AGAAAGAGCGGCUUAAGUG NM_024954
921 FLJ11807 ACACGGGCCUUGCAACCUU NM_024954
922 FLJ12552 GGUGAUUGAUGUAGGGAAA NM_022832
923 FLJ12552 GGGAGAAUGUGUUGGCAUA NM_022832
924 FLJ12552 AGUCAUAAGUUCAGGAUAU NM_022832
925 FLJ12552 GGGAAAUGUUUGUACUAUA NM_022832
926 FLJ12552 GGAACUGAUUCAUAAGAAA NM_022832
927 FLJ12552 CAGAAGAAUUGGGUAGAUA NM_022832
928 FLJ12552 GCAGGAUGCUCAUGAAUUU NM_022832
929 FLJ12552 GGGUGCAAGUAUAGCUUUA NM_022832
930 FLJ12552 CCAUGAAACUUACGCAGUA NM_022832
931 FLJ12552 UGAGUAACCUCGAUAUUAA NM_022832
932 FLJ12552 UUGGAAGGCUGUAGAAGUA NM_022832
933 FLJ12552 CAGCAUUCAUGGAUAGAUU NM_022832
934 FLJ12552 GCCCAAAGGCUCUGCAGUA NM_022832
935 FLJ12552 CAAGAGAGUAACUGAAAGA NM_022832
936 FLJ12552 GAGCAGAAUACAUCCAUUA NM_022832
937 FLJ12552 GAAACAGGGUGAAGAGAAG NM_022832
938 FLJ12552 CAAACAAGAAGCCCAGAAA NM_022832
939 FLJ12552 GUAGCAAAGAUGAAGAUUU NM_022832
940 FLJ12552 UGGAGCAGCUGCACAGAUA NM_022832
941 FLJ14981 GGAGUGAGGUCGUGGGUUA NM_032868
942 FLJ14981 CCAUCGAAGAGGAGAUCUA NM_032868
943 FLJ14981 UGGAAGAGGAGGAGGAGGA NM_032868
944 FLJ14981 GGAAGCGGGUGGACAGCAA NM_032868
945 FLJ14981 GGGCUCAGGUAAUAAAGAA NM_032868
946 FLJ14981 AGGAGUUGCUGAUGGAAGA NM_032868
947 FLJ14981 GGGUCUCAGCAGAGGACAA NM_032868
948 FLJ14981 GGACAAGAGUCGGAGACCA NM_032868
949 FLJ14981 AGAAACUGGACAAGUACAA NM_032868
950 FLJ14981 GCAAGAAGCUGGUGAACCC NM_032868
951 FLJ14981 UGAUGGAAGAGGAGGAGGA NM_032868
952 FLJ14981 CGGAUGGGCUCAGGUAAUA NM_032868
953 FLJ14981 GGGCCUCUGUCAAGUACAA NM_032868
954 FLJ14981 AGUACAAAGGCCAGAAACU NM_032868
955 FLJ14981 CUUAAGAUCUCCUUGGCCA NM_032868
956 FLJ14981 AGUCCAAGAUCUCGCCUUU NM_032868
957 FLJ14981 UCAACAAGUUCCAGCCGUU NM_032868
958 FLJ14981 CAGCCAGACGGAAGGAUCA NM_032868
959 FLJ14981 CCGAGAUGCUGCUGGUGGA NM_032868
960 FLJ14981 AGGAGGAGUUGCUGAUGGA NM_032868
961 FLJ14981 CUGCAGGGCUCCAGCAAUG NM_032868
962 FLJ14981 AGAUGCUGCUGGUGGAGUU NM_032868
963 FLJ14981 CAAGUACAAAGGCCAGAAA NM_032868
964 FLJ14981 ACGCACAGAUGGACUACCA NM_032868
965 FLJ14981 UCGACAAGCUUAAGAUCUC NM_032868
966 FLJ14981 ACACCUACCUCGACAAGCU NM_032868
967 FLJ14981 GGUGGAAGUAACAUCCUUU NM_032868
968 FLJ14981 GGAGCCAGGAGCACACCUA NM_032868
969 FLJ14981 GGAUGGGCUCAGGUAAUAA NM_032868
970 FLJ14981 GCUCAGGUAAUAAAGAAAC NM_032868
971 FLJ20113 ACGAUAUCCUCUACAAAUA NM_017670
972 FLJ20113 GAUCAAGGACCUCCACAAA NM_017670
973 FLJ20113 GGUUGUAAAUGGUCCUAUU NM_017670
974 FLJ20113 AGGAGUAUGCUGAAGAUGA NM_017670
975 FLJ20113 CAAUUGAGGAUUUCCACAA NM_017670
976 FLJ20113 GCAAGGAGAGCGACCACAU NM_017670
977 FLJ20113 CCUAUCUACUCCUGAGCUU NM_017670
978 FLJ20113 UGGAGGCACUGCUGGAUGA NM_017670
979 FLJ20I13 UCUAUGGGAUCCUGGAAGU NM_017670
980 FLJ20113 ACUACGAUAUCCUCUACAA NM_017670
981 FLJ20113 GACCGAAUUCAGCAAGAGA NM_017670
982 FLJ20113 CAACAUCUAUCAACAGAAG NM_017670
983 FLJ20113 GCCAGGCGCUAGACAUGUA NM_017670
984 FLJ20727 AGAUAAAGAUGGUGAACAA NM_017944
985 FLJ20727 CGAGAGAAGCUUAGUGAAA NM_017944
986 FLJ20727 GGAUAAGACAUUAAAGGAA NM_017944
987 FLJ20727 CAACAUGUCAGCAGGAUAA NM_017944
988 FLJ20727 GGAUGGAGCACCAAAUAAA NM_017944
989 FLJ20727 GAGAAGUGAUGGUGAAAGU NM_017944
990 FLJ20727 GGAAUCAUGUUGUGCACUA NM_017944
991 FLJ20727 CCAUUUACCUGCUGAAACA NM_017944
992 FLJ20727 CAGUAGAAAUGGCUUAUAA NM_017944
993 FLJ23251 GGGAGAAGGACAAGGCAUA NM_024818
994 FLJ23251 GAACAUACUCUGAGGAACA NM_024818
995 FLJ23251 GCAUACAGCUUAUUGAUUA NM_024818
996 FLJ23251 CAAAGGAUAUUGUAGGAUA NM_024818
997 FLJ23251 AGACUUACCUGAAGGAAUU NM_024818
998 FLJ23251 GCUCAGAGGUGGUGGAUUC NM_024818
999 FLJ23251 AAGAAAACCUCAAAGGAUA NM_024818
1000 FLJ23251 GAUUAGAGCUGGCAAGCAU NM_024818
1001 FLJ23251 GGACAAAUCUGAUCCUGUA NM_024818
1002 FLJ23251 GGACAUGGACAAUAAAGUA NM_024818
1003 FLJ23251 AGUAUAUGAUCCUCAGAUA NM_024818
1004 FLJ23251 UGUAAGCGACUAUGAGAAA NM_024818
1005 FLJ23251 GGACAAGGCAUACAGCUUA NM_024818
1006 FLJ23251 GGAACUAGCCAAUAUGAAU NM_024818
1007 FLJ23251 GAAAUAACAUCCUCUCAAA NM_024818
1008 FLJ23251 AUGAGGACAUGGACAAUAA NM_024818
1009 FLJ23277 CAGAAAGGAUGGAGAACAU NM_032236
1010 FLJ23277 CAAUAAAGCAUGAAAGUGA NM_032236
1011 FLJ23277 GGUGAAUGGUAUAAGUUUA NM_032236
1012 FLJ23277 CAUCAGACUUGAAGGAAAU NM_032236
1013 FLJ23277 AGACGAAACUGCAAAGGAA NM_032236
1014 FLJ23277 GUAGAAGAGUGGCGGAAAU NM_032236
1015 FLJ23277 CCAAAUGCCUUAUGUCAAA NM_032236
1016 FLJ23277 GAAAUUACAACUAGGGAUU NM_032236
1017 FLJ23277 GGAAGAAAAUGAAGCCUUA NM_032236
1018 FLJ23277 GCAAGAUGGUGAUGCAGAA NM_032236
1019 FLJ23277 GAUGUAAACCCUUCAGAAA NM_032236
1020 FLJ23277 GAGGAGUGGUGUAUUGAAA NM_032236
1021 FLJ23277 GAACAAAGCAACGGAAAGA NM_032236
1022 FLJ23277 GCAUAUUGCGUCUGAAGAA NM_032236
1023 FLJ25157 GCAAGAACCAGAAAGAGAA NM_152653
1024 FLJ25157 AGAAGGAACUUGCAGAAAU NM_152653
1025 FLJ25157 CCAAAGGAGACAACAUUUA NM_152653
1026 FLJ25157 CUGUAGUGCUGGACCCAAA NM_152653
1027 FLJ25157 ACAAAGAGUUGAUGACAGU NM_152653
1028 FLJ25157 CCAACAGAGCAGAGCAUGA NM_152653
1029 FLJ25157 GAAUGGAGGUCAACUAUAU NM_152653
1030 FLJ25157 CGAUGGAGAUCAACGUGAA NM_152653
1031 FLJ25157 CCACACAGUACAUGACCAA NM_152653
1032 FLJ25157 GCUGCUAAAUUGUCAACUA NM_152653
1033 FLJ25157 GAUGACAGUCCAAGCACUA NM_152653
1034 FLJ25157 GGAGACAACAUUUAUGAAU NM_152653
1035 FLJ25157 CUAAAAGAAUUCAGAAGGA NM_152653
1036 FLJ25157 GAAGGAACUUGCAGAAAUC NM_152653
1037 FLJ25157 CAGAAGGAACUUGCAGAAA NM_152653
1038 FLJ25157 UCAGCAAGAACCAGAAAGA NM_152653
1039 FLJ25157 CCACUGAGGCACAAAGAGU NM_152653
1040 FLJ25157 UCAGAAGGAACUUGCAGAA NM_152653
1041 FLJ25157 CAAGAAUCUAUCACUGUAA NM_152653
1042 FLJ25157 GAUGGAGAUCAACGUGAAA NM_152653
1043 FLJ25157 UAUGAAUGGAGGUCAACUA NM_152653
1044 FLJ25157 GCACAAAGAGUUGAUGACA NM_152653
1045 FLJ25157 UCACCAGACUAUCCGUUUA NM_152653
1046 FLJ25157 AGAUCAACGUGAAAGUGUU NM_152653
1047 FLJ25157 ACAAGAAUCUAUCACUGUA NM_152653
1048 FLJ25157 CAACUGGAGUCCGGCUUUA NM_152653
1049 FLJ25157 GAGAUCAACGUGAAAGUGU NM_152653
1050 FLJ25157 UGAAUGGAGGUCAACUAUA NM_152653
1051 FLJ25157 GCAAAACCGCUGCUAAAUU NM_152653
1052 FLJ25157 CAACUAGUGCUAAAAGAAU NM_152653
1053 FLJ30626 GAAGAUGGUUGCAGAGGAA NM_153210
1054 FLJ30626 GCAAGGAAACUCAAGGAAA NM_153210
1055 FLJ30626 CAAGGAAACUCAAGGAAAA NM_153210
1056 FLJ30626 GUGAAAGGCAGAAGCAUUA NM_153210
1057 FLJ30626 CGUGAAAGGCAGAAGCAUU NM_153210
1058 FLJ30626 ACAUCAAGCUUCCCAGAAA NM_153210
1059 FLJ30626 CAAUAUAGAUCUUCCUUGA NM_153210
1060 FLJ30626 GAGAACAGGAGGAAUGAGA NM_153210
1061 FLJ30626 GCACUGGGCAUGUCACAAA NM_153210
1062 FLJ30626 GGCAGAAGCAUUAGCAUGA NM_153210
1063 FLJ30626 GGGCUUAUAUCCUGUUCUA NM_153210
1064 FLJ30626 AGAGGGAGAUAAUGUGUAU NM_153210
1065 FLJ30626 GAAGGCUGCUCGAGGAACA NM_153210
1066 FLJ30626 GGAUGGUGAAGCUGAGUUU NM_153210
1067 FLJ30626 GCAGCAGGCUAGCAGGUUU NM_153210
1068 FLJ30626 GCACUGCGGGUGAGGAUGA NM_153210
1069 FLJ37318 GCUCAGUCGUCAAUGUAAA NM_152586
1070 FLJ37318 GGGAAGAGUCCACUGAACA NM_152586
1071 FLJ37318 GGAAGAGUCCACUGAACAU NM_152586
1072 FLJ37318 AAAGAUGAAUCCAUGGUAU NM_152586
1073 HP43.8KD GGUAAUAGAUUUUCCAGAA NM_032557
1074 HP43.8KD GGAAGUAAUUUUCGUGCUA NM_032557
1075 HP43.8KD CAAAAUGCAUCAUGGAAAA NM_032557
1076 HP43.8KD CCAGUGAAGAGAAGAUUAA NM_032557
1077 HP43.8KD CCAAUGGAUUUGAUGACAA NM_032557
1078 HP43.8KD UGUUUGAACUGCAGGAGUA NM_032557
1079 HP43.8KD AAAGAGAGCUGCGGGAAUA NM_032557
1080 HP43.8KD UAUACAAGAUGGUGGUCUA NM_032557
1081 HP43.8KD UUAGAAGAAUUCAGAGGAA NM_032557
1082 HP43.8KD GAGUAUAUCUUCUGUGGUU NM_032557
1083 HP43.8KD GAUCAGAAGUAUCAUGUGA NM_032557
1084 HP43.8KD AGACCCACCUCUACAGAAA NM_032557
1085 HP43.8KD GAUGAAGCUUCCUGCACAA NM_032557
1086 HP43.8KD UCACACAAGCCUUCUGAAA NM_032557
1087 HP43.8KD AGAAGAACCAGUAGUUUAU NM_032557
1088 HSA243666 GGACAUAAAGAAAGGGAAU NM_017582
1089 HSA243666 AUGCUGAGGUUGAGAUAAA NM_017582
1090 HSA243666 AGAGAAACUUGGAGCUGAA NM_017582
1091 HSA243666 CAGUCGAACUCGUGAAUGA NM_017582
1092 HSA243666 GAGAUAAAGACGGGACAUA NM_017582
1093 HSA243666 GGAUGGUGAUCAUUGGUAA NM_017582
1094 HSA243666 CCAAAGGAUGAAACAAAUA NM_017582
1095 HSA243666 CUAGAAAGGGUUAGCAUUU NM_017582
1096 HSA243666 UACCAAAGGAUGAAACAAA NM_017582
1097 HSA243666 GCAACAUCACGGAGUCAUA NM_017582
1098 HSA243666 ACACAGAAGACUUAGAUCA NM_017582
1099 HSA243666 GCAUGGAACUUCUCACCAA NM_017582
1100 HSA243666 AGAUAAAGACGGGACAUAA NM_017582
1101 HSA243666 CUGAAACGAUGGUGUUAAU NM_017582
1102 HSA243666 CAACAAAUCUCAAUACAGU NM_017582
1103 HSA243666 AGAAAGGGUUAGCAUUUUA NM_017582
1104 HSA243666 GGGAAAUUAUGGAUUCUUU NM_017582
1105 HSA243666 CCAAAGAUGGCCAAGUGAA NM_017582
1106 HSHIN1 GGAAGUAGCUGAUGAAGAU NM_017493
1107 HSHIN1 GGGUAGGACAAGUGGAAAU NM_199324
1108 HSHIN1 UCGAGAGAACAGAGAGAAA NM_017493
1109 HSHIN1 GAGAGAACAGAGAGAAAUU NM_017493
1110 HSHIN1 GAUGAAGAUAACAGUGAAA NM_017493
1111 HSHIN1 AGAGAAAUUUGAAGCGUUU NM_017493
1112 HSHIN1 GGAUGACAGUUGCAAGUAA NM_017493
1113 HSHIN1 AUGAAUUGCUGUAUGAGAA NM_017493
1114 HSHIN1 GAGAGAAAUUUGAAGCGUU NM_199324
1115 HSHIN1 AGAAGGAUCAUUUGAAGAA NM_017493
1116 HSHIN1 UAUCAGAUUCAGAGGAUGA NM_017493
1117 HSHIN1 UCACAUACCCAGUAAUGAA NM_017493
1118 HSHIN1 UGCCAUACAAGGAAAGUUA NM_017493
1119 HSHIN1 UGGAAGUAGCUGAUGAAGA NM_017493
1120 HSHIN1 ACAGGAAUGGGUAGGACAA NM_017493
1121 HSHIN1 GGUAGGACAAGUGGAAAUA NM_017493
1122 HSHIN1 CUUCGAGAGAACAGAGAGA NM_017493
1123 HSHIN1 GAACAGAGAGAAAUUUGAA NM_017493
1124 HSHIN1 CGUUGGAAGUAGCUGAUGA NM_017493
1125 HSHIN1 GGGACUGUUUGCUUUGAAA NM_017493
1126 HSHIN1 CAUACCCAGUAAUGAAAUA NM_017493
1127 HSHIN1 CUUAUGUACAGGAAAGAUU NM_199324
1128 HSHIN1 CUGAUGAAGAUAACAGUGA NM_017493
1129 HSHIN1 UCACUAUCUUCGAGAGAAC NM_017493
1130 HSHIN1 AAUAUCAGAUUCAGAGGAU NM_017493
1131 HSHIN1 GUGUAUCCCAUAAAGUAUA NM_017493
1132 HSHIN1 UGAUGAAGAUAACAGUGAA NM_017493
1133 HSHIN1 CGAGAGAACAGAGAGAAAU NM_017493
1134 HSHIN1 AAGUAGCUGAUGAAGAUAA NM_199324
1135 HSHIN1 CUUCACAAGUAACAGAAAA NM_199324
1136 KIAA0063 CAGAAGAGGUAGAGGCUCA NM_014876
1137 KIAA0063 GCAAAUGGCACUUGAAAGA NM_014876
1138 KIAA0063 GGACAAAAGAGAAGCCAAA NM_014876
1139 KIAA0063 GGAAAGGAGACAAGGCCAA NM_014876
1140 KIAA0063 CGGCAGAGUUUUAUAAUGA NM_014876
1141 KIAA0063 AGAAGAGCAUGCUGGGAAA NM_014876
1142 KIAA0063 GCAUGUUGAUCCUGAGCAA NM_014876
1143 KIAA0063 UGAAGGACCCAGAGCAUAA NM_014876
1144 KIAA0063 CGUUAUAUCUUCUCAGCAA NM_014876
1145 KIAA0063 GCAAAGACGCUUAAACAUU NM_014876
1146 KIAA0063 AGACAGGCUUCUUGGAGUA NM_014876
1147 KIAA0063 ACAAAUCUACCAUGAGAAA NM_014876
1148 KIAA0063 AAACAUCAUUUGCGAGGAA NM_014876
1149 KIAA0063 GGAUAUGCAAAGACGCUUA NM_014876
1150 KIAA0063 CCACAAAUCUACCAUGAGA NM_014876
1151 KIAA0063 AUAAAGGUCUCUCAGGAAA NM_014876
1152 KIAA0063 CAUGGACACCAGAGAAUAA NM_014876
1153 KIAA0063 UCACUAACGUCAUGGGCUU NM_014876
1154 KIAA0063 CAUAAAGGUCUCUCAGGAA NM_014876
1155 KIAA0063 CCAAGCGGCUACUGCGUUA NM_014876
1156 KIAA0063 AAGAAGAGCAUGCUGGGAA NM_014876
1157 KIAA0063 GGAAACUCCUCUCCACAAA NM_014876
1158 KIAA0063 UGGCAGCACUUCAGACCAA NM_014876
1159 KIAA0063 AAAUCUACCAUGAGAAACA NM_014876
1160 KIAA0063 UGACAGUGGUAGCAAAAUA NM_014876
1161 KIAA0063 GCAACUACGAUGUGAAUGU NM_014876
1162 KIAA0063 GGAAAGUAUUGUGAAGACA NM_014876
1163 KIAA0063 GGGAGGGAAUCCUAGCUUA NM_014876
1164 KIAA0063 CGGGAUACGCUGCAAGAGA NM_014876
1165 KIAA0063 CCACUGGCACUGUCAGAUA NM_014876
1166 KIAA0710 CAAGAUGGCAGUAAAGAAA NM_014871
1167 KIAA0710 AGGAGCAGGUGGUGGAUUA NM_014871
1168 KIAA0710 GAAUUGACCCAGAUGGAAA NM_014871
1169 KIAA0710 GGGUAUACAUUGUGCCUUU NM_014871
1170 KIAA0710 GGUCACAGAUGGUGCUAUU NM_014871
1171 KIAA0710 CCAAACAAGUCCCAAGAAU NM_014871
1172 KIAA0710 UGACCCAGAUGGAAAGUAA NM_014871
1173 KIAA0710 CACAGUAGUUCAAGACUUA NM_014871
1174 KIAA0710 CAUCAAAUAUUCCAAGCUA NM_014871
1175 KIAA0710 CCACAGUAGUUCAAGACUU NM_014871
1176 KIAA0710 GAUACAACCUGAACAUCAA NM_014871
1177 KIAA0710 GCUAUUAAUUGAACUGGAA NM_014871
1178 KIAA0710 CCUGAUGGCUACUGUGGUA NM_014871
1179 KIAA0710 AAGAACAACCUCAAGUAUA NM_014871
1180 KIAA0710 GAUGGAAAGUAAUUGGUAU NM_014871
1181 KIAA1203 GGUCAGUGUUGUUGGAAUA NM_020718
1182 KIAA1203 AGAAGGAAAUCUUGGAGAA NM_020718
1183 KIAA1203 UGAAAUUUGGCUUGGAUUA NM_020718
1184 KIAA1203 AGAAAGGAGUGAAGAUGAU NM_020718
1185 KIAA1203 CAGAUUGUGUUAACAGAAA NM_020718
1186 KIAA1203 UGGAGAAGAUGAAGUAUUU NM_020718
1187 KIAA1203 GAACCAAGCGACAGUCAUA NM_020718
1188 KIAA1203 CAUCGUUCCUUUUGUGAUA NM_020718
1189 KIAA1203 AGAAAGUGUUCGUCUGCAA NM_020718
1190 KIAA1203 GAAGCAGUGUCUAUGGAAA NM_020718
1191 KIAA1203 GUAUAUUCCUGAUGCAGAA NM_020718
1192 KIAA1203 UGGCACUGCUCAUGUGAAA NM_020718
1193 KIAA1203 CUUUGAGACUCCCGAAAUA NM_020718
1194 KIAA1203 GAGAAAGGAGUGAAGAUGA NM_020718
1195 KIAA1203 UGAAGAUGAUGGAGGCUUU NM_020718
1196 KIAA1203 GACAAGGAGACAAGAGAUU NM_020718
1197 KIAA1203 GCAGGGAAGCAUUACGUUA NM_020718
1198 KIAA1203 CCUCAAACCUGCACUUUAU NM_020718
1199 KIAA1203 CAGGGAAGCAUUACGUUAA NM_020718
1200 KIAA1203 UGUAGUGUAUCAAGGCAAA NM_020718
1201 KIAA1203 CAUGAAAGCGACUGCAUUU NM_020718
1202 KIAA1203 CGUCAGAGUUUGUCAUCCA NM_020718
1203 KIAA1453 CCGUAUAUGUCCCAGAAUA NM_025090
1204 KIAA1453 GCACACAGCCACAGGUGAA NM_025090
1205 KIAA1453 GAACAUCGGCAAUGGGAUU NM_025090
1206 KIAA1915 GGACUGAGAAACAGAGCAA XM_055481
1207 KIAA1915 GGUUAUAAGUGAGGAAAUU XM_055481
1208 KIAA1915 AAGCUAAAUACCAGAGUUA XM_055481
1209 KIAA191S GUUAGAGGCUUCAGUGUUA XM_055481
1210 KIAA1915 AAAUGAAGAUAAAGGGACA XM_055481
1211 KIAA1915 GGAUAAAGAAACACCAAAU XM_055481
1212 KIAA1915 GGUUAGAAUUCAAGUAGUU XM_055481
1213 KIAA1915 GAAAAGACAAGAUGGAUAA XM_055481
1214 KIAA1915 AGGAAAGCCAUGAGGAAGA XM_055481
1215 KIAA1915 CAGAAAAGAUGCAGUAGAA XM_055481
1216 KIAA1915 GUACAGGACUACAGUGUGA XM_055481
1217 KIAA1915 AAAGAAGAGAAGAGGAAAA XM_055481
1218 KIAA1915 UGAAAAGACAAGAUGGAUA XM_055481
1219 KIAA1915 AGAGGAAAGCCAUGAGGAA XM_055481
1220 KIAA1915 GUGCAAAGUUCAUUGGGAU XM_055481
1221 KIAA1915 GCCACAAACAGUUGACAAA XM_055481
1222 KIAA1915 GCCAAAUGGUAGAGGAAAG XM_055481
1223 KIAA1915 ACUCAGAAGUUGAUAAAGU XM_055481
1224 KIAA1915 CAAAGGACUUAGAAGGACA XM_055481
1225 KIAA1915 GAAAUAAUCCCUUACCAUA XM_055481
1226 KIAA1915 GGCCAUAAUCUUCAAGUUA XM_055481
1227 KIAA1915 CUGCUGAGGAGUUGGCAAA XM_055481
1228 KIAA1915 ACAGAGCAAUGGUGACAAA XM_055481
1229 KIAA1915 GCUUUAUGGCUGAAGAAUU XM_055481
1230 KIAA1915 UCAAAUGCGGUCUGGAUAA XM_055481
1231 KIAA1915 CUACAAAACCAGCCAGUUA XM_055481
1232 KIAA1915 GAUAAAGGGACAAAGGCAU XM_055481
1233 KIAA1915 UGAGGAAGACUCUGAGCAA XM_055481
1234 KIAA1915 CAACCAAGAGAAUGGAGUA XM_055481
1235 KIAA1915 AGUGAAGAGUUAUGCAAGA XM_055481
1236 LOC161725 GCAAGAACGGCAAGGACAA NM_130901
1237 LOC161725 CAGCAGACGCAGCAGAAUA NM_130901
1238 LOC161725 GAUACAAUGUUAAGAGACU NM_130901
1239 LOC161725 GCAAGGACAAGGAGAAGGA NM_130901
1240 LOC161725 GUUCUACCUUCGAGGAUUU NM_130901
1241 LOC161725 ACAAGGAGAAGGAGAAGCA NM_130901
1242 LOC161725 AGAAGCAGCGCAAGGAGAA NM_130901
1243 LOC161725 AGAGAGACCAGCAAAGAGA NM_130901
1244 LOC220213 CAAACAAACUCAAGUGCAA XM_166659
1245 LOC220213 CGACGAAGAACUUGCCAAA XM_166659
1246 LOC220213 GAGUAAUGGCCACAGGAAA XM_166659
1247 LOC220213 AGACAGAACACCAGCUAAU XM_166659
1248 LOC220213 UGGAGGAGCACUUGACAAA XM_166659
1249 LOC220213 CCAGCUAAUGAAAGAGUUA XM_166659
1250 LOC220213 AUGAAAGAGUUAAGCGUGA XM_166659
1251 LOC220213 GGGCAGAUGCUGAAUGUGA XM_166659
1252 LOC220213 CCUAAGUGAUACUGCAUUU XM_166659
1253 LOC220213 UGGAGAAGCAGGACAAGUA XM_166659
1254 LOC220213 GCAAAGGAAACGCGACGAA XM_166659
1255 LOC220213 GGAUGGGCCCUAAGUGAUA XM_166659
1256 LOC220213 GGUCAGAGGUGCAAAGUUG XM_166659
1257 LOC220213 GAGGAUUCCCUGAGGCCUA XM_166659
1258 LOC220213 GCGAAGAGCACUUGGCGGA XM_166659
1259 LOC220213 CAACAGAUGCUCAACAAAU XM_166659
1260 LOC220213 ACGAGAAGCUGGCCCUAUA XM_166659
1261 LOC220213 GGGAGCAGACGGUGCACUA XM_166659
1262 LOC220213 GAGGAGCACUUGACAAAGA XM_166659
1263 LOC220213 AGGUGGAGAAGCAGGACAA XM_166659
1264 LOC220213 CAGUUAGGCUGGAGAAAUG XM_166659
1265 LOC220213 UGGCCGAGGUGGAGAAGCA XM_166659
1266 LOC220213 AAACUCAAGUGCAAAGGAA XM_166659
1267 LOC220213 AAGGAAACGCGACGAAGAA XM_166659
1268 LOC220213 GGAGAAAUGAGACAGAACA XM_166659
1269 LOC220213 GACAACUGGUGCAAACAAA XM_166659
1270 LOC220213 GCUCAGUAACGGACACUAU XM_166659
1271 LOC220213 ACACUAUGAUGCUGUAUUU XM_166659
1272 LOC220213 CCACCUACCUUGAGUAAUG XM_166659
1273 LOC220213 GAAAUGAGACAGAACACCA XM_166659
1274 MGC10702 AGAAAUAACUCCCAAACAA NM_032663
1275 MGC10702 AGGCAACAAUUUAGAAGAA NM_032663
1276 MGC10702 GUGCAAGUCUGAAGAAUGA NM_032663
1277 MGC10702 GAAAGAAAGAAGCGUAGAA NM_032663
1278 MGC10702 CCAAGAAGUUACUGAUGAU NM_032663
1279 MGC10702 GGAAGACUCACUAGUAAUA NM_032663
1280 MGC10702 ACAGGAUGCUCACGAAUUA NM_032663
1281 MGC10702 CAAAUUACCUGCCGCACAA NM_032663
1282 MGC10702 GGAGCAGCAGUCAGAAAUA NM_032663
1283 MGC10702 GGGAGGUACCUUUGUCUAA NM_032663
1284 MGC10702 CAGCAGGAAUAUAUGUUAU NM_032663
1285 MGC10702 UGACAACUGUACAAAGAUU NM_032663
1286 MGC10702 CAACACAACCCUAAACUGA NM_032663
1287 MGC10702 AGGUGGUUCUGUUGUGUUA NM_032663
1288 MGC10702 AUGGAAGACUCACUAGUAA NM_032663
1289 MGC10702 CCACACCAGUUCUGAAUCA NM_032663
1290 MGC14793 UGAUAUUGCUGUAGGUUUA NM_032929
1291 MGC14793 CAUGAAACUUUGUGAAGAA NM_032929
1292 MGC14793 GGUGAAAGAUCCAACUAAA NM_032929
1293 MGC14793 GGAAAUGGAGACACAGAAA NM_032929
1294 MGC14793 AGAAAGUACCGUAAGAUAA NM_032929
1295 MGC14793 GCAAAUAGAGUUUAAGUGA NM_032929
1296 MGC14793 GAGCAAUAGCUGAGAAUCU NM_032929
1297 MGC14793 GCACAGACUUAUACUCUUA NM_032929
1298 MGC14793 GUGAAUUUCUCAAGGUAUU NM_032929
1299 MGC14793 GAUCAAAGAAAGUAGUACA NM_032929
1300 MGC14793 GGAGGAAAAUGCAGAAAUU NM_032929
1301 MGC14793 UAGAAAGUACCGUAAGAUA NM_032929
1302 MGC14793 GCUCUAUGCUUUAUGAAAA NM_032929
1303 MGC14793 AUAAGGAAAUGGAGACACA NM_032929
1304 MGC14793 CUCAGAAUGUUUAGAAGAA NM_032929
1305 MGC14793 AAAUGGAGACACAGAAAUU NM_032929
1306 MGC14793 CGUGAAUCAUGUAAAGAGA NM_032929
1307 MGC14793 GCUCAGAAUGUUUAGAAGA NM_032929
1308 MGC14793 GAGAAUCUGUGGUCAGUUU NM_032929
1309 MGC14793 GGGUGAAAGAUCCAACUAA NM_032929
1310 MGC14793 GAGAAAGCCAAAAGAAGUA NM_032929
1311 MGC14793 CAGCUUAUCCUCAUAUAUA NM_032929
1312 MGC14793 UGAGGCAAAUAGAGUUUAA NM_032929
1313 MGC14793 UCUAGAAAGUACCGUAAGA NM_032929
1314 MGC14793 GCCUGGAAAUAAACACAUA NM_032929
1315 MGC14793 GAACAGAGCCCCAUUGUAU NM_032929
1316 MGC14793 UUACUGAUCUGAUGAAUGA NM_032929
1317 MGC14793 UGUUACAGCUCUAUGCUUU NM_032929
1318 MGC14793 GUAAUACCAUAAAGUGAGA NM_032929
1319 MGC14793 CAGAAUGUUUAGAAGAAAG NM_032929
1320 MJD CCAAAGAGGCAUUCAGCAA NM_004993
1321 MJD CAAACAAAAUGAUGGGAAA NM_030660
1322 MJD CUUUAGAAACUGUCAGAAA NM_004993
1323 MJD GUUCAACAGUCCAGAGUAU NM_030660
1324 MJD UCAAAGAGAUGAGGAAAUA NM_030660
1325 MJD GCACUAAGUCGCCAAGAAA NM_004993
1326 MJD ACGAAGAUGAGGAGGAUUU NM_030660
1327 MJD GAAACAGCCUUCUGGAAAU NM_030660
1328 MJD CCGCAGGGCUAUUCAGCUA NM_004993
1329 MJD CAAGGUAGUUCCAGAAACA NM_004993
1330 MJD CAAAUUAACCUUUCAGGAA NM_030660
1331 MJD CAGGAAUGUUAGACGAAGA NM_004993
1332 MJD AGUAAUGGUUCUAGAAGGA NM_004993
1333 MJD AAUUACAACAGGAAGGUUA NM_030660
1334 MJD CGAGAAGCCUACUUUGAAA NM_030660
1335 MJD UGACAUGGAAGAUGAGGAA NM_030660
1336 MJD UGGAGAAGAAUUAGCACAA NM_030660
1337 MJD CUUGACGGGUCCAGAAUUA NM_030660
1338 MJD CAACAGAUGCAUCGACCAA NM_004993
1339 MJD ACUAAGUCGCCAAGAAAUU NM_004993
1340 MJD GAUCACAACUUUUCUGCUA NM_004993
1341 MJD GCUCAACAUUGCCUGAAUA NM_004993
1342 MJD AGACCUGGAACGAGUGUUA NM_030660
1343 MJD GGUAAUGUGUCAAAGAGAU NM_030660
1344 MJD GGAAGAGACGAGAAGCCUA NM_030660
1345 MJD CCAAGAAAUUGACAUGGAA NM_030660
1346 MJD UGAAAUCAGCCUUGCACAA NM_030660
1347 MJD ACAGGAAGGUUAUUCUAUA NM_004993
1348 MJD AAGAAAUUGACAUGGAAGA NM_030660
1349 MJD AGGUAGUUCCAGAAACAUA NM_030660
1350 NY-REN-60 GGGAAGAAAUGGAAAGAAU NM_032582
1351 NY-REN-60 GCUAAGAUCUCAAGUAAAA NM_032582
1352 NY-REN-60 UCUCAAAGGCUGCGCAUUA NM_032582
1353 NY-REN-60 AGGAAAGGGUUGUAGAUGA NM_032582
1354 OTUB1 CCGACUACCUUGUGGUCUA NM_017670
1355 OTUB1 CCGAAUUCAGCAAGAGAUU NM_017670
1356 OTUB1 AGACCAGGCCUGACGGCAA NM_017670
1357 OTUB1 CUGCCAAGAGCAAGGAAGA NM_017670
1358 OTUB1 AGGUGGAGCCCAUGUGCAA NM_017670
1359 OTUB1 GAGCAGGUGGAGAGGCAGA NM_017670
1360 OTUB1 AGGAAGACCUGGUGUCCCA NM_017670
1361 OTUB1 CGGCCUGGACACUACGAUA NM_017670
1362 OTUB1 AAGAGAUUGCUGUGCAGAA NM_017670
1363 OTUB1 AGAUCAAGGACCUCCACAA NM_017670
1364 OTUB1 UCUAUCAACAGAAGAUCAA NM_017670
1365 OTUBI ACAAGGAGUAUGCUGAAGA NM_017670
1366 OTUB1 CAAGGAGUAUGCUGAAGAU NM_017670
1367 OTUB1 GGAGUAUGCUGAAGAUGAC NM_017670
1368 OTUB1 CCACCAAUCCGCACAUCUU NM_017670
1369 OTUB1 GGCCUGGACACUACGAUAU NM_017670
1370 OTUB1 CCGAAGGUGUUAACUGUCU NM_017670
1371 POH1 CAAUAAGGCUGUAGAAGAA NM_005805
1372 POH1 GGCAUUAAUUCAUGGACUA NM_005805
1373 POH1 CUGAACAGCUGGCAAUAAA NM_005805
1374 POH1 CAGAAGAUGUUGCUAAAUU NM_005805
1375 POH1 ACAAUAAGGCUGUAGAAGA NM_005805
1376 POH1 AAGGAAAGGUUGUUAUUGA NM_005805
1377 POH1 CCAGAAAUAUGGACAGACU NM_005805
1378 POH1 GUUUGACACUUCAGGACUA NM_005805
1379 POH1 CUUAAGAGUUGUAGUUACU NM_005805
1380 PRPF8 AGGAGAAGCUGCAGGAGAA NM_006445
1381 PRPF8 GGGCCAAGUUCCUGGACUA NM_006445
1382 PRPF8 GGAUAUGGCCGGAGUGUUU NM_006445
1383 PRPF8 UGGCAAAGACAGUAACAAA NM_006445
1384 PRPF8 GCUCAAAAGAAGAGGUAUU NM_006445
1385 PRPF8 UGACAGACUUGGUGGAUGA NM_006445
1386 PRPF8 CCAAGAUCAUGAAGGCAAA NM_006445
1387 PRPF8 CAACAUGAAAUAUGAGCUA NM_006445
1388 PRPF8 GGAUCAAGGUCGAGGUGCA NM_006445
1389 PRPF8 CGGAUGAUGAUGAGGAAUU NM_006445
1390 PRPF8 GAUGAAGACUGGAAUGAAU NM_006445
1391 PRPF8 GGAAAUUGAGACAGUACAA NM_006445
1392 PRPF8 CAGAAAUACUGGAUUGACA NM_006445
1393 PRPF8 AGGAAUGAGCCAUGAAGAA NM_006445
1394 PRPF8 GCAGAUGGAUUGCAGUAUA NM_006445
1395 PRPF8 AACCAAGGAAAGAAAGAAA NM_006445
1396 PRPF8 ACACAUCACUGGAGCCAUU NM_006445
1397 PRPF8 ACAAAGAGUUCUACCACGA NM_006445
1398 PRPF8 GAUUAAGCCUGCAGACACA NM_006445
1399 PRPF8 GGACAUGAACCAUACGAAU NM_006445
1400 PRPF8 CCAAAUUGCAGGAUACCUA NM_006445
1401 PRPF8 CCAAGAAUGUGCUUAAGAA NM_006445
1402 PRPF8 GAUAAGGGCUGGCGUGUCA NM_006445
1403 PRPF8 CAGACUUGGUGGAUGACAA NM_006445
1404 PRPF8 AGAACAACGUCGUCAUCAA NM_006445
1405 PRPF8 CCUAUAAGCAUGACACCAA NM_006445
1406 PRPF8 CAAUGUAUAUGUAGGCUUU NM_006445
1407 PRPF8 AAGACUGAGUGGAGGGUCA NM_006445
1408 PRPF8 GAAUCUAUGAAGUGGAAGA NM_006445
1409 PRPF8 CGAGUGAAGGCGAGUGCAA NM_006445
1410 PSMD14 GGACAUGAACCAAGACAAA NM_005805
1411 PSMD14 CAAUAAAGAAUGUUGGCAA NM_005805
1412 PSMD14 CUGUAGAAGAAGAAGAUAA NM_005805
1413 PSMD14 CAAUGGAAGUUAUGGGUUU NM_005805
1414 PSMD14 ACAAUGAAUCAGUGGUAAA NM_005805
1415 PSMD14 GGACAGACUUCUUAGACUU NM_005805
1416 PSMD14 UAAAGGAGAUGUUGGAAUU NM_005805
1417 PSMD14 GAUUAUACCGUCAGAGUGA NM_005805
1418 PSMD14 GUAAAGGAGAUGUUGGAAU NM_005805
1419 PSMD14 ACACAAUGAAUCAGUGGUA NM_005805
1420 PSMD14 CAAAUAUUGUCCAGUGUUU NM_005805
1421 PSMD14 GUACUUAUGACCUCAAAUA NM_005805
1422 PSMD14 AAUCAGUGGUAAAGGAGAU NM_005805
1423 PSMD14 CAGCAGAACAAGUCUAUAU NM_005805
1424 PSMD14 GGUCUUAGGACAUGAACCA NM_005805
1425 PSMD14 AAGAAGAGUUGGAUGGAAG NM_005805
1426 PSMD14 GAAGAAGAAGAUAAGAUGA NM_005805
1427 PSMD14 AGAGUUGGAUGGAAGGUUU NM_005805
1428 PSMD14 GAACCAAGACAAACAACUU NM_005805
1429 PSMD14 GGGUUUGAUGCUUGGAGAA NM_005805
1430 PSMD14 CAGAGUGAUUGAUGUGUUU NM_005805
1431 AD1 UGUUAGAGGUGGAGGAUUU NM_006590
1432 AD1 GGACUUUGACUUUGAGAAA NM_006590
1433 AD1 ACAUAAAGGCCAAUGAUUA NM_006590
1434 AD1 UUGGAGAGCUGAUGAGAAA NM_006590
1435 AD1 AGGCAAAUGGUAUGAAUUA NM_006590
1436 AD1 CUGAAGAAGUACACAAGAA NM_006590
1437 AD1 GGAACUACUUUCUGGAAGA NM_006590
1438 AD1 GAAGAAGUACACAAGAAUA NM_006590
1439 AD1 GAGAAGGAAUAUAAGACUU NM_006590
1440 AD1 GGCUGAUGAUGGUAAAUAA NM_006590
1441 AD1 GAGAUAAUGAUGAAACCAA NM_006590
1442 AD1 ACAGAUAAUUCCUUCCAAA NM_006590
1443 AD1 GGAAGAGGCGAGAUAAUGA NM_006590
1444 AD1 GGGAGUAGUUGAAGAACAG NM_006590
1445 AD1 GAGGCGAGAUAAUGAUGAA NM_006590
1446 AD1 GCAAAUGGUAUGAAUUACA NM_006590
1447 AD1 GUAAAUAAGAACACAGAAG NM_006590
1448 AD1 GCAAGCAGAAAGCCAGUAA NM_006590
1449 SBBI54 CCAAGGAGGUGGAGGAGAA NM_138334
1450 SBBI54 UGACCAAGGAGGUGGAGGA NM_138334
1451 SBBI54 GGGAAAGGCCAGCACUUCA NM_138334
1452 SBBI54 CGGCAACUAUGAUGUCAAU NM_138334
1453 SBBI54 GCGAGGUGCUGCUGGUAGU NM_138334
1454 SBBI54 GCAACUAUGAUGUCAAUGU NM_138334
1455 SBBI54 UGGACGGUGUCUACUACAA NM_138334
1456 SBBI54 GGAAAGGCCAGCACUUCAU NM_138334
1457 SBBI54 ACUAUGAUGUCAAUGUGAU NM_138334
1458 SBBI54 CCGCUGCUGCCUCAAUAAA NM_138334
1459 SBBI54 GGAGGCUGCCGAUGAGAUC NM_138334
1460 SBBI54 GCACCGGCAACUAUGAUGU NM_138334
1461 SBBI54 GCUGCUGCCUCAAUAAAUC NM_138334
1462 SBBI54 CAACUAUGAUGUCAAUGUG NM_138334
1463 SBBI54 CCGAUGAGAUCUGCAAGAG NM_138334
1464 SBBI54 GGACGGUGUCUACUACAAC NM_138334
1465 SBBI54 UGCCGCUGCUGCCUCAAUA NM_138334
1466 SBBI54 GGUGGACGGUGUCUACUAC NM_138334
1467 SBBI54 GAGGUGGUGGUGGUAGUGA NM_138334
1468 SBBI54 GAAAGGCCAGCACUUCAUG NM_138334
1469 SENP2 GCGAAUUACUCGAGGAGAU NM_021627
1470 SENP2 CCUCAUGCAUUGUGGGUUA NM_021627
1471 SENP2 GAUUAUAUUUCUAGGGACA NM_021627
1472 SENP2 GGAGUGGACUGGAGCGUAA NM_021627
1473 SENP2 GAACAAACGCUAACUAAUA NM_021627
1474 SENP2 AAGAAGAUGGUGUGGGAAA NM_021627
1475 SENP2 GGUAAAUCUCUUUGAACAA NM_021627
1476 SENP2 GGGUAAAUCUCUUUGAACA NM_021627
1477 SENP2 CAGAGAAGAUGGUCGGAAU NM_021627
1478 SENP2 GGAAGAAGAUGGUGUGGGA NM_021627
1479 SENP2 GGAGAUAUUCAGACAUUAA NM_021627
1480 SENP2 GGACAAACCUAUCACAUUU NM_021627
1481 SENP2 CAAAGAAGUCAGAUGGACA NM_021627
1482 SENP2 GGAAAUCAGUAAUGCCCUA NM_021627
1483 SENP2 AGAGAAGUACCGAAAGUUA NM_021627
1484 SENP2 GAGGAGAUAUUCAGACAUU NM_021627
1485 SENP2 CCACAAAGCCCAUGGUAAC NM_021627
1486 SENP2 GCUGAAACUGGGUAAUAAA NM_021627
1487 SENP2 GGAACAACAUGCUGAAACU NM_021627
1488 SENP2 AAAGAGAGGGACAGAAGAA NM_021627
1489 SENP2 GGAGGAAAGUGUCAAUAAU NM_021627
1490 SENP2 AAAGAGAGAAGUACCGAAA NM_021627
1491 SENP2 GCAAAAUCACGGAGUCAAA NM_021627
1492 SENP2 UUACAGAGGACAUGGAAAA NM_021627
1493 SENP2 UGGAAAAGGAAAUCAGUAA NM_021627
1494 SENP2 GAUGAAAGUAAGACCAAAA NM_021627
1495 SENP2 CAGUAAUGCCCUAGGCCAU NM_021627
1496 SENP2 CAUGAAACCACACGAGAUU NM_021627
1497 SENP2 AAGAGGAAAGAGAGAAGUA NM_021627
1498 SENP2 UGAUGAAAUACCAGCCAAA NM_021627
1499 TAMBP CAGAAGAGCUGAAGGCAGA NM_201647
1500 TAMBP CCAGCUGGGUAGUGCGGUA NM_006463
1501 TAMBP UGGAAUUCUCUGUGGAAAA NM_006463
1502 TAMBP UGUCAUUCCUGAAAAGAAA NM_006463
1503 TAMBP CCAAAGCAGAAGAGCUGAA NM_201647
1504 TAMBP GAAGGUAGACCCUGGCCUA NM_006463
1505 TAMBP AGUGGAGACAUGUGGAAUU NM_006463
1506 TAMBP CCUUCAUCCUCUAUAACAA NM_201647
1507 TAMBP UCACACAACUGUAAGGCCA NM_201647
1508 TNFAIP3 GGGAAGAUUUGAAGACUUA NM_006290
1509 TNFAIP3 GCACCAUGUUUGAAGGAUA NM_006290
1510 TNFAIP3 GAGCAGGAGAGGAAAGAUA NM_006290
1511 TNFAIP3 CAUAUUUGCUCUAGAAGAA NM_006290
1512 TNFAIP3 GCGGAAAGCUGUGAAGAUA NM_006290
1513 TNFAIP3 UCACAAGAGUCAACAUUAA NM_006290
1514 TNFAIP3 CAGCAUGAGUACAAGAAAU NM_006290
1515 TNFAIP3 GCUAAGAAGUUUGGAAUCA NM_006290
1516 TNFAIP3 GGGACGAGCAAGUGCAGAA NM_006290
1517 TNFAIP3 CAGACUUGGUACUGAGGAA NM_006290
1518 TNFAIP3 CAAAGUUGGAUGAAGCUAA NM_006290
1519 TNFAIP3 GGAAUUGCAUCCAAGGUAU NM_006290
1520 TNFAIP3 UACAAGAAAUGGCAGGAAA NM_006290
1521 TNFAIP3 CAAAAGGACAGAAGAGCAA NM_006290
1522 TNFAIP3 ACAAGAAAUGGCAGGAAAA NM_006290
1523 TNFAIP3 GAAAAUGAGAUGAAGGAGA NM_006290
1524 TNFAIP3 CAGAAGAGCAACUGAGAUC NM_006290
1525 TNFAIP3 GCACAAUGGCUGAACAAGU NM_006290
1526 TNFAIP3 GCUCAAGGAAACAGACACA NM_006290
1527 TNFAIP3 AAAAUGAGAUGAAGGAGAA NM_006290
1528 TNFAIP3 CAAUAGGAAGGCUAAAUAA NM_006290
1529 TNFAIP3 CAACUCACUGGAAGAAAUA NM_006290
1530 TNFAIP3 CCAGUAACCAUGAGUAUGA NM_006290
1531 TNFAIP3 UUUGAAAGUGGGUGGAAUU NM_006290
1532 TNFAIP3 GAAUUGCAUCCAAGGUAUA NM_006290
1533 TNFAIP3 AGUACUUAAUGGUGAUAGA NM_006290
1534 TNFAIP3 AGGCUUUGUAUUUGAGCAA NM_006290
1535 TNFAIP3 AAACGAACGGUGACGGCAA NM_006290
1536 TNFAIP3 AGAGAUUUCAUGAGGCCAA NM_006290
1537 TNFAIP3 UCAUUGAAGCUCAGAAUCA NM_006290
1538 TRABID GGGAGAAACUUUAGGAUAU NM_017580
1539 TRABID GGUAAUAGCCAAAGGAGAU NM_017580
1540 TRABID GGAGCUAGGUAAUGAGGAA NM_017580
1541 TRABID GCAUGCAUCUUUUGAGAAA NM_017580
1542 TRABID GGUUGUAGAAGGUGAUUUA NM_017580
1543 TRABID UGUAAUGACCCUAAAGUUA NM_017580
1544 TRABID GGAGAAACUUUAGGAUAUA NM_017580
1545 TRABID CAGCAGAUAUUGAAGAUUU NM_017580
1546 TRABID GAAGAAGAAUCUCCAAUUA NM_017580
1547 TRABID GAAUUUAUCUCCAGUGUUU NM_017580
1548 TRABID GGAAGUAGUCCUUUGAUAU NM_017580
1549 TRABID ACAGAGAACUUUUGUUGAA NM_017580
1550 TRABID CGUUAUAUCUCCUGCCUAU NM_017580
1551 TRABID UCAAACAGCAGAAGACCAA NM_017580
1552 TRABID GGAAGAUGAGGAUGAUGAA NM_017580
1553 TRFP CAGAGAUGGUCUUGGAGAA NM_004275
1554 TRFP GAAGGCAUCUAAAGAGAAA NM_004275
1555 TRFP AGGCACAACUGGUUUGAUA NM_004275
1556 TRFP CCUCAAGAAUGGUAAUUAU NM_004275
1557 TRFP ACUACAAGAUGAAAGACAA NM_004275
1558 TRFP GCAGUCAUGUGCUGAGUUA NM_004275
1559 TRFP UAUGAAGAGUGGAGAAGUU NM_004275
1560 TRFP ACAUGGAACUCUUCAACAA NM_004275
1561 TRFP UCUACAAGGUUAUCAGGAA NM_004275
1562 TRFP UCCUAGAGAUGGAGUAGAA NM_004275
1563 TRFP GUUAAUGGCUUCUGUUACA NM_004275
1564 TRFP GGAUUGUGCUGUAAUAAGA NM_004275
1565 TRFP CCUGUUUGCUGAAGUGAUU NM_004275
1566 TRFP GCUCAGUUCAGUACCAUAA NM_004275
1567 TRFP GUGAAUGUAUGUACUGUAU NM_004275
1568 TRFP GCUAUAAGAUCGAAGUUUG NM_004275
1569 TRFP GAGGUAAUCAGAUGGUCUA NM_004275
1570 TRFP GAAAUAUUCAUCCAGGUUA NM_004275
1571 TRFP GAUCUUAGGGUUAGAAUAC NM_004275
1572 TRFP AGGCCAAACUGCUAUAAGA NM_004275
1573 TRFP AAAGAGAUGCUGGGACAUA NM_004275
1574 TRFP CAAGUCAGGUGGUGGUCAU NM_004275
1575 TRFP GAUCAAAGCAGACUCAUCA NM_004275
1576 TRFP GCAAGAGUGUUCAGCAAAC NM_004275
1577 UBE1 GCUCAGACCUGCAAGAGAA NM_003334
1578 UBE1 GGGAGGAGGACAUCGGUAA NM_003334
1579 UBE1 CGGCAGUGAAGCAGACAUA NM_153280
1580 UBE1 GGUCAAGGCUGUUACCCUA NM_003334
1581 UBE1 CAGCAGAACUGGUAGCCUU NM_153280
1582 UBE1 UUUCAGAAGUACAGGGCAU NM_153280
1583 UBE1 CCUUCUACCUUGUUUGAAA NM_153280
1584 UBE1 CCUUAUACCUUUAGCAUCU NM_003334
1585 UBE1 GGAGGAGGACAUCGGUAAA NM_003334
1586 UBE1 GGAAAUCAGCCCAUGGAGA NM_003334
1587 UBE1 CCAUUGACUUUGAGAAGGA NM_153280
1588 UBE1 GAGAAAUCAUCGUUACAGA NM_153280
1589 UBE1 GCUAUGGUUUCUAUGGUUA NM_153280
1590 UBE1 AGUCAAAUCUGAAUCGACA NM_153280
1591 UBE1 UCAAAGUACCUAAGAAGAU NM_003334
1592 UBE1 AGAAGGAUGAUGACAGCAA NM_153280
1593 UBE1 CAGACAAGCUCCCUGGAUU NM_153280
1594 UBE1 GAAAUGAUCCUCACAGAUU NM_153280
1595 UBE1 GCGUGGAGAUCGCUAAGAA NM_003334
1596 UBE1 UCAAACAGUUCCUCGACUA NM_003334
1597 UBE1 CCUGAAUCCUAAUAAAGAA NM_153280
1598 UBE1 GGUCAAAGUACCUAAGAAG NM_153280
1599 UBE1 UGCAAGAGAAGCUGGGCAA NM_003334
1600 UBE1 UGGCCAAUGCCCUGGACAA NM_003334
1601 UBE1 CAGAAAAUGUCAACCAGUA NM_003334
1602 UBE1 GGGAUGAGUUUGAAGGCCU NM_153280
1603 UBE1 GGGAUGUCACGAAGUUAAA NM_153280
1604 UBE1 CGGCGAGGAUGUCGAGGUU NM_003334
1605 UBE1 GAGUGGACAUUGUGGGAUC NM_003334
1606 UBE1 GAAAUCAGCCCAUGGAGAU NM_153280
1607 UBE1C AGAGAGAGAUUAUGAGCAA NM_003968
1608 UBE1C GCGAGGAGCCGGAGAAGAA NM_003968
1609 UBE1C GCCUAAAGAUAUUGGAAGA NM_003968
1610 UBE1C AAUGAUACCUGGAGAGAGA NM_003968
1611 UBE1C CAUUUGAAGCAGAAAGAAA NM_198197
1612 UBE1C CAGAAGGUUUUAAAGGAAA NM_198197
1613 UBE1C ACAGAAGGUUUUAAAGGAA NM_003968
1614 UBE1C CAUUGGAGCUGGCGGCUUA NM_003968
1615 UBE1C UGAAGUUGCUGCAGAAUUU NM_003968
1616 UBE1C UACAGGAGGUUUUGGAUUA NM_003968
1617 UBE1C GCUAAGAAGUUGAAUCGAU NM_003968
1618 UBE1C GGAGCAGCCUUUUGGAGAA NM_003968
1619 UBE1C GCUGAAUACCUGUGCAUGA NM_003968
1620 UBE1C AAGCAGAAAGAAAGGAAAA NM_003968
1621 UBE1C GAAGCAGAAAGAAAGGAAA NM_003968
1622 UBE1C GCUGAUAUCUCUUCUAAAU NM_003968
1623 UBE1C CAAUAGUGCUUCUCUGCAA NM_003968
1624 UBE1C AGAGAGAGCAUCACAAUAU NM_003968
1625 UBE1C GGUGUUACGUAUAGGCUCA NM_198195
1626 UBE1C AGAUGAUCCUGAACAUAUA NM_003968
1627 UBE1C CAGCUAAACUACAGGAGGU NM_003968
1628 UBE1C GAAGAUGGAUAAAUGGCAU NM_003968
1629 UBE1C GGCUGAAGUUGCUGCAGAA NM_003968
1630 UBE1C GGUAACCUCUAUUGAAGAA NM_003968
1631 UBE1C GGAACCAUGUAAAGAAGUU NM_003968
1632 UBE1C AGAACACUGUAUUGAGUAU NM_003968
1633 UBE1C GCUGGAACCAUGUAAAGAA NM_003968
1634 UBE1C GAGAUGAUCCUGAACAUAU NM_003968
1635 UBE1C GAAGAAAAGAAGGAGAAUA NM_003968
1636 UBE1C GAAGAACGAACAAGGCCAA NM_198195
1637 UBE1DC1 GGACAAACAUGGAUGGAAU NM_024818
1638 UBE1DC1 GGAAGCAGCAGGAGGAAUA NM_024818
1639 UBE1DC1 GCUUAUAAUUCCUGGAGAA NM_198329
1640 UBE1DC1 AAUAAGUAAUGGUGGGUUA NM_198329
1641 UBE1DC1 ACAAGAAGAGGAAGAGAUA NM_024818
1642 UBE1DC1 GGUUAUACAAGAAGAGGAA NM_198329
1643 UBE1DC1 AAGAAGAGGAAGAGAUAAU NM_198329
1644 UBE1DC1 UGGAAGACCUCAUGGCCAA NM_198329
1645 UBE1DC1 AGGAAAACCUGUUGAUCUA NM_024818
1646 UBE1DC1 GCUCGAAUGACAAUAAAUA NM_198329
1647 UBE1DC1 GAACUAGCCAAUAUGAAUA NM_024818
1648 UBE1DC1 GGGAAUUGUAAGCGACUAU NM_024818
1649 UBE1DC1 AAGUAAAGUUCAAGCAGCA NM_024818
1650 UBE1DC1 ACAAGAGGUUAUACAAGAA NM_198329
1651 UBE1L CUGCAAAGCUGGAGGAGCA NM_003335
1652 UBE1L AGGAAGAGCCACUGGAAGA NM_003335
1653 UBE1L AGGAAGUGCUGAAGGCAAU NM_003335
1654 UBE1L CAGCACGGGUUGAGGGUGA NM_003335
1655 UBE1L CUUCGAAGCUACUGGAUGA NM_003335
1656 UBE1L UGGAAGAGCCACUGGAUGA NM_003335
1657 UBE1L GGACAGAGGAAGAGCCACU NM_003335
1658 UBE1L CCACAGAACUGGCAAGACU NM_003335
1659 UBE1L CCCAAGACUGUGAGACAUA NM_003335
1660 UBE1L CAGGAAGUGCUGAAGGCAA NM_003335
1661 UBE1L GGGCCUGAACCCAGACUUA NM_003335
1662 UBE1L UAAUAAAGUGCUUGAGGAU NM_003335
1663 UBE1L UCUCGGGAAUUGAGGGAAU NM_003335
1664 UBE1L GACCCAAGACUGUGAGACA NM_003335
1665 UBE1L CAUCUUUGCUAGUAAUCUA NM_003335
1666 UBE1L UGUCAUAAGCAUGGAGUUU NM_003335
1667 UBE1L GGGCAGUGCUACAGUAUUC NM_003335
1668 UBE1L AGCAGAAGGAACUGAACAA NM_003335
1669 UBE1L GGGCUAUCACUGAAGUCAA NM_003335
1670 UBE1L UGAACAAAGCCCUGGAAGU NM_003335
1671 UBE1L CUAAUAAAGUGCUUGAGGA NM_003335
1672 UBE1L GCAGGUGUCUUGAGCCCUA NM_003335
1673 UBE1L GAAUUGAGGGAAUGGUUGA NM_003335
1674 UBE1L CCUGGAGAUUGGAGACACA NM_003335
1675 UBE1L GCGAAUUGUGGGCCAGAUU NM_003335
1676 UBE1L CUACAGUAUUCAUGCCACA NM_003335
1677 UBE1L AUGGAGACUUGGUGACUUU NM_003335
1678 UBE1L CCAUGUGGACUUUGUGGUA NM_003335
1679 UBE1L CACAGUAGGCACUCAAUAA NM_003335
1680 UBE2A AUGCCAAGUUUCAGAAUUA NM_003336
1681 UBE2A CUAAAGGAGUACAGCAAUU NM_003336
1682 UBE2A GGAAUAUGGCCUACAGAGA NM_003336
1683 UBE2A GCAGAGGAAUGGAAACAAU NM_003336
1684 UBE2A GAACAAACGGGAAUAUGAA NM_003336
1685 UBE2A GGAAGGGAGCAUAGCAUAU NM_003336
1686 UBE2A GCAAGAAGGAGAAAGUUGA NM_003336
1687 UBE2A GUUGAAGGACUCAGCUAAA NM_003336
1688 UBE2A CAGGAGAACAAACGGGAAU NM_003336
1689 UBE2A GAGCAGAGGAAUGGAAACA NM_003336
1690 UBE2A CUAUGCAGAUGGUAGUAUA NM_003336
1691 UBE2A GGGAGCAGAGGAAUGGAAA NM_003336
1692 UBE2A AAUAUGGCCUACAGAGAAU NM_003336
1693 UBE2A AAUGAUUGCUGAAGUGUUU NM_003336
1694 UBE2A ACAAGUAACCCAUGUAAAA NM_003336
1695 UBE2A GAAUAUGGCCUACAGAGAA NM_003336
1696 UBE2A CAGCAAUUGUAGUAACUGA NM_003336
1697 UBE2A GUGAAUGUGUUUGGAAUAU NM_003336
1698 UBE2A GCAUAUCUGUGGCAAACUA NM_003336
1699 UBE2A GGAUGGAACAUUUAAACUU NM_003336
1700 UBE2A GAGAAUAGAAACAAAUCCA NM_003336
1701 UBE2A AAUAAACCACCUACAGUUA NM_003336
1702 UBE2A AGAACAAACGGGAAUAUGA NM_003336
1703 UBE2A AGCUGUACCAGGAGAACAA NM_003336
1704 UBE2A ACUCAAUUGUCCAUCUUUA NM_003336
1705 UBE2A AGUUAUUGCUGCAUGCUUU NM_003336
1706 UBE2A GCACAAGUAACCCAUGUAA NM_003336
1707 UBE2A CAAGAAGGAGAAAGUUGAA NM_003336
1708 UBE2A UCACUGAAGAAUAUCCAAA NM_003336
1709 UBE2A GAUACUAAGAUCUCAGUCA NM_003336
1710 UBE2B GAACAAAGCUGGAAUGAUU NM_003337
1711 UBE2B AUACAUAACUUCAGUGCAA NM_003337
1712 UBE2B CAAACGAGAAUAUGAGAAA NM_003337
1713 UBE2B AGGCUGAGGUGGCAGAAUA NM_003337
1714 UBE2B GGAGGGAAAUCUUGGUGUA NM_003337
1715 UBE2B CAAGAGACUUUGUCACUUA NM_003337
1716 UBE2B GGAAAACAAACGAGAAUAU NM_003337
1717 UBE2B CAUCUUAGUUUACUGGAUA NM_003337
1718 UBE2B GGCAAAGGCGGGAGGAUCA NM_003337
1719 UBE2B GCUUGUGUAUCUUGAUUAA NM_003337
1720 UBE2B AGACAUAACUGGUUUGACU NM_003337
1721 UBE2B GGUAGCAUAUGUUUAGAUA NM_003337
1722 UBE2B AGUUAUAUUUGGACCAGAA NM_003337
1723 UBE2B GCACAGCUUUAUCAGGAAA NM_003337
1724 UBE2B GCAGUGGAAUGCAGUUAUA NM_003337
1725 UBE2B GUAUUUAGGCCAUUUGUUA NM_003337
1726 UBE2B CAGGAAAACAAACGAGAAU NM_003337
1727 UBE2B ACACAGAGAACACAAAUUU NM_003337
1728 UBE2B ACAACAUCAUGCAGUGGAA NM_003337
1729 UBE2B GCACAUAUUGGAGGGAAAU NM_003337
1730 UBE2B GUUUAGAUAUCCUUCAGAA NM_003337
1731 UBE2B UAUCCUAUGCCUUCAAAUA NM_003337
1732 UBE2B GAGGGAAAUCUUGGUGUAA NM_003337
1733 UBE2B GAGUAAUUCUAGACAUAAC NM_003337
1734 UBE2B GAGCUGUGAUUAUGCCAUU NM_003337
1735 UBE2B GCACUUGCCUGUAGUCUCA NM_003337
1736 UBE2B GGGAGACGGGAUAGUGUUU NM_003337
1737 UBE2B ACUAAGUUAUUGCUGCAUA NM_003337
1738 UBE2B ACAAACGAGAAUAUGAGAA NM_003337
1739 UBE2B AGCAAUACCCUGUCUUUAA NM_003337
1740 UBE2C GGUAUAAGCUCUCGCUAGA NM_007019
1741 UBE2C AAGAAGUACCUGCAAGAAA NM_007019
1742 UBE2C CGGUUGAGCCCUUGUAUAU NM_007019
1743 UBE2C CCACAGCUUUUAAGAAGUA NM_007019
1744 UBE2C CCAUGGAGCAGCUGGAACA NM_007019
1745 UBE2C GGAGAACCCAACAUUGAUA NM_007019
1746 UBE2C GUAUAGGACUCUUUAUCUU NM_007019
1747 UBE2C CUGGAACAGUAUAUGAAGA NM_007019
1748 UBE2C UGGAGCAGCUGGAACAGUA NM_007019
1749 UBE2C UAAAUUAAGCCUCGGUUGA NM_007019
1750 UBE2C AGAAGUACCUGCAAGAAAC NM_007019
1751 UBE2C UUAAGAAGUACCUGCAAGA NM_007019
1752 UBE2C UAUCUUGAGCUGUGGUAUU NM_007019
1753 UBE2C GUUGAGCCCUUGUAUAUUA NM_007019
1754 UBE2C UGCAAGAAACCUACUCAAA NM_007019
1755 UBE2C CAGACAACCUUUUCAAAUG NM_007019
1756 UBE2C UAGGAGAACCCAACAUUGA NM_007019
1757 UBE2C CAAGAAACCUACUCAAAGC NM_181799
1758 UBE2C CAGCUGGAACAGUAUAUGA NM_007019
1759 UBE2C GCAAGAAACCUACUCAAAG NM_007019
1760 UBE2C GAGCAGCUGGAACAGUAUA NM_007019
1761 UBE2C GAGCCCUUGUAUAUUAAAU NM_007019
1762 UBE2C CGAGCGAGUUCCUGUCUCU NM_007019
1763 UBE2C GGACCAUUCUGCUCUCCAU NM_007019
1764 UBE2C GGUCUGCCCUGUAUGAUGU NM_007019
1765 UBE2C UACAAUGCGCCCACAGUGA NM_007019
1766 UBE2C UCUAGGAGAACCCAACAUU NM_007019
1767 UBE2C UAACAUAUGCCUGGACAUC NM_007019
1768 UBE2C ACAAUGCGCCCACAGUGAA NM_007019
1769 UBE2C GGUUGAGCCCUUGUAUAUU NM_007019
1770 UBE2D1 GAGAAUGGACUCAGAAAUA NM_003338
1771 UBE2D1 CAACAGACAUGCAAGAGAA NM_003338
1772 UBE2D1 GCAUUGAGAAAGACAUUUA NM_003338
1773 UBE2D1 CAGAAAGAAUUGAGUGAUC NM_003338
1774 UBE2D1 GGAAGUAUUUGUCUCGAUA NM_003338
1775 UBE2D1 GAAAGAAUUGAGUGAUCUA NM_003338
1776 UBE2D1 UUGUAUGCAUUGAGAAAGA NM_003338
1777 UBE2D1 CCAUGAAACCAUUUGAUUU NM_003338
1778 UBE2D1 CAGCUGGACCUGUGGGAGA NM_003338
1779 UBE2D1 CAUAAACAGUAAUGGAAGU NM_003338
1780 UBE2D1 AGGAAGAUGUGUAACUUUU NM_003338
1781 UBE2D1 CUAAGUAGGAAGAUGUGUA NM_003338
1782 UBE2D1 UGAAUUAAUUGCACUGCUA NM_003338
1783 UBE2D1 AGGAUAUUCUGUAGAUUGA NM_003338
1784 UBE2D1 GUAGAUUGAUUGCAGAUUU NM_003338
1785 UBE2D1 CUGAAAAGCAACCAAAUUA NM_003338
1786 UBE2D1 AAGAGAAUGGACUCAGAAA NM_003338
1787 UBE2D1 GCAAGAGAAUGGACUCAGA NM_003338
1788 UBE2D1 GCACAAAUCUAUAAAUCAG NM_003338
1789 UBE2D1 CAUCCAAACAUAAACAGUA NM_003338
1790 UBE2D1 AGAGAAUGGACUCAGAAAU NM_003338
1791 UBE2D1 AGUACCAGAUAUUGCACAA NM_003338
1792 UBE2D1 CCAUGGCGCUGAAGAGGAU NM_003338
1793 UBE2D1 GGAAGAUGUGUAACUUUUA NM_003338
1794 UBE2D1 CAACAUUAGCAGUAAAUUG NM_003338
1795 UBE2D1 UGUCUAAGAUGUCAGUUUU NM_003338
1796 UBE2D1 CCCAACGGCUGAUAAUUAA NM_003338
1797 UBE2D1 GAUCUACAAUGCAGCUGAA NM_003338
1798 UBE2D1 GAAAUGAUCUUUACACUGU NM_003338
1799 UBE2D1 CAAUGCAGCUGAAAAGCAA NM_003338
1800 UBE2D2 UGGAUAACCUCUACAAAUA NM_003339
1801 UBE2D2 GGGAAUGGACUCAGAAGUA NM_003339
1802 UBE2D2 CAGCAUUUGUCUUGAUAUU NM_003339
1803 UBE2D2 GAGAAAAGUACAACAGAAU NM_003339
1804 UBE2D2 CUAUCAGGGUGGAGUAUUU NM_003339
1805 UBE2D2 CAACAGAAUAGCUCGGGAA NM_003339
1806 UBE2D2 AGAGAAUCCACAAGGAAUU NM_003339
1807 UBE2D2 CUACAAAACAGAUAGAGAA NM_003339
1808 UBE2D2 GAAGAGAAUCCACAAGGAA NM_003339
1809 UBE2D2 AGAGAAAAGUACAACAGAA NM_003339
1810 UBE2D2 AGAAGUAUGCGAUGUAAUU NM_003339
1811 UBE2D2 GGAUAACCUCUACAAAUAA NM_003339
1812 UBE2D2 AAGAGAAUCCACAAGGAAU NM_003339
1813 UBE2D2 CAAAACAGAUAGAGAAAAG NM_003339
1814 UBE2D2 GGAAUGGACUCAGAAGUAU NM_003339
1815 UBE2D2 CUACAAUAAUGGGGCCAAA NM_003339
1816 UBE2D2 GGAGAUGAUAUGUUCCAUU NM_003339
1817 UBE2D2 CAAAAGUACUCUUGUCCAU NM_003339
1818 UBE2D2 ACAAGGAAUUGAAUGAUCU NM_003339
1819 UBE2D2 UGAAGAGAAUCCACAAGGA NM_003339
1820 UBE2D2 UUGGAUAACCUCUACAAAU NM_003339
1821 UBE2D2 CAGAAUAGCUCGGGAAUGG NM_181838
1822 UBE2D2 GAAAAGUACAACAGAAUAG NM_003339
1823 UBE2D2 GCUCGGGAAUGGACUCAGA NM_003339
1824 UBE2D2 CAAUCCAGAUGAUCCUUUA NM_003339
1825 UBE2D2 GCAUUUGUCUUGAUAUUCU NM_003339
1826 UBE2D2 GAAGUAUGCGAUGUAAUUA NM_003339
1827 UBE2D2 CACAAGGAAUUGAAUGAUC NM_003339
1828 UBE2D2 CAGCACUAACUAUUUCAAA NM_003339
1829 UBE2D2 GGCAGCAUUUGUCUUGAUA NM_003339
1830 UBE2D3 UGGCAGAGCUGGUGUGAGA NM_003340
1831 UBE2D3 GCUCUAACAUGCUGAAGAA NM_003340
1832 UBE2D3 GAGCAUACACCGAGAGAGU NM_003340
1833 UBE2D3 GCUUGGAGCUAUUAGUUAA NM_003340
1834 UBE2D3 GGAAAUUGGAAGUCAAACA NM_003340
1835 UBE2D3 AGAGAUAAGUACAACAGAA NM_003340
1836 UBE2D3 GAGAUAAGUACAACAGAAU NM_003340
1837 UBE2D3 GCGCUGAAACGGAUUAAUA NM_003340
1838 UBE2D3 GAACAGAAAAUGUGAUGUA NM_003340
1839 UBE2D3 GCAUACACCGAGAGAGUGA NM_003340
1840 UBE2D3 GUGAGGAGCCAGACGACAA NM_003340
1841 UBE2D3 AAAUGGAGCAUGUGUAUUA NM_003340
1842 UBE2D3 CCGGGAUAAUCAAGAGUUU NM_003340
1843 UBE2D3 CUGAAUAAAUGAUGCAAGU NM_003340
1844 UBE2D3 CAACAGAAUAUCUCGGGAA NM_181887
1845 UBE2D3 GAUGAGUGAUCAACUAAUA NM_003340
1846 UBE2D3 GAUUUGAGGUUACAUGAUA NM_003340
1847 UBE2D3 CAGCAUUUGUCUCGAUAUU NM_003340
1848 UBE2D3 GAGAAUGGAAAUUGGAAGU NM_003340
1849 UBE2D3 AUCAAAGGAUACAGCAUUA NM_003340
1850 UBE2D3 GAAACGGAUUAAUAAGGAA NM_003340
1851 UBE2D3 GCAAGUUGUCAAUGGAUGA NM_003340
1852 UBE2D3 UGUUAGAGAUUUGAGGUUA NM_003340
1853 UBE2D3 CAGACAGAGAUAAGUACAA NM_181886
1854 UBE2D3 AAACAGACAGAGAUAAGUA NM_003340
1855 UBE2D3 GGUUACAUGAUAUGCUUUA NM_003340
1856 UBE2D3 CAUCAAAGGAUACAGCAUU NM_003340
1857 UBE2D3 CUAACAUGCUGAAGAAAUC NM_003340
1858 UBE2D3 UGAUAUGUUUCAUUGGCAA NM_181888
1859 UBE2E1 CCAAGAAGAAGGAGAGUAA NM_003341
1860 UBE2E1 GAGCAAACCGAGAAAGAAA NM_182666
1861 UBE2E1 GUGAAAACCUGUAGUGAAA NM_003341
1862 UBE2E1 GAGCAGAACAUGACAGAAU NM_182666
1863 UBE2E1 GGUUCUAUGUUGUGGACUA NM_003341
1864 UBE2E1 UGUCAUUAGUUCUGCAAUA NM_003341
1865 UBE2E1 CGGAGGAGCCAGACACAAA NM_003341
1866 UBE2E1 AGAGAUGAGUAGUGCGUUU NM_003341
1867 UBE2E1 GGUAAAGAGUAGGGUAUUU NM_003341
1868 UBE2E1 GCUUGGACAUAUUGAAAGA NM_003341
1869 UBE2E1 AGAAGGAGCUGGCGGACAU NM_003341
1870 UBE2E1 GACAGUGGACCAAGAGAUA NM_003341
1871 UBE2E1 GGAAGGGAACAUUGAUAUU NM_003341
1872 UBE2E1 CCAUAUAAGAGAUGAGUAG NM_003341
1873 UBE2E1 GCUUGUAGUCUGUAAAUUU NM_003341
1874 UBE2E1 UGAAAUACCUUAAGCUGUU NM_003341
1875 UBE2E1 UGAAUCAGGACUUGUGAAA NM_003341
1876 UBE2E1 CCAAGAGAAUUCAGAAGGA NM_003341
1877 UBE2E1 GAGGGUGGGAGUUGGUAAA NM_003341
1878 UBE2E1 AAACCGAGAAAGAAACAAA NM_003341
1879 UBE2E1 GUAAAGUCAGCAUGAGCAA NM_003341
1880 UBE2E1 GAAAACCUGUAGUGAAAUA NM_003341
1881 UBE2E1 GAGAUACGCUACAUAAAUU NM_003341
1882 UBE2E1 GGGAGUUGGUAAAGAGUAG NM_003341
1883 UBE2E1 GAAGAGAGCUGCUUAUGAU NM_003341
1884 UBE2E1 GAGUAGGGUAUUUCUAUAA NM_003341
1885 UBE2E1 CAACCAGCAAACCGAGAAA NM_003341
1886 UBE2E1 GAGAGUAAAGUCAGCAUGA NM_003341
1887 UBE2E1 AAGAAGGAGAGUAAAGUCA NM_182666
1888 UBE2E1 CAAGAGAUACGCUACAUAA NM_182666
1889 UBE2E3 AAGAACAAGAGGAAAGAAA NM_006357
1890 UBE2E3 AUAUGAAGGUGGUGUGUUU NM_006357
1891 UBE2E3 GAGCAGAACACGACAGGAU NM_006357
1892 UBE2E3 ACCAAGAUGUCCAGUGAUA NM_006357
1893 UBE2E3 AGAAGGAGCUAGCUGAAAU NM_006357
1894 UBE2E3 GGUAAAUGCUAUCAAGAGU NM_006357
1895 UBE2E3 AGAGAUAACUUCACCAAGA NM_006357
1896 UBE2E3 CUGAAGAACAAGAGGAAAG NM_182678
1897 UBE2E3 AAGCAUAGCCACUCAGUAU NM_006357
1898 UBE2E3 ACACCAAACUCUCUAGCAA NM_006357
1899 UBE2E3 UGUAUUAAACCCAGAUCUA NM_006357
1900 UBE2E3 GCCUGAAGAACAAGAGGAA NM_182678
1901 UBE2E3 CAAGAGAUACGCAACAUAA NM_006357
1902 UBE2E3 CAAUAAACAUGCUCCUGAA NM_006357
1903 UBE2E3 GAAGGAGCUAGCUGAAAUA NM_006357
1904 UBE2E3 GCUAUCAAGAGUAGAACUU NM_006357
1905 UBE2E3 GGCAAAGGUCCGAUGAUGA NM_006357
1906 UBE2E3 GCAAAUCUUUAUAGCCUUU NM_006357
1907 UBE2E3 CCUAAAGGAGAUAACAUUU NM_006357
1908 UBE2E3 CUCCAGAGCCUGAAGAACA NM_006357
1909 UBE2E3 CCAAGAGAUACGCAACAUA NM_006357
1910 UBE2E3 GCCUAAAGGAGAUAACAUU NM_006357
1911 UBE2E3 UGAAAUAACCCUUGAUCCU NM_006357
1912 UBE2E3 GUAAAUGCUAUCAAGAGUA NM_006357
1913 UBE2E3 AGAACAAGAGGAAAGAAAA NM_182678
1914 UBE2E3 CACCAAACUCUCUAGCAAA NM_006357
1915 UBE2E3 GCAGUGUGAAGGAGCAGAA NM_006357
1916 UBE2E3 ACUCAGUAUUUGACCAACA NM_006357
1917 UBE2G1 GAGAAGUGGUUUAGGAAAA NM_003342
1918 UBE2G1 GGAUAGAACUUGAGACAGU NM_003342
1919 UBE2G1 GGAAGUAGUCUUUGGCUUA NM_003342
1920 UBE2G1 GGGAAGAUAAGUAUGGUUA NM_003342
1921 UBE2G1 ACAAAGAAAUUGCGAUGUA NM_003342
1922 UBE2G1 CUACUUAACUUCUGGGUUU NM_003342
1923 UBE2G1 GCACCCAAAUGUUGAUAAA NM_003342
1924 UBE2G1 GGAAGAUAGAAAUGGAGAA NM_003342
1925 UBE2G1 GGGUAAAUGCUUUGCUAUU NM_003342
1926 UBE2G1 GGUGUUUGAUUGUGAGAAU NM_003342
1927 UBE2G1 GAUUAAUGUUUGAGCUUCA NM_003342
1928 UBE2G1 GUAUAGAUCCCGUCACUAA NM_003342
1929 UBE2G1 CAAUAAAACAUGCCAGUUA NM_003342
1930 UBE2G1 GAGAAAUGCUUUGGCAGAA NM_003342
1931 UBE2G1 GUGGAAACCAUCAUGAUUA NM_003342
1932 UBE2G1 GAAGAUAGAAAUGGAGAAU NM_003342
1933 UBE2G1 GGAACUGGGCUGCAAUAAA NM_003342
1934 UBE2G1 GCAGAAGAGUGAAAGAACU NM_003342
1935 UBE2G1 UAAUGUUGAUGCUGCGAAA NM_003342
1936 UBE2G1 UCAUGUACAUCCACAAAUA NM_003342
1937 UBE2G1 GGGAAGAUAGAAAUGGAGA NM_003342
1938 UBE2G1 GUACAUAGCACAACAUGAU NM_003342
1939 UBE2G1 AGAGACUGCUUUUGAGUGA NM_003342
1940 UBE2G1 GCUAGUAACUUCACUUAUU NM_003342
1941 UBE2G1 GCACAACAUGAUCCGGAUA NM_003342
1942 UBE2G1 AUGCACAGCUACAGGCUUU NM_003342
1943 UBE2G1 GUUGAUUCCUUAUGCAAAU NM_003342
1944 UBE2G1 GCUACAGGCUUUCUACUUA NM_003342
1945 UBE2G1 AAUGGAGGGAAGAUAGAAA NM_003342
1946 UBE2G1 CCAGAGAAGUGGUUUAGGA NM_003342
1947 UBE2G2 ACAAAGGGCUUCAGGUAGA NM_003343
1948 UBE2G2 GAUCACAAGGUCAGGAAAU NM_003343
1949 UBE2G2 CCAUGAAUGAAGAGAACUU NM_003343
1950 UBE2G2 UCACAAAGGGCUUCAGGUA NM_003343
1951 UBE2G2 GAAAUGGGGUAAAUAGAAA NM_003343
1952 UBE2G2 GCUCUGUGCUGGUACCAAA NM_003343
1953 UBE2G2 UGACGAAAGUGGAGCUAAC NM_003343
1954 UBE2G2 UUACAAACCAUCACACUUA NM_003343
1955 UBE2G2 GGCCAAGGCAGGUAGAUCA NM_003343
1956 UBE2G2 UUACAGUAUUCCUCACAAA NM_003343
1957 UBE2G2 CCAAGCAGAUCGUCCAGAA NM_003343
1958 UBE2G2 GAGAUUUACCUGUGAGAUG NM_003343
1959 UBE2G2 GGCAGAUGCUUUUCUUAUA NM_003343
1960 UBE2G2 GGGAGCAGUUCUAUAAGAU NM_003343
1961 UBE2G2 GCAGAUGCUUUUCUUAUAA NM_003343
1962 UBE2G2 GCGAUGACCCCAUGGGCUA NM_182688
1963 UBE2G2 ACAGCUUACUGCAGUUUUA NM_003343
1964 UBE2G2 GUCAGGAAAUUGAGACCAU NM_003343
1965 UBE2G2 CAAGGCAGGUAGAUCACAA NM_003343
1966 UBE2G2 UGGCAGAGCCCAAUGACGA NM_182688
1967 UBE2G2 GCGAUGACCGGGAGCAGUU NM_003343
1968 UBE2G2 CCACUUGAUUACCCGUUAA NM_182688
1969 UBE2G2 GGCAACAGAGCGAGACUCA NM_003343
1970 UBE2G2 GAUCAUGGGCCCAGAAGAC NM_182688
1971 UBE2G2 GAGCAGUUCUAUAAGAUUG NM_003343
1972 UBE2G2 ACCAUCACACUUAGAAAUA NM_003343
1973 UBE2G2 CAACAGAGCGAGACUCAGU NM_003343
1974 UBE2G2 CAUCACACUUAGAAAUACU NM_003343
1975 UBE2G2 GGUUGUACCUGCCAGACUU NM_003343
1976 UBE2G2 GGAGCAGUUCUAUAAGAUU NM_182688
1977 UBE2H GGAAAUAGCCGCUCUGAUA NM_003344
1978 UBE2H AAGAGUACAUCCAGAAAUA NM_003344
1979 UBE2H GGACAGCACAGGAGGAGAA NM_003344
1980 UBE2H GAUAGGUAGAUGUGAGUAA NM_003344
1981 UBE2H CAGAAGAAUACAAGCAGAA NM_003344
1982 UBE2H GGGAGGACUUAAUGAAUUU NM_003344
1983 UBE2H CGGAGGAGGCGCUGAAAGA NM_003344
1984 UBE2H CAUGAGAAGCAGACUAUAA NM_003344
1985 UBE2H GGCAAGAGGCGGAUGGACA NM_003344
1986 UBE2H AAGAUGAGGCCCAGGAUAU NM_003344
1987 UBE2H ACUGAACUGUCGAAGGAAA NM_003344
1988 UBE2H UUAGAAAGGUUGCAGAUUU NM_003344
1989 UBE2H GGGAGCUAAUUAAGAGUAU NM_003344
1990 UBE2H UCAAGCUCAUCGAGAGUAA NM_003344
1991 UBE2H GUAUAAAGCAGGGAGCUAA NM_003344
1992 UBE2H AUAUGGAGUUGUAGUAGAA NM_003344
1993 UBE2H GCAGAAAAUUAAAGAGUAC NM_003344
1994 UBE2H CCAGAAGAAUACAAGCAGA NM_003344
1995 UBE2H GAAGAUGAGGCCCAGGAUA NM_003344
1996 UBE2H CCAAUAUAUUUGAGUCCUU NM_182697
1997 UBE2H CGCUGAAAGAACAGGAAGA NM_003344
1998 UBE2H GAUAUGGAGUUGUAGUAGA NM_003344
1999 UBE2H GAGAAGCAGACUAUAAUAU NM_003344
2000 UBE2H GAAGAAUACAAGCAGAAAA NM_182697
2001 UBE2H GAGAGUAAACAUGAGGUUA NM_003344
2002 UBE2H CUACUGAACUGUCGAAGGA NM_003344
2003 UBE2H GAGUGGACCUACCUGAUAA NM_182697
2004 UBE2H UGGGAGGACUUAAUGAAUU NM_182697
2005 UBE2H AGAAAUACGCCACGGAGGA NM_182697
2006 UBE2H AGUUAUUGGCCUAUCCUAA NM_003344
2007 UBE2I GAGGAAAGCAUGGAGGAAA NM_003345
2008 UBE21 GGGAAGGAGGCUUGUUUAA NM_003345
2009 UBE21 CCAUCUUAGAGGAGGACAA NM_194260
2010 UBE2I GAAAAGGGUCCGAGCACAA NM_003345
2011 UBE2I GAGCACAAGCCAAGAAGUU NM_003345
2012 UBE2I AGGAAAGCAUGGAGGAAAG NM_003345
2013 UBE2I GGAGGAACGUGUGGAGUUU NM_003345
2014 UBE2I AAUCUAAAGUUGCUCCAUA NM_003345
2015 UBE2I CAGCUCAAGCAGAGGCCUA NM_003345
2016 UBE2I GAAUACAGGAACUUCUAAA NM_003345
2017 UBE2I CAGAGUGGAGUACGAGAAA NM_003345
2018 UBE2I GCAGAGGCCUACACGAUUU NM_003345
2019 UBE2I GGGCCUGUGUCUUGGACUU NM_003345
2020 UBE2I ACAGGAACUUCUAAAUGAA NM_003345
2021 UBE2I GGAUCUGUGUUUGGUGAAA NM_003345
2022 UBE2I AGAGGAAAGCAUGGAGGAA NM_003345
2023 UBE2I CUGUGUUGCUGUUUAGGUA NM_003345
2024 UBE2I GAGGAAAGACCACCCAUUU NM_003345
2025 UBE2I GGAAGGAGGCUUGUUUAAA NM_003345
2026 UBE2I UAAAGUUGCUCCAUACAAU NM_003345
2027 UBE2I AGAAGGAAGGGAUUGGUUU NM_003345
2028 UBE2I GGGAUUGGUUUGGCAAGAA NM_003345
2029 UBE2I UGGAGGAACGUGUGGAGUU NM_003345
2030 UBE2I ACAGAGUGGAGUACGAGAA NM_194259
2031 UBE2I GCCAAAACAGAGUGGAGUA NM_194259
2032 UBE2I GCCCAGGAGAGGAAAGCAU NM_194259
2033 UBE2I GGAGGAAAGACCACCCAUU NM_194260
2034 UBE2I AAGCAGAGGCCUACACGAU NM_003345
2035 UBE2I GAGAGGAAAGCAUGGAGGA NM_194259
2036 UBE2I UAUCCAAGACCCAGCUCAA NM_194259
2037 UBE2J1 UGUAGAAUGUAUAGGGAUA NM_016021
2038 UBE2J1 GAGUAUAAGGACAGCAUUA NM_016336
2039 UBE2J1 AAGAAGAGCACUUGCCAAA NM_016336
2040 UBE2J1 GCAAAUAAGCUUUAAGGCA NM_016021
2041 UBE2J1 GCUUUAAGGCAGAAGUCAA NM_016021
2042 UBE2J1 CAGCCUUCGUGGAGUAUAA NM_016021
2043 UBE2J1 UGAAAGAAGCGGCAGAAUU NM_016021
2044 UBE2J1 CCAAAGAACUGGCUAGGCA NM_016021
2045 UBE2J1 GAAUAUAUCUGGCAAACGA NM_016021
2046 UBE2J1 GAGAAUUACUAGUUACUCA NM_016336
2047 UBE2J1 GGGUAUAAUCUAAGAAUUG NM_016336
2048 UBE2J1 GUAUAGGGAUAGAAGAGUU NM_016021
2049 UBE2J1 CGACGAAUAUAUCUGGCAA NM_016021
2050 UBE2J1 AAAUAAGCUUUAAGGCAGA NM_016021
2051 UBE2J1 UAGGAGAUGUACUGGAAUU NM_016021
2052 UBE2J1 CUAUAUUGCCCUUUGAAAU NM_016336
2053 UBE2J1 CAGAGAAGGUUGUCUACUU NM_016021
2054 UBE2J1 CAGCAGAGUCAGAGAAGGU NM_016021
2055 UBE2J1 CAUAGGAGAUGUACUGGAA NM_016021
2056 UBE2J1 CCUAAACAUUCUUCAGUGA NM_016021
2057 UBE2J1 AAGCAAAACUCCUCAAGUA NM_016021
2058 UBE2J1 GUCAAACAUUUAUGAGGAA NM_016021
2059 UBE2J1 GAAUGGCACUUCACGGUUA NM_016336
2060 UBE2J1 AGUCAGAGAAGGUUGUCUA NM_016021
2061 UBE2J1 CCAUAGGUUCUCUAGAUUA NM_016021
2062 UBE2J1 GAAAGAAGCGGCAGAAUUG NM_016021
2063 UBE2J1 CAAAUAAGCUUUAAGGCAG NM_016021
2064 UBE2J1 GGCUAAUGGUCGAUUUGAA NM_016021
2065 UBE2J1 UGGCAGCCUUCGUGGAGUA NM_016021
2066 UBE2J1 GCUAAGAAUACCUCCAUGA NM_016021
2067 UBE2J2 ACAGAAAGCACAAGACGAA NM_058167
2068 UBE2J2 GCUCCUAGGUUUAGCUUUU NM_058167
2069 UBE2J2 UCAGUGAGUUGAAAGGAAA NM_058167
2070 UBE2J2 CUGAAGUCGUGGAGGAGAU NM_194457
2071 UBE2J2 GUUGAAAGGAAAUGUGUUU NM_058167
2072 UBE2J2 UAUUAGAUGUGGUCACUUA NM_058167
2073 UBE2J2 ACAAAUGUGUUUACAGUCA NM_058167
2074 UBE2J2 GUAUAGAGACGUCGGACUU NM_058167
2075 UBE2J2 CCACCAGGCUCCUAGGUUU NM_058167
2076 UBE2J2 GUGGAGGAGAUUAAACAAA NM_194458
2077 UBE2J2 GUGCUGGAUUUGUAGCUUA NM_058167
2078 UBE2J2 CGAACUUGUUUGUGAUAGU NM_194458
2079 UBE2J2 AAGUCGUGGAGGAGAUUAA NM_058167
2080 UBE2J2 CAGAGAAUUUCCUUUCAAA NM_194315
2081 UBE2J2 GUGCAGAGUUUAGCAUUUA NM_194457
2082 UBE2J2 AGUGCAGAGUUUAGCAUUU NM_058167
2083 UBE2J2 GGGUUUGGUCUCAGCAUUU NM_058167
2084 UBE2J2 ACGGGAGGUUUAAGUGCAA NM_194457
2085 UBE2J2 UGGAGGAGAUUAAACAAAA NM_194458
2086 UBE2J2 UGGCUAUUAUCAUGGAAAA NM_058167
2087 UBE2J2 CACCAGGCUCCUAGGUUUA NM_058167
2088 UBE2J2 UGAGCUUCAUGGUGGAGAA NM_058167
2089 UBE2J2 GCACAAGACGAACUCAGUA NM_058167
2090 UBE2J2 GGCCUUGUGUGCUGGAUUU NM_058167
2091 UBE2J2 GUGUUUACAGUCAGAAUGA NM_058167
2092 UBE2J2 UUAUGAAGGUGGCUAUUAU NM_058167
2093 UBE2J2 AGACGAACUCAGUAGCAGA NM_194315
2094 UBE2J2 GUGGCUAUUAUCAUGGAAA NM_194316
2095 UBE2J2 CCAGAGAAUUUCCUUUCAA NM_194315
2096 UBE2J2 CCCAGUAUCUAUAUGAUCA NM_194458
2097 UBE2L3 CCUCAGUUCUUGUGUGAAA NM_003347
2098 UBE2L3 UGAAGGAGCUUGAAGAAAU NM_003347
2099 UBE2L3 UAAGAAUGCUGAAGAGUUU NM_003347
2100 UBE2L3 GCUGAAGAGUUUACAAAGA NM_003347
2101 UBE2L3 CCGCAAAUGUGGGAUGAAA NM_003347
2102 UBE2L3 UGAUGAAUCUCGCCAGAAA NM_003347
2103 UBE2L3 ACAAAGAAAUAUGGGGAAA NM_003347
2104 UBE2L3 CUGAAGAGUUUACAAAGAA NM_003347
2105 UBE2L3 GAAAAGUGAUGAUGGAUUU NM_003347
2106 UBE2L3 CCAGAAUGUCCGUUUGAAA NM_003347
2107 UBE2L3 GUGGAGAAGAUGACUUAAA NM_003347
2108 UBE2L3 GAUGAAGGAGCUUGAAGAA NM_198157
2109 UBE2L3 GACUAGAUCCUGUGGAGAA NM_003347
2110 UBE2L3 CAGAGAAGCCCUAUAAUCA NM_003347
2111 UBE2L3 GCACAGAGAAGCCCUAUAA NM_003347
2112 UBE2L3 CCACCGAAGAUCACAUUUA NM_003347
2113 UBE2L3 GCAGAAAAGUGAUGAUGGA NM_003347
2114 UBE2L3 CCUCAUAGCACUGGUGAAU NM_003347
2115 UBE2L3 GUAAGAAUGCUGAAGAGUU NM_003347
2116 UBE2L3 UGACCUAGCUGAAGAAUAC NM_003347
2117 UBE2L3 CCUUCAGAAUCGAAAUCAA NM_003347
2118 UBE2L3 GAGAAGAUGACUUAAACUU NM_003347
2119 UBE2L3 GCAGGAGGCUGAUGAAGGA NM_003347
2120 UBE2L3 GCCAGUAAUUAGUGCCGAA NM_003347
2121 UBE2L3 GGGCUGACCUAGCUGAAGA NM_003347
2122 UBE2L3 ACCCAAACAUCGACGAAAA NM_003347
2123 UBE2L3 AAGCAGGACUCUGUGGAAA NM_003347
2124 UBE2L3 GCUUGAAGAAAUCCGCAAA NM_003347
2125 UBE2L3 CCAGGUUGAUGAAGCUAAU NM_003347
2126 UBE2L3 GGUUGAUGAAGCUAAUUUA NM_003347
2127 UBE2L6 GGACGAGAACGGACAGAUU NM_004223
2128 UBE2L6 GUGAAUAGACCGAAUAUCA NM_004223
2129 UBE2L6 UGAAGGAGCUGGAGGAUCU NM_004223
2130 UBE2L6 CCUCAGACUGUGAAGUAUA NM_004223
2131 UBE2L6 GAAAGAAUGCCGAAGAGUU NM_004223
2132 UBE2L6 AAACCAUGUUCUUGCUUAA NM_004223
2133 UBE2L6 GAGUUUAAGUUUGCAGUUA NM_004223
2134 UBE2L6 CUUCUUAGGUUGUUAGUCA NM_004223
2135 UBE2L6 GGUUGUUAGUCAUUAGUUU NM_004223
2136 UBE2L6 GCACUGGAUCCUCGGCAUA NM_004223
2137 UBE2L6 AGUGAGAACUGGAAGCCUU NM_004223
2138 UBE2L6 GAGUGUGUGUGUUGUGUAU NM_004223
2139 UBE2L6 GUCACAAUCUGAAGAAUCA NM_004223
2140 UBE2L6 AUCCGGAGCUGUUCAGAAA NM_004223
2141 UBE2L6 UGAUGGGAAUAUACAGAUU NM_004223
2142 UBE2L6 CCGGAGCUGUUCAGAAAGA NM_004223
2143 UBE2L6 GCUGGUGAAUAGACCGAAU NM_004223
2144 UBE2L6 GUUCAGAAAGAAUGCCGAA NM_004223
2145 UBE2L6 GUUUAAGUUUGCAGUUACA NM_004223
2146 UBE2L6 UCAGAAAGAAUGCCGAAGA NM_004223
2147 UBE2L6 CCAAGCCACUGAUGGGAAU NM_004223
2148 UBE2L6 AAAGAAUGCCGAAGAGUUC NM_004223
2149 UBE2L6 GGCCUCAGACUGUGAAGUA NM_004223
2150 UBE2L6 UGAUCAAAUUCACAACCAA NM_004223
2151 UBE2L6 GGACCAGGCCUCAGACUGU NM_004223
2152 UBE2L6 GAAACCAUGUUCUUGCUUA NM_004223
2153 UBE2L6 CAUCAUCAGCAGUGAGAAC NM_004223
2154 UBE2L6 GCAUGCGAGUGGUGAAGGA NM_004223
2155 UBE2L6 GGAGCUGUUCAGAAAGAAU NM_004223
2156 UBE2L6 GUAUAUAUCCUCCAGCAUU NM_004223
2157 UBE2M ACAUUGACCUCGAGGGCAA NM_003969
2158 UBE2M CAGAGGUCCUGCAGAACAA NM_003969
2159 UBE2M CCGAGGACCCACUGAACAA NM_003969
2160 UBE2M GGAAGUUUGUGUUCAGUUU NM_003969
2161 UBE2M AGGUGAAGUGUGAGACAAU NM_003969
2162 UBE2M CUACAAGAGUGGGAAGUUU NM_003969
2163 UBE2M GGAUCCAGAAGGACAUAAA NM_003969
2164 UBE2M GAAAUAGGGUUGGCGCAUA NM_003969
2165 UBE2M CUGCCCAAGACGUGUGAUA NM_003969
2166 UBE2M UUAAGGUGGGCCAGGGUUA NM_003969
2167 UBE2M AGAAGAAGGAGGAGGAGUC NM_003969
2168 UBE2M AGCCAGUCCUUACGAUAAA NM_003969
2169 UBE2M GAUGAGGGCUUCUACAAGA NM_003969
2170 UBE2M AGGACAUAAACGAGCUGAA NM_003969
2171 UBE2M CAAGGUGAAGUGUGAGACA NM_003969
2172 UBE2M CUGCGGAUCCAGAAGGACA NM_003969
2173 UBE2M AAGCCAGUCCUUACGAUAA NM_003969
2174 UBE2M GAAGCCAGUCCUUACGAUA NM_003969
2175 UBE2M GAGCUGAACCUGCCCAAGA NM_003969
2176 UBE2M CAGACGACCUCCUCAACUU NM_003969
2177 UBE2M GCACCAAGGGCAGCAGCAA NM_003969
2178 UBE2M GCCUCAACAUCCUCAGAGA NM_003969
2179 UBE2M UGAAGCAGCAGAAGAAGGA NM_003969
2180 UBE2M AAAUAGGGUUGGCGCAUAC NM_003969
2181 UBE2M GAUAUCAGCUUCUCAGAUC NM_003969
2182 UBE2M GCCCAAGACGUGUGAUAUC NM_003969
2183 UBE2M UAAUUUAUGGCCUGCAGUA NM_003969
2184 UBE2M GGACAUAAACGAGCUGAAC NM_003969
2185 UBE2M CCACGUGCCCCUAGUUAUU NM_003969
2186 UBE2M UUUAACACCAGGCUAACUA NM_003969
2187 UBE2N CAACGAAGCCCAAGCCAUA NM_003348
2188 UBE2N GGACACAGUCUUAGAAACA NM_003348
2189 UBE2N GGCUAUAUGCCAUGAAUAA NM_003348
2190 UBE2N AGACAAGUUGGGAAGAAUA NM_003348
2191 UBE2N GAAGGUAGUUGUCAGGUUA NM_003348
2192 UBE2N CAUCUGGAUUGUUGUGAAA NM_003348
2193 UBE2N CAUCCUGGUUUAAGUAUAA NM_003348
2194 UBE2N GGGAGGUAGUUUAAUUUUA NM_003348
2195 UBE2N CCGAACCAGAUGAGAGCAA NM_003348
2196 UBE2N CAGAUGAUCCAUUAGCAAA NM_003348
2197 UBE2N GGACUAGGCUAUAUGCCAU NM_003348
2198 UBE2N GUAGACAAGUUGGGAAGAA NM_003348
2199 UBE2N UAUAAAGCACUGUGAAUGA NM_003348
2200 UBE2N GCAUCAAAGCCGAACCAGA NM_003348
2201 UBE2N CAUCAAAGCCGAACCAGAU NM_003348
2202 UBE2N GGGAGGGACUUUUAAACUU NM_003348
2203 UBE2N GGGAAGAAUAUGUUUAGAU NM_003348
2204 UBE2N ACACAGUCUUAGAAACAUU NM_003348
2205 UBE2N UCUGGAAACUUCUGUAAAU NM_003348
2206 UBE2N CCAGAUGAUCCAUUAGCAA NM_003348
2207 UBE2N CUAAUAACAUUGCUGUCAA NM_003348
2208 UBE2N AGCCCAAGCCAUAGAAACA NM_003348
2209 UBE2N CAAAUGAUGUAGCGGAGCA NM_003348
2210 UBE2N CCAUCCUGGUUUAAGUAUA NM_003348
2211 UBE2N GAUCUAAUUGCAUUGGUUA NM_003348
2212 UBE2N GAGCAGAGGCUAGAAGUAU NM_003348
2213 UBE2N UAACCAGGUCUUUAGAAUA NM_003348
2214 UBE2N AUAGAAACAGCUAGAGCAU NM_003348
2215 UBE2N AGAUGAUCCAUUAGCAAAU NM_003348
2216 UBE2N AACCAGGUCUUUAGAAUAU NM_003348
2217 UBE2Q AUGAAGGAGCUCAGGGAUA NM_017582
2218 UBE2Q CAGAAGACUUAGAUCACUA NM_017582
2219 UBE2Q CCAUAGAGUCAGUGAUCAU NM_017582
2220 UBE2Q AUGAAAUGAAAGAGGAAGA NM_017582
2221 UBE2Q CUAUGAAAUGAAAGAGGAA NM_017582
2222 UBE2Q CCAGAUCCUCAAAGAGAAA NM_017582
2223 UBE2Q UGGAGAGGCUGGUGGACAU NM_017582
2224 UBE2Q CCUCAAAGAGAAAGAAGGA NM_017582
2225 UBE2Q AAGAUGAAGAUGAGGAGAU NM_017582
2226 UBE2Q GCUGGUGGACAUAAAGAAA NM_017582
2227 UBE2Q AGAUGAUGGCAUUGGAAAA NM_017582
2228 UBE2Q CUUAAAUGGUGCAGUGUCU NM_017582
2229 UBE2R2 GGAAAUGGAGAGACAGUAA NM_017811
2230 UBE2R2 CCACAACCCUGGCGGAAUA NM_017811
2231 UBE2R2 CAGUAAAGGAAAAGACAAA NM_017811
2232 UBE2R2 CGACAUUGAUGAUGAAGAU NM_017811
2233 UBE2R2 GGAGAGACAGUAAAGGAAA NM_017811
2234 UBE2R2 GGAUCGAAAGCCUGAAAUA NM_017811
2235 UBE2R2 GCAUAUACUGGGUAGCAAA NM_017811
2236 UBE2R2 GUGCUAAGCCUGAUGAAAU NM_017811
2237 UBE2R2 AGACAAAGAAUAUGCUGAA NM_017811
2238 UBE2R2 AGGAAGAUGCCGACUGUUA NM_017811
2239 UBE2R2 AAGAUGAGGAGGAGGAAGA NM_017811
2240 UBE2R2 CCACUAAGGCCGAAGCAGA NM_017811
2241 UBE2R2 GAGAGACAGUAAAGGAAAA NM_017811
2242 UBE2R2 GUUCACAAGUGCUGCAUAU NM_017811
2243 UBE2R2 UCAGUUAUGUUCAGGAAAU NM_017811
2244 UBE2R2 GACCUUUAAUGGAGAGAGA NM_017811
2245 UBE2R2 UCUGAAAGGUGGAAUCCUA NM_017811
2246 UBE2R2 AGGUUUAGCUGCUCAUUUA NM_017811
2247 UBE2R2 GAUCGAAAGCCUGAAAUAA NM_017811
2248 UBE2R2 CAUCAGGGACUUUGUGCUA NM_017811
2249 UBE2R2 GAGUAACCCUCCACAGAAU NM_017811
2250 UBE2R2 GCGGAAUACUGCAUCAAAA NM_017811
2251 UBE2R2 CCUUCAGAUUCUUGACCAA NM_017811
2252 UBE2R2 UUAUGAGAAUGGAGAUGUA NM_017811
2253 UBE2R2 AUCGAAAGCCUGAAAUAAA NM_017811
2254 UBE2R2 UCGAAAGCCUGAAAUAAAU NM_017811
2255 UBE2R2 ACAGAAUGUUCACAGCAAA NM_017811
2256 UBE2R2 GUGGAAUCCUACUCAGAAU NM_017811
2257 UBE2R2 CCAUGAAACCAUCGUAACA NM_017811
2258 UBE2R2 GCUGAAAUUAUUAGGAAAC NM_017811
2259 UBE2S UGGAGAACUACGAGGAGUA NM_014501
2260 UBE2S GCAUCAAGGUCUUUCCCAA NM_014501
2261 UBE2S CCAAGAAGCAUGCUGGCGA NM_014501
2262 UBE2S UCAACGUGCUCAAGAGGGA NM_014501
2263 UBE2V2 GGAAAUAGGUGUAUGGAUA NM_003350
2264 UBE2V2 GGACAAACAUACAACAAUU NM_003350
2265 UBE2V2 GAUGAAAGCGUGUGGAGAA NM_003350
2266 UBE2V2 CUAAUGAUGUCCAAAGAAA NM_003350
2267 UBE2V2 GGAAGAACUUGAAGAAGGA NM_003350
2268 UBE2V2 CAGAAUAUAUAGCCUGAAA NM_003350
2269 UBE2V2 CGAAAUAGAAUUCAGGUUU NM_003350
2270 UBE2V2 GUGUACUUCUUGUGAAUUA NM_003350
2271 UBE2V2 AGUAGAAUGUGGACCUAAA NM_003350
2272 UBE2V2 AGUUGUACUUCAAGAGCUA NM_003350
2273 UBE2V2 CCUCAGAGACUGUGCCAUU NM_003350
2274 UBE2V2 GAGUUAAAGUUCCUCGUAA NM_003350
2275 UBE2V2 AAAGAGAGCUGCAGUUGAA NM_003350
2276 UBE2V2 AGUUAAAGUUCCUCGUAAU NM_003350
2277 UBE2V2 GUUCAGGAUUGUUUUGAUA NM_003350
2278 UBE2V2 GCACUGUCAUUUAAACAUA NM_003350
2279 UBE2V2 AGGCAUGAUUAUUGGGCCA NM_003350
2280 UBE2V2 GAAAUAGGUGUAUGGAUAU NM_003350
2281 UBE2V2 GUUGGAAGAACUUGAAGAA NM_003350
2282 UBE2V2 GAUGAAGAUAUGACACUUA NM_003350
2283 UBE2V2 AUAAAUAAUUCCAGUGGGA NM_003350
2284 UBE2V2 CCAAGGACAAAUUAUGAAA NM_003350
2285 UBE2V2 GCAUACCAGUGUUAGCAAA NM_003350
2286 UBE2V2 AAGCUGUUCUUGUGUGUUA NM_003350
2287 UBE2V2 CUGGACAUUUGUAAGAAUA NM_003350
2288 UBE2V2 AGAACUUGAAGAAGGACAA NM_003350
2289 UBE2V2 ACAGAAAUGGCAUGCUUUA NM_003350
2290 UBE2V2 CUUACAAGGUGGACAGGCA NM_003350
2291 UBE2V2 AAGCAUGUGUGUUUCUAAA NM_003350
2292 UBE2V2 AGUGGAAGCAUGUGUGUUU NM_003350
2293 UBE3A AGACAAAGAUGAAGAUGAA NM_000462
2294 UBE3A GUAGAGAAAGAGAGGAUUA NM_130838
2295 UBE3A CCUCAGAACUUUAGUAACA NM_130838
2296 UBE3A UAACAGAAGAGAAGGUAUA NM_130839
2297 UBE3A AAGUAGAAACAGAGAACAA NM_000462
2298 UBE3A GGAAUUUGAAGGAGAACAA NM_130839
2299 UBE3A GGGAGAAAUUGGAAUGUUU NM_130839
2300 UBE3A GUAAUUAAAGUGAGGAGAA NM_000462
2301 UBE3A GGAGAAGAAAGAAGAAACA NM_000462
2302 UBE3A CAACAAAGUUAGGAAGUUU NM_000462
2303 UBE3A CAAAUGAAAUGGUAGUCAA NM_000462
2304 UBE3A CAAGAAAGGCGCUAGAAUU NM_130839
2305 UBE3A AGCAAAAGAUGAAGACAAA NM_000462
2306 UBE3A AGGCAUUGGUACAGAGCUU NM_000462
2307 UBE3A GCACCAGUGUUAUUGGAAA NM_000462
2308 UBE3A GGAAGAAGACUCAGAAGCA NM_130838
2309 UBE3A GAAGAGAAGGUAUAUGAAA NM_130839
2310 UBE3A GUUCAAGGCUUUUCGGAGA NM_130839
2311 UBE3A UCAGAAGUUUGGCGAAAUA NM_130839
2312 UBE3A CAGUCGAAAUCUAGUGAAU NM_000462
2313 UBE3A GCGUGAAAGUGUUACAUAU NM_000462
2314 UBE3A UGAAUGAGGUUCUAGAAAU NM_000462
2315 UBE3A GAGAUGAUCGCUAUGGAAA NM_000462
2316 UBE3A AGAUGAAGACAAAGAUGAA NM_000462
2317 UBE3A GAAGAAAGAAGAAACAAGA NM_130838
2318 UBE3A GGUGAUUGAUUGAUUGAUU NM_130838
2319 UBE3A AUUAGGGAGUUCUGGGAAA NM_130839
2320 UBE3A CAAUGAAGAAGAUGAUGAA NM_000462
2321 UBE3A AAGCAAAAGAUGAAGACAA NM_000462
2322 UBE3A GCUCACAGGGAGACAACAA NM_130839
2323 UBE3B AAGAAAGGCUUGUGCAGAA NM_130466
2324 UBE3B GUGCAAAUAUAAUGGGACA NM_183415
2325 UBE3B GGAGAGAGAUUGAUGACUU NM_130466
2326 UBE3B CCACAGUCCUUCAGAGUUU NM_130466
2327 UBE3B CAAAGAGGAUAAUGAGAGA NM_130466
2328 UBE3B AGAGAUAUCAGGAGAGAGA NM_130466
2329 UBE38 GCACAGGGCUGCAGAAAAU NM_130466
2330 UBE3B GGAACAAACACUAACCUAA NM_130466
2331 UBE3B CCUACAUCCAUGAGAAUUA NM_130466
2332 UBE3B CAGAUGGGUUCGUGAGUUU NM_130466
2333 UBE3B GGAAACAUGGCAAGGAAUU NM_130466
2334 UBE3B UCAGAAUCAAAGAGGAUAA NM_130466
2335 UBE3B UGGAAGAGCUGGUCACUAU NM_130466
2336 UBE3B GGGAGAGAGUGAUUUAUAA NM_130466
2337 UBE3B GGAUGGAAUUGUAGAGAAC NM_183414
2338 UBE3B GGGAUGGAAUUGUAGAGAA NM_130466
2339 UBE3B GCAGAGAGAUAUCAGGAGA NM_183414
2340 UBE38 UGUUAGAGGAGGAGACAGA NM_183415
2341 UBE3B GCAGAAGUCCAGAAGGUUU NM_130466
2342 UBE3B AGAUAUCAGGAGAGAGAUU NM_183414
2343 UBE3B CCGUCAGGCACGAGAAGAA NM_183414
2344 UBE3B GGGAAAAGGUGAAAGUCUU NM_183414
2345 UBE3B GAAUCAAAGAGGAUAAUGA NM_183414
2346 UBE3B CAACAGAUCAAGAACAUUU NM_130466
2347 UBE3B CCAGAGUGUUAGAGGAGGA NM_130466
2348 UBE3B GUGUGAAGUUUGUCAAUGA NM_130466
2349 UBE3B CAACAUGCCAGGUGACAUU NM_130466
2350 UBE3B UCAAGAACAUUUUGUGGUA NM_183414
2351 UBE3B CAGCAUGGGUUGAGUGUAC NM_130466
2352 UBE3B CAGAAGAAGUCCAACCUGA NM_183414
2353 UBE4A GGAGAAAACUGGAGGAAAA NM_004788
2354 UBE4A UGACAGACCAGGAGAAUAA NM_004788
2355 UBE4A GGAAAUGAACCUAGAAACA NM_004788
2356 UBE4A AGAAAUGGCAGUAGAGCUA NM_004788
2357 UBE4A GAAUAGAUACUGUGAACUA NM_004788
2358 UBE4A CAGUAGAGCUAGAAGAUCA NM_004788
2359 UBE4A CAUUAAUGCUGCUGAAUAU NM_004788
2360 UBE4A GCAACUUGGCAGAGAGAAU NM_004788
2361 UBE4A CAGAGUAACUUCACAUAAA NM_004788
2362 UBE4A GCAGGAAAUAUGUGAGCAA NM_004788
2363 UBE4A GCAUAGAAAGAAUGAAGAA NM_004788
2364 UBE4A GGAGCAACUUGAAUAGAUA NM_004788
2365 UBE4A GAGCAGACUUUCUAACAUA NM_004788
2366 UBE4A GAUAAUAGCGUGUCAGAGA NM_004788
2367 UBE4A UGAGAAGGAUCGAGGUGAA NM_004788
2368 UBE4A GGAAUAUGAUUAUGGCUUU NM_004788
2369 UBE4A GGGAGAGCAUUAAGGAUUU NM_004788
2370 UBE4A CGGGAGAGCAUUAAGGAUU NM_004788
2371 UBE4A AUAAAUAAGCCUGGGAAUA NM_004788
2372 UBE4A GGGCAAAUGUACCAGAAGA NM_004788
2373 UBE4A CCAAGAGGCUAAUACUAAA NM_004788
2374 UBE4A GAGGAUACCUUAAAGUGAA NM_004788
2375 UBE4A GCAUUAAGGAUUUGGCUGA NM_004788
2376 UBE4A GGAGUUGAAUGAUGAAGAA NM_004788
2377 UBE4A UCAAAGUACAGGAGGCCAA NM_004788
2378 UBE4A ACAACAACAUCUCAAGUAA NM_004788
2379 UBE4A AGUCAUGAUUCCAGUGUUU NM_004788
2380 UBE4A GGCCAAACACAGAACUAAA NM_004788
2381 UBE4A UAACUUACCAAGAGGCUAA NM_004788
2382 UBE4A UGUGUAGACUUCUGAAUAA NM_004788
2383 UBE4B AGGAAGAGAUGAAGAACAA NM_006048
2384 UBE4B CAAUAGAACUGUAGAAGAU NM_006048
2385 UBE4B CCGAGAAAGUGGAGGAGAU NM_006048
2386 UBE4B ACAGAAAUCUCUUGCUAAA NM_006048
2387 UBE4B GAAAAUGAUCGAAGAGAAA NM_006048
2388 UBE4B AGACAGAUAUGCUGAACUA NM_006048
2389 UBE4B CAAAGAAGCUGUUGGACCA NM_006048
2390 UBE4B UUGAAAACCCUGAGAAAUA NM_006048
2391 UBE4B AGAAGAUGUUGCAGAAUUU NM_006048
2392 UBE4B CGAUGGAAGAUGUGAAUGA NM_006048
2393 UBE4B CGGCAGACGCUGACAGAGA NM_006048
2394 UBE4B GAAAGGACAUGGAUGAGAA NM_006048
2395 UBE4B GGAGCAAGUAAUUGGGAUU NM_006048
2396 UBE4B GAGUUGGAAUAGAGGAAAA NM_006048
2397 UBE4B GCAACUAGACACCGCGAAA NM_006048
2398 UBE4B GGAGAUGAGGGUUGGGUUU NM_006048
2399 UBE4B UGUAGAAGAUGUUGCAGAA NM_006048
2400 UBE4B CGAGAAAGUGGAGGAGAUA NM_006048
2401 UBE4B UAAUGAAAGCCAAUGGAAA NM_006048
2402 UBE4B UGACACACGUUCAGAAGAA NM_006048
2403 UBE4B GGACAGACCUCUCAGCCAA NM_006048
2404 UBE4B CCGAGUUGGAAUAGAGGAA NM_006048
2405 UBE4B UGGAGGAGAUAGUGGCCAA NM_006048
2406 UBE4B AAGCGGAGCCUCAGUGAUA NM_006048
2407 UBE4B CUGCAAUGCUGAACUUUAA NM_006048
2408 UBE4B GAACUUUAAUCUUCAGCAA NM_006048
2409 UBE4B UGAAAAUGAUCGAAGAGAA NM_006048
2410 UBE4B UUGAAAUGAUUGAGAACCA NM_006048
2411 UBE4B GCUCAAUAGAACUGUAGAA NM_006048
2412 UBE4B ACAUGGAGGUUGAUGAAAA NM_006048
2413 UBL3 GAGAGUAAUUGUUGUGUAA NM_007106
2414 UBL3 AGACAUUACCAGAGCCAAA NM_007106
2415 UBL3 GAAAUAAACUGGUUCACUA NM_007106
2416 UBL3 UGAGAAGACUGGAGAGAGU NM_007106
2417 UBL3 CCAAAUAUUCUACGACUUA NM_007106
2418 UBL3 GUACAUAAAGCCUGAAUGA NM_007106
2419 UBL3 GGUCAGAGGAAUCGUGAGA NM_007106
2420 UBL3 GCACAGAAUACUAAACUGA NM_007106
2421 UBL3 GCACAGCACUAAAGCAUGA NM_007106
2422 UBL3 UCACAACAAUGGAUAGAAU NM_007106
2423 UBL3 GCAUAGAUCCAGUAAUGUA NM_007106
2424 UBL3 GUAUAUGACAAUUGGCCAA NM_007106
2425 UBL3 GUAAAUAGCACUAAACGUU NM_007106
2426 UBL3 GUUAAUUUGUGGACAGUCA NM_007106
2427 UBL3 GAGCAGAGUUUUAAAAUGA NM_007106
2428 UBL3 CAUAAAGCCUGAAUGAUGA NM_007106
2429 UBL3 GAUAUUAGUGCUUGCAAUU NM_007106
2430 UBL3 AAACAACAGUGAUGCAUUU NM_007106
2431 UBL3 GAAAGAAUUACGUCGCUUA NM_007106
2432 UBL3 GUAACUGAGUGUUUGUUUA NM_007106
2433 UBL3 AGAAGACUGGAGAGAGUAA NM_007106
2434 UBL3 GGUCAGCAGUCCAAAUAUU NM_007106
2435 UBL3 CAGCGUUGUUUAAAUGUAA NM_007106
2436 UBL3 GUAAACACAUGGAACUGAA NM_007106
2437 UBL3 UGUCACAUUAGGAGCAUUA NM_007106
2438 UBL3 GGUGAGAGCUGCAUAGAUC NM_007106
2439 UBL3 CAAAGCAUGUAUAUGACAA NM_007106
2440 UBL3 CGACAUUGCUUCAGAAACC NM_007106
2441 UBL3 GAGUAAUUGUUGUGUAAUC NM_007106
2442 UBL3 UGUGUGGUAUCUAGAAAUA NM_007106
2443 UBL4 GGAAACGACUCUCGGAUUA NM_014235
2444 UBL4 AGACAAUGGAGAAGGGCUU NM_014235
2445 UBL4 CUGAAGUGACUGAGACAAU NM_014235
2446 UBL4 GAACAGCUACAGAGGGAUU NM_014235
2447 UBL4 UGGAACAGCUACAGAGGGA NM_014235
2448 UBL4 UGACUGAGACAAUGGAGAA NM_014235
2449 UBL4 GGCCCUGGCAGAUGGGAAA NM_014235
2450 UBL4 GGGAAACGACUCUCGGAUU NM_014235
2451 UBL4 CUACAGAGGGAUUACGAGA NM_014235
2452 UBL4 GAAGGUGCUACUAGAAGAA NM_014235
2453 UBL4 AGAAGGUGCUACUAGAAGA NM_014235
2454 UBL4 AGCUCAACCUAGUGGUCAA NM_014235
2455 UBL4 GGAGAAGGUGCUACUAGAA NM_014235
2456 UBL4 UAGAAGAAGGCGAGGCCCA NM_014235
2457 UBL4 UGGAGAAGGUGCUACUAGA NM_014235
2458 UBL4 CAGCUGAUCUCCAAAGUCU NM_014235
2459 UBL4 ACUCCAAGCUCAACCUAGU NM_014235
2460 UBL4 GAAACGACUCUCGGAUUAU NM_014235
2461 UBL4 GCAGAUGGGAAACGACUCU NM_014235
2462 UBL4 GAGAAGGUGCUACUAGAAG NM_014235
2463 UBL4 AAACGACUCUCGGAUUAUA NM_014235
2464 UBL4 UCUGGCAGCUGAUCUCCAA NM_014235
2465 UBL4 UGAAGUGACUGAGACAAUG NM_014235
2466 UBL4 GCUGAUCUCCAAAGUCUUG NM_014235
2467 UBL4 GGCAGCUGAUCUCCAAAGU NM_014235
2468 UBL4 GAAGUGACUGAGACAAUGG NM_014235
2469 UBL4 CAACUCCAAGCUCAACCUA NM_014235
2470 UBL5 GGAUGAACCUGGAGCUUUA NM_024292
2471 UBL5 GGGAAGAAGGUCCGCGUUA NM_024292
2472 UBL5 GAUAGAUGCUUGUUUGUAA NM_024292
2473 UBL5 GAAGAAGGUCCGCGUUAAA NM_024292
2474 UBL5 GGAAGAAGGUCCGCGUUAA NM_024292
2475 UBL5 CUGAAGAAGUGGUACACGA NM_024292
2476 UBL5 AAGAAGUGGUACACGAUUU NM_024292
2477 UBL5 UGAUCGAGGUUGUUUGCAA NM_024292
2478 UBL5 CUAGGAUGAUCGAGGUUGU NM_024292
2479 UBL5 GGGAUGAACCUGGAGCUUU NM_024292
2480 UBL5 GCAACACGGAUGAUACCAU NM_024292
2481 UBL5 UGAAGAAGUGGUACACGAU NM_024292
2482 UBL5 GAACCUGGAGCUUUAUUAU NM_024292
2483 UBL5 UUAAAUGCAACACGGAUGA NM_024292
2484 UBL5 CCUGGAGCUUUAUUAUCAA NM_024292
2485 UBL5 GAAGAAGUGGUACACGAUU NM_024292
2486 UBL5 GGUACCCGUUGGAACAAGA NM_024292
2487 UBL5 GGAUAGAUGCUUGUUUGUA NM_024292
2488 UBL5 AAGAUUGUCCUGAAGAAGU NM_024292
2489 UBL5 ACCUGGAGCUUUAUUAUCA NM_024292
2490 UBL5 AAAUGCAACACGGAUGAUA NM_024292
2491 UBL5 UGGGAUAGAUGCUUGUUUG NM_024292
2492 UBL5 AGAUUGUCCUGAAGAAGUG NM_024292
2493 UBL5 UGAACCUGGAGCUUUAUUA NM_024292
2494 UBL5 GACCUUAAGAAGCUGAUUG NM_024292
2495 UBL5 AGAAGGUCCGCGUUAAAUG NM_024292
2496 UBL5 AAGAAGGUCCGCGUUAAAU NM_024292
2497 UBL5 GAAGGUCCGCGUUAAAUGC NM_024292
2498 UBL5 GAUGAUCGAGGUUGUUUGC NM_024292
2499 UBR1 GGAUGAAUAUGGAGAAACA NM_174916
2500 UBR1 UCAAAUAGCAUCAAGGAAA NM_174916
2501 UBR1 GAUUAUGGCUCAUCAGAAA NM_174916
2502 UBR1 GUGAAGCGAUUAAGAGAAA NM_174916
2503 UBR1 CUGCAGAUGAUGAGCGAAA NM_174916
2504 UBR1 GGACAAAUUGGGAAGAGUA NM_174916
2505 UBR1 GGACAGAAAGAUUAAGAAU NM_174916
2506 UBR1 AGAAAUGACUAUAUGGGAA NM_174916
2507 UBR1 CUUGGAAAGUGGAGAAUAU NM_174916
2508 UBR1 GAACAUAUGCAGAAGAAAA NM_174916
2509 UBR1 AAGAAGAACAGGAGGUGAA NM_174916
2510 UBR1 CCAGAAAUCUACUGCCUUA NM_174916
2511 UBR1 GCUUAGAGAAUGUCAUAAA NM_174916
2512 UBR1 GGGAAGAGUAUAUGCAGUA NM_174916
2513 UBR1 GGUCCUGGUUGAAGGUAAA NM_174916
2514 UBR1 CAAAUAGCAUCAAGGAAAU NM_174916
2515 UBR1 CUAUGGAAUUUGUGAAGUA NM_174916
2516 UBR1 GGAGAAAACAAGAAAACAA NM_174916
2517 UBR1 UAGAGGUACUAGUGGAAUA NM_174916
2518 UBR1 ACAAAGUCCUACAGAGUAU NM_174916
2519 UBR1 AGGAAGAUAUAAAGAGUCA NM_174916
2520 UBR1 AUAAACAACUGCAGAAAGA NM_174916
2521 UBR1 GCUGAGAUGUGGCGAAGAA NM_174916
2522 UBR1 CCAAAGAAGAGGUCACAAU NM_174916
2523 UBR1 CCAAAUGGCUUUUCAUAUU NM_174916
2524 UBR1 CUAUAUGGGAAGAGGAAAA NM_174916
2525 UBR1 UUUCAAAAGUGGAGAGACA NM_174916
2526 UBR1 CAAUAUGGACAGAAAGAUU NM_174916
2527 UBR1 GGUACUGAGAGGAUGGAAA NM_174916
2528 UBR1 CCGAAGACAGGUUGGGCAA NM_174916
2529 UCHL1 GGCCAAUAAUCAAGACAAA NM_004181
2530 UCHL1 CAUGAGAACUUCAGGAAAA NM_004181
2531 UCHL1 UUGAAGAGCUGAAGGGACA NM_004181
2532 UCHL1 GGGUAGAUGACAAGGUGAA NM_004181
2533 UCHL1 CCGCGAAGAUGCAGCUCAA NM_004181
2534 UCHL1 GCCAAGGUCUGCAGAGAAU NM_004181
2535 UCHL1 GAAGCAGACCAUUGGGAAU NM_004181
2536 UCHL1 GCAUGAGAACUUCAGGAAA NM_004181
2537 UCHL1 AGACCUUGGAUGUGGUUUA NM_004181
2538 UCHL1 GCUGAAGGGACAAGAAGUU NM_004181
2539 UCHL1 CUAUGAACUUGAUGGACGA NM_004181
2540 UCHL1 CUAAAAUGCUUCAGUACUU NM_004181
2541 UCHL1 GGAUGUGGUUUAAUUGUUU NM_004181
2542 UCHL1 CCAAUAAUCAAGACAAACU NM_004181
2543 UCHL1 CGGCCCAGCAUGAGAACUU NM_004181
2544 UCHL1 UAGAUGACAAGGUGAAUUU NM_004181
2545 UCHL1 CCCUGAAGACAGAGCAAAA NM_004181
2546 UCHL1 CAGCUCAAGCCGAUGGAGA NM_004181
2547 UCHL1 CCGAGAUGCUGAACAAAGU NM_004181
2548 UCHL1 GGGAUUUGAGGAUGGAUCA NM_004181
2549 UCHL1 GGUUUCUGUCUGUAAGUUA NM_004181
2550 UCHL1 GUUUCUGUCUGUAAGUUAA NM_004181
2551 UCHL1 CCUUGGAUGUGGUUUAAUU NM_004181
2552 UCHL1 GGAGGGACUUUGCUGAUUU NM_004181
2553 UCHL1 AAGCAGACCAUUGGGAAUU NM_004181
2554 UCHL1 ACGCAGUGGCCAAUAAUCA NM_004181
2555 UCHL1 UUAACAACGUGGAUGGCCA NM_004181
2556 UCHL1 CAGAGGACACCCUGCUGAA NM_004181
2557 UCHL1 CUGAAGGGACAAGAAGUUA NM_004181
2558 UCHL1 GGUGUGAGCUUCAGAUGGU NM_004181
2559 UCHL3 CAGCAUAGCUUGUCAAUAA NM_006002
2560 UCHL3 GAACAGAAGAGGAAGAAAA NM_006002
2561 UCHL3 CAGCAAUGCCUGUGGAACA NM_006002
2562 UCHL3 UGGUGAAACUAGUGAUGAA NM_006002
2563 UCHL3 GGCAAUUCGUUGAUGUAUA NM_006002
2564 UCHL3 AUUCAGAACAGAAGAGGAA NM_006002
2565 UCHL3 CUGAAGAACGAGCCAGAUA NM_006002
2566 UCHL3 CCUGAUGAACUAAGAUUUA NM_006002
2567 UCHL3 CCAAUUAACCAUGGUGAAA NM_006002
2568 UCHL3 GAACUAAGAUUUAAUGCGA NM_006002
2569 UCHL3 CCAUAGAAGUUUGCAAGAA NM_006002
2570 UCHL3 CAGUAUAUUUCAUGAAGCA NM_006002
2571 UCHL3 AAAUAAAAUCUCAGGGACA NM_006002
2572 UCHL3 GAAGUUUGCAAGAAGUUUA NM_006002
2573 UCHL3 ACCAAGUAUAGAUGAGAAA NM_006002
2574 UCHL3 GCGCGACCCUGAUGAACUA NM_006002
2575 UCHL3 UGGAACAAUUGGACUGAUU NM_006002
2576 UCHL3 UCAGAACAGAAGAGGAAGA NM_006002
2577 UCHL3 GUCAAUGAGCCCUGAAGAA NM_006002
2578 UCHL3 CAAGUAUAGAUGAGAAAGU NM_006002
2579 UCHL3 CAAUAAUGGAAACACCAAA NM_006002
2580 UCHL3 GCACUUUGAAUCUGGAUCA NM_006002
2581 UCHL3 ACAAUAAAGACAAGAUGCA NM_006002
2582 UCHL3 GCAAUUCGUUGAUGUAUAU NM_006002
2583 UCHL3 GUAUAGAUGAGAAAGUAGA NM_006002
2584 UCHL3 CACCAAGUAUAGAUGAGAA NM_006002
2585 UCHL3 GAACAAUUGGACUGAUUCA NM_006002
2586 UCHL3 UCGUUGAUGUAUAUGGAAU NM_006002
2587 UCHL3 UGAAACUAGUGAUGAAACU NM_006002
2588 UCHL3 AGACUGAGGCACCAAGUAU NM_006002
2589 UCHL5 GUUUAGAGCCUGAGAAUUU NM_015984
2590 UCHL5 GCAGAAGAUAGCAGAGUUA NM_015984
2591 UCHL5 GGAUACAGAUCAAGGUAAU NM_015984
2592 UCHL5 GCAAAGAAAGCUCAGGAAA NM_015984
2593 UCHL5 UGAAGAAGAAGUACAGAAA NM_015984
2594 UCHL5 GUACAGUGAAGGUGAAAUU NM_015984
2595 UCHL5 GUUAAUACCACUAGUAGAA NM_015984
2596 UCHL5 GCUUAUUGAAGAAGAAGUA NM_015984
2597 UCHL5 GUAGAAAAGGCAAAAGAAA NM_015984
2598 UCHL5 GAGCCCAAGUAGAAGAAAU NM_015984
2599 UCHL5 GCACAAACGAUAUUCCUUA NM_015984
2600 UCHL5 UAGCAGAGUUACAAAGACA NM_015984
2601 UCHL5 UAAAGAACUUAGAGCAACA NM_015984
2602 UCHL5 CAAAGAAAGCUCAGGAAAC NM_015984
2603 UCHL5 GAUUAAACUGGUUGUCUUA NM_015984
2604 UCHL5 CCGAGGAGCCCAAGUAGAA NM_015984
2605 UCHL5 GAGUUUAGAGCCUGAGAAU NM_015984
2606 UCHL5 AGCCAUAGUGAGUGUGUUA NM_015984
2607 UCHL5 GAGGAGGAACCCAUGGAUA NM_015984
2608 UCHL5 AGAAGGACCGAUUGAUUUA NM_015984
2609 UCHL5 GAGCAAUUCAGAUGUGAUU NM_015984
2610 UCHL5 GUUAAGUGCUAUUCAGUCA NM_015984
2611 UCHL5 AGCCCAAGUAGAAGAAAUA NM_015984
2612 UCHL5 UCAGAUGCUUAUUGAAGAA NM_015984
2613 UCHL5 UGAUAUAUGAGCAGAAGAU NM_015984
2614 UCHL5 GAGAAGGACCGAUUGAUUU NM_015984
2615 UCHL5 AGAUGUGAUUCGACAAGUA NM_015984
2616 UCHL5 CAGUAAGGCCUGUCAUAGA NM_015984
2617 UCHL5 GAUGCUUAUUGAAGAAGAA NM_015984
2618 UCHL5 GAUACGAAGACAUCAGCAA NM_015984
2619 UEV3 GGGCAAAUCAUGAGAAUAA NM_018314
2620 UEV3 AGAAAGACCUGCUGAAUUU NM_018314
2621 UEV3 CAACAGGGAUAUUAUGAUA NM_018314
2622 UEV3 CGAGCAAGGAGAAGACAAA NM_018314
2623 UEV3 GCAAAGAAGUAUGGGUUAU NM_018314
2624 UEV3 AAGAAGAAGUAGUGAGUCU NM_018314
2625 UEV3 GGCACAGACUUCAGGCAAA NM_018314
2626 UEV3 GGACCUAACUGUGGAAGAA NM_018314
2627 UEV3 GGCAAAGAAGUAUGGGUUA NM_018314
2628 UEV3 UCACAGAGAUUACAGUAUA NM_018314
2629 UEV3 GAUCGGAAUUGGAUGUAAU NM_018314
2630 UEV3 UGGGAAUCUUAGUCGGAAA NM_018314
2631 UEV3 UUACAAACUGCUUGGUUAA NM_018314
2632 UEV3 CAGUGGAAAUCAUGACCUA NM_018314
2633 UEV3 GUACAGAGCAAUGUGGAUA NM_018314
2634 UEV3 GUAGAGGGUUUCUUGAUUA NM_018314
2635 UEV3 CAGAAAGACCUGCUGAAUU NM_018314
2636 UEV3 CGGUAUUGCCUGCACAUUA NM_018314
2637 UEV3 GCUCAAGGCAGAAUAUAUU NM_018314
2638 UEV3 UUUACAAACUGCUUGGUUA NM_018314
2639 UEV3 AGAAAUGAUUGCCAAGUUU NM_018314
2640 UEV3 CAUCUCAACCAGUGGAAAU NM_018314
2641 UEV3 CCAAGAAGAAGUAGUGAGU NM_018314
2642 UEV3 AAUUCAAAGAGCUGGGCAA NM_018314
2643 UEV3 AGGCAAAGAAGUAUGGGUU NM_018314
2644 UEV3 GAAAGAAGAUACAGUUACU NM_018314
2645 UEV3 GGUUGGAGGUGGAGAACUC NM_018314
2646 UEV3 UUGAUGUGGUACAGAGCAA NM_018314
2647 UEV3 CCAAUUCGUUUCUGGAUUU NM_018314
2648 UEV3 GCAGAAUAUAUUUGCCCUA NM_018314
2649 UFD1L GCAAUAGACUGGAUGGAAA NM_005659
2650 UFD1L GGAUGAAGCUGGAGGCAGA NM_005659
2651 UFD1L GAGAAAGGAGGGAAGAUAA NM_005659
2652 UFD1L ACAAAGAACCCGAAAGACA NM_005659
2653 UFD1L GGAGAAAGGAGGGAAGAUA NM_005659
2654 UFD1L AAUCAAGCCUGGAGAUAUU NM_005659
2655 UFD1L GGAAGAAAGCCCUAAGUGA NM_005659
2656 UFD1L CUACAAAGAACCCGAAAGA NM_005659
2657 UFD1L CAAAGAACCCGAAAGACAA NM_005659
2658 UFD1L GGACAGUCAUUGCGUAAAA NM_005659
2659 UFD1L AGAAAGGAGGGAAGAUAAU NM_005659
2660 UFD1L GGUCAGAUGUGGAGAAAGG NM_005659
2661 UFD1L GGAGAUAUUAAAAGAGGAA NM_005659
2662 UFD1L CCAAUCAAGCCUGGAGAUA NM_005659
2663 UFD1L CGACAGAAGGUGAAGCCGA NM_005659
2664 UFD1L GCCAUCAACUAUAAUGAAA NM_005659
2665 UFD1L UGUUCAAACUGACCAAUAA NM_005659
2666 UFD1L AAAGACAAGUCCAGCAUGA NM_005659
2667 UFD1L AAAGGAGGGAAGAUAAUUA NM_005659
2668 UFD1L CCAAAGCCGUAUUAGAAAA NM_005659
2669 UFD1L AAGGACAGUCAUUGCGUAA NM_005659
2670 UFD1L CAAACUGACCAAUAAGAAU NM_005659
2671 UFD1L ACUGUUGGCUGAUUGGAAA NM_005659
2672 UFD1L CAGGUCAGAUGUGGAGAAA NM_005659
2673 UFD1L GGUAAGAUAACUUUCAUCA NM_005659
2674 UFD1L CCCAAAGCCGUAUUAGAAA NM_005659
2675 UFD1L CGAAAGACAAGUCCAGCAU NM_005659
2676 UFD1L GUGACAUGAACGUGGACUU NM_005659
2677 UFD1L UGGAAAGAAGAAAGGGGUA NM_005659
2678 UFD1L CAUGAGGAGUCGACAGAAG NM_005659
2679 USP1 AAACAAAGGUGAAGAACAA NM_003368
2680 USP1 GAAGAGAACCAGAGACAAA NM_003368
2681 USP1 GCAUAGAGAUGGACAGUAU NM_003368
2682 USP1 AGAAAGGAUUGUAGGAGAA NM_003368
2683 USP1 AAUUAGAGUUGGUGGAAAU NM_003368
2684 USP1 AGAAAUACCUCAUCCGAAA NM_003368
2685 USP1 GAAAGAAGCUCUAAAGGAU NM_003368
2686 USP1 GAUUGUAGGAGAAGAUAAA NM_003368
2687 USP1 GGGAAACAUUCAAGAAACA NM_003368
2688 USP1 GUUUUGAGCUAGUGGAGAA NM_003368
2689 USP1 UGACCAAAUGUGUGAAAUA NM_003368
2690 USP1 GGUUAAAGUCUGCAACUAA NM_003368
2691 USP1 CCAAGGAGUCAAAGGACAA NM_003368
2692 USP1 GGGAAGUGUGAAAGUGAUA NM_003368
2693 USP1 GGUUUUAAAUCUGGAGUAA NM_003368
2694 USP1 GUGCAAAGCUUAAAGGAGU NM_003368
2695 USP1 CUAGAAGAAUGGAGCACAA NM_003368
2696 USP1 GAGACAAACUAGAUCAAAA NM_003368
2697 USP1 GAAUAUAGAGCAUCUGAAA NM_003368
2698 USP1 UGGAAGAGAACCAGAGACA NM_003368
2699 USP1 UGUAGAAGCUAUUGGACUU NM_003368
2700 USP1 CAAAGCAGAUUAUGAGCUA NM_003368
2701 USP1 CUGAAGACUUUAAAGAGAA NM_003368
2702 USP1 GGGAAAUUGCAAAGAAGAU NM_003368
2703 USP1 AGUCAAAGGACAAUCUAAA NM_003368
2704 USP1 GGAAAUACACAGCCAAGUA NM_003368
2705 USP1 UGUCAUACCUAGUGAAAGU NM_003368
2706 USP1 UAGAAAGGAUUGUAGGAGA NM_003368
2707 USP1 GGAAGAAAGAAGCUCUAAA NM_003368
2708 USP1 GGGGUGUGGUUGAGAAUUA NM_003368
2709 USP10 AAGAAGAUGCUGAGGAAUA NM_005153
2710 USP10 CAAACAAGAGGUUGAGAUA NM_005153
2711 USP10 GAUAAAAUCGUGAGGGAUA NM_005153
2712 USP10 ACAAGAAGAUGCUGAGGAA NM_005153
2713 USP10 GAGAUAAGAAAGUGGAUUU NM_005153
2714 USP10 CCACAGAAGCCCUGGUCAA NM_005153
2715 USP10 GAGGAAAUGUUGAACCUAA NM_005153
2716 USP10 GAGAUAAGUCGAAGAGUGA NM_005153
2717 USP10 GGACAAAGGGAGCGUAAAA NM_005153
2718 USP10 GGACAAGAAUAUCAGAGAA NM_005153
2719 USP10 GACAAGAAUAUCAGAGAAU NM_005153
2720 USP10 AAGAAGAGCAGGAAGAACA NM_005153
2721 USP10 AGGAAAUGUUGAACCUAAA NM_005153
2722 USP10 CCAUAAAGAUUGCAGAGUU NM_005153
2723 USP10 GAGAAUCUGUCCAAGGUUA NM_005153
2724 USP10 AUGCAGAAUUUAUGGGUGA NM_005153
2725 USP10 CAGCCUACCUCCUGUAUUA NM_005153
2726 USP10 UUGCAGAGUUGCUGGAGAA NM_005153
2727 USP10 UAAACUACCUGAUGGACAA NM_005153
2728 USP10 AUGAAGAAGAGCAGGAAGA NM_005153
2729 USP10 GCAGGAAGAACAAGGUGAA NM_005153
2730 USP10 GGAAGAACAAGGUGAAGGA NM_005153
2731 USP10 GGGAACUGGUGCUACAUUA NM_005153
2732 USP10 UGGAGUUGCUAAUGGACAA NM_005153
2733 USP10 CAGCAGAGUUCAAAAGAAU NM_005153
2734 USP10 GGAAAUUAGUAAAGAACUG NM_005153
2735 USP10 UGAAAAGGGUCGACAAGAA NM_005153
2736 USP10 CCACAUAUAUUUACAGACU NM_005153
2737 USP10 GGACUUGGAAAUUAGUAAA NM_005153
2738 USP10 GUGAAGGAAGCGAGGAUGA NM_005153
2739 USP11 AGGUAGAGGCUGAGGGCUA NM_004651
2740 USP11 CGGAAGAGGAUGAGGACUU NM_004651
2741 USP11 GGGUGAAGAAGAAGGAGUA NM_004651
2742 USP11 AAGAUGACGAGGAGGAUAA NM_004651
2743 USP11 GUGGAGAAGCACUGGUAUA NM_004651
2744 USP11 UCAGAAGGCUCUUUGGAUA NM_004651
2745 USP11 GCACAGGAGGCAUGGCAAA NM_004651
2746 USP11 UGGUGGAAGGCGAGGAUUA NM_004651
2747 USP11 CAGAGAUGAAGAAGCGUUA NM_004651
2748 USP11 GGGAUGAGAAAGAAGAUGA NM_004651
2749 USP11 GAACAAGGUUGGCCAUUUU NM_004651
2750 USP11 GGACGAUGGGGAUGAGAAA NM_004651
2751 USP11 GAGAUAAACUGGCGCCUCA NM_004651
2752 USP11 UGUAUAACGUCCUGAUGUA NM_004651
2753 USP11 AGAAAGAAGAUGACGAGGA NM_004651
2754 USP11 ACAACAACAUGUCGGAAGA NM_004651
2755 USP11 AGAAUCAGAUCGAGUCCAA NM_004651
2756 USP11 GCUGGUUCCUUGUGGAGAA NM_004651
2757 USP11 GGCACAAUGAUUUGGGCAA NM_004651
2758 USP11 AUGACGAGGUAGAGGCUGA NM_004651
2759 USP11 CCGAGUACUUCCUCAACAA NM_004651
2760 USP11 GCUCUGAGUUCAUGGAUGU NM_004651
2761 USP11 AUGCAGACCUGGUGAAGCA NM_004651
2762 USP11 GGCACUACUUUGAUGACAA NM_004651
2763 USP11 CUGGUAUGGUCUAGAGCAU NM_004651
2764 USP11 AAGAAGAUGACGAGGAGGA NM_004651
2765 USP11 GGGCAUGAAGGGUGAGAUC NM_004651
2766 USP11 GUUACUAUGACGAGGUAGA NM_004651
2767 USP11 GUUCAUGGAUGUUAAUUGA NM_004651
2768 USP11 GUGAGAUCGCAGAGGCCUA NM_004651
2769 USP12 CAGCAAAGAUGAAGAUUUU NM_182488
2770 USP12 CCUAAGAAGUUCAUCACAA NM_182488
2771 USP12 GAAGAGAGAAAGCAGGAAA NM_182488
2772 USP12 CAUCACAAGAUUACGGAAA NM_182488
2773 USP12 UUGCAAUAGUUAAGAGUCA NM_182488
2774 USP12 CCACCAAUCCAGACAGAAU NM_182488
2775 USP12 GCAGCAAAGAUGAAGAUUU NM_182488
2776 USP12 ACAAGAUUACGGAAAGAAA NM_182488
2777 USP12 UGCACAAGCUAUUGAAGAA NM_182488
2778 USP12 GGAUCAACUUCAUCGAUAU NM_182488
2779 USP12 CACAAACGGAUGAAAGUUA NM_182488
2780 USP12 GAAAGAGAUUGGUCCAGAA NM_182488
2781 USP12 ACAAACGGAUGAAAGUUAA NM_182488
2782 USP12 GCGUAUAAGAGUCAACCUA NM_182488
2783 USP12 CAGAACAGUUUCCGGUCAA NM_182488
2784 USP12 CAUCAGAUAUCUCAAAGAA NM_182488
2785 USP12 GGCAUUAGAGAAAGAGAUU NM_182488
2786 USP12 GCCCAUGAUUCUAGCUCUA NM_182488
2787 USP12 GCAAACAGGAAGCACACAA NM_182488
2788 USP12 GCAACAAGAUGCCCAUGAA NM_182488
2789 USP12 UGGAUCAACUUCAUCGAUA NM_182488
2790 USP12 GCAUAGCCACUCAGAAGAA NM_182488
2791 USP12 GUUUAACACUUCAGGUGAU NM_182488
2792 USP12 CAAACAGGAAGCACACAAA NM_182488
2793 USP12 GAUCAACUUCAUCGAUAUA NM_182488
2794 USP12 GCAGCAAACAGGAAGCACA NM_182488
2795 USP12 UGAAGAGUGUCGCAGCAAA NM_182488
2796 USP12 UUGAAGAAUUCUACGGGUU NM_182488
2797 USP12 CGGCAUUAGAGAAAGAGAU NM_182488
2798 USP12 UCAAUUACUCACUGCUUAA NM_182488
2799 USP13 UGAUUGAGAUGGAGAAUAA NM_003940
2800 USP13 GCACGAAACUGAAGCCAAU NM_003940
2801 USP13 GGGAACAUGUUGAAAGACA NM_003940
2802 USP13 GGUCAUUACAUUUGCCAUA NM_003940
2803 USP13 AGAAUGGGCUCCAGGACAA NM_003940
2804 USP13 AGACAGUGAUUUUGUGAUU NM_003940
2805 USP13 UGAUGAAGGAGGAGCACAA NM_003940
2806 USP13 AUAUGAAGAUGAAGCCAAA NM_003940
2807 USP13 GAAGGGAAGCAGAAGCAAA NM_003940
2808 USP13 GCGACAGGGUCUACAAGAA NM_003940
2809 USP13 UGAAAUAGCACUACCAAAU NM_003940
2810 USP13 GGACAAUGGAGUCAGGAUU NM_003940
2811 USP13 ACACGGAGAGGGUGGAUUA NM_003940
2812 USP13 UGAAGAAGACAGUGAUUUU NM_003940
2813 USP13 GAGAAUAAUGCCAAUGCAA NM_003940
2814 USP13 GGAUGGAUCUGGAACAUAU NM_003940
2815 USP13 ACGAAUAAUAACCUGGAAA NM_003940
2816 USP13 AGAAUAAUGCCAAUGCAAA NM_003940
2817 USP13 ACUUGGUAGUGCAGAUAAA NM_003940
2818 USP13 AGGAUGAACUGAUCGCUUA NM_003940
2819 USP13 GGGCAGAUGUUUAUUCUUU NM_003940
2820 USP13 GUUACAGCCAGGAGAGGAA NM_003940
2821 USP13 GCACUGGAUUGGAUCUUUA NM_003940
2822 USP13 GGAAGAUGGCUGCAGGAGA NM_003940
2823 USP13 UGAACUAACGAGAAGGGAA NM_003940
2824 USP13 GAAGAUGGGUGAUUUACAA NM_003940
2825 USP13 AGGAGGAAUUCCAAGAUUU NM_003940
2826 USP13 CAGAGGAAAUCGUAGCUAU NM_003940
2827 USP13 GCUUAUGAACUAACGAGAA NM_003940
2828 USP13 GGAAGGAAGAUGGGUGAUU NM_003940
2829 USP14 GGAGAAAUUUGAAGGUGUA NM_005151
2830 USP14 GGAUUAAGUUUGAUGAUGA NM_005151
2831 USP14 UGAAAUAAUGGAAGAGGAA NM_005151
2832 USP14 GAAACAAGAUGAAUGGAUU NM_005151
2833 USP14 AGAGGAAAGUGAACAGUAA NM_005151
2834 USP14 GGUGAAAGGAGGAACGCUA NM_005151
2835 USP14 GCCAAAUACAAGUGACAAA NM_005151
2836 USP14 GAGUAUUGCAACAGAAAUU NM_005151
2837 USP14 ACCAGAACUUCAAGAGAAA NM_005151
2838 USP14 CCAGAAAGAAGUUAAGUAU NM_005151
2839 USP14 GAGUUGAAAUAAUGGAAGA NM_005151
2840 USP14 ACAGAAAGUUAUGGUGAAA NM_005151
2841 USP14 CAACAGAAAUUGGAAGCAA NM_005151
2842 USP14 CGAGAAAGGUGAACAAGGA NM_005151
2843 USP14 AUCCAGAGCUUUAGAGGAA NM_005151
2844 USP14 AGAAGAACCCUCAGCCAAA NM_005151
2845 USP14 GAGGAACGCUAAAGGAUGA NM_005151
2846 USP14 CACCAGAACUUCAAGAGAA NM_005151
2847 USP14 GACAGAAAGUUAUGGUGAA NM_005151
2848 USP14 GCUGAAGACAUGUUUAAUA NM_005151
2849 USP14 GCUAAUGAAUGUUGGAUAC NM_005151
2850 USP14 GCAAAGAAAUGCCUUGUAU NM_005151
2851 USP14 CAUGAAAUGUACAGAAUCU NM_005151
2852 USP14 GAAAUUUGAAGGUGUAGAA NM_005151
2853 USP14 GCAGGUGCCUUGAGAGCUU NM_005151
2854 USP14 CCAAAGUUCUUAAGGAUGU NM_005151
2855 USP14 UCUAUAAUCCAGAGCUUUA NM_005151
2856 USP14 GCGAGUAUUGCAACAGAAA NM_005151
2857 USP14 CUUGAGAGCUUCAGGGGAA NM_005151
2858 USP14 GGAUACAAAUGAUGCGAGU NM_005151
2859 USP15 GGAACAAAUACAUGAGUAA NM_006313
2860 USP15 GCAGAUAAGAUGAUAGUUA NM_006313
2861 USP15 AGGAAUGAGAGGUGAAAUA NM_006313
2862 USP15 GCAUAAACACCUUGAAUUU NM_006313
2863 USP15 GAAUUGAAGCUAUGUGAAA NM_006313
2864 USP15 AUGAAAGUGUGGAGUAUAA NM_006313
2865 USP15 GAUUUUAACUUGUGCAGUA NM_006313
2866 USP15 GGAAACAGGUUCUAGAUUU NM_006313
2867 USP15 ACAAAUACCAGAUGGGAGA NM_006313
2868 USP15 CAUUUGAACCACUGAAUAA NM_006313
2869 USP15 GAAACAAUACUGAAGACAA NM_006313
2870 USP15 UAGCAAAGCUGACACAAUA NM_006313
2871 USP15 GAUGUGAGUUGAUGACAAA NM_006313
2872 USP15 CUGCAAAGUAGAAGUAUAU NM_006313
2873 USP15 GGAGAUAAUGAUUCUGAAA NM_006313
2874 USP15 AUACAGAGCACGUGAUUAU NM_006313
2875 USP15 ACACAUUGAUGGAAGGUCA NM_006313
2876 USP15 ACUGCAAAGUAGAAGUAUA NM_006313
2877 USP15 CCUGUUUGCCUAAGAGAAA NM_006313
2878 USP15 GAUGGAAGGUCAAGAGCCA NM_006313
2879 USP15 GAGACCAGAUUGUGGAACA NM_006313
2880 USP15 UGUUGUAACUCGAAGAUUU NM_006313
2881 USP15 AAGCAAAUGUGGUCUGGAA NM_006313
2882 USP15 ACAAUUGGCUAUAAAGGUA NM_006313
2883 USP15 UCAGAUAACCGAAUGUAAA NM_006313
2884 USP15 GAAUAUUCGCUAUGGAUGA NM_006313
2885 USP15 GCAGAUGGAAGGCCAGAUA NM_006313
2886 USP15 AGGACAGGUAUUAGUGAUA NM_006313
2887 USP15 UCAGCAAGCCACAAAGAAA NM_006313
2888 USP15 CCGAACUGAUCAAGCAAAU NM_006313
2889 USP16 AGAUAAAGCUGAAGAAGAA NM_006447
2890 USP16 GGAACAAGGUAAUUUGAAA NM_006447
2891 USP16 AAACAUGGCUAAAGAGAAU NM_006447
2892 USP16 AGAUCAAGAUAGUGAGGAA NM_006447
2893 USP16 CAGAGAAAGAUAAUGGAAA NM_006447
2894 USP16 AAGAGUGAGUAAAGGAAUA NM_006447
2895 USP16 CCACAGAGGAAGUAGAUAU NM_006447
2896 USP16 AGAAUGAACAAGAGAGAGA NM_006447
2897 USP16 UGAUCAGAGUGGUAAGAAA NM_006447
2898 USP16 CAUCUUUGGUGGUGAACUA NM_006447
2899 USP16 AGAAACGGACAAAGGGAAA NM_006447
2900 USP16 GUUCAAACCAGUUGGGUCA NM_006447
2901 USP16 GACCAAAGGCAAAUAUAAA NM_006447
2902 USP16 GGACCAAAGGCAAAUAUAA NM_006447
2903 USP16 GGAUGAAGAUCAAGAUAGU NM_006447
2904 USP16 UGAAGAAGAAACAGAAGAA NM_006447
2905 USP16 GUAAUGGACCAAAGGCAAA NM_006447
2906 USP16 GUGAAUGUGGAAUGGAAUA NM_006447
2907 USP16 UAAGAAUGUUGCAGAAGAA NM_006447
2908 USP16 AGUGAAAGAUAAAGCUGAA NM_006447
2909 USP16 GAACAAAGGUGUAUGAGGU NM_006447
2910 USP16 GAACCAACGAAGACAACAA NM_006447
2911 USP16 GUGAAAGGACUCAGUAAUU NM_006447
2912 USP16 CAGAGGAAGUAGAUAUGAA NM_006447
2913 USP16 GGAAGGGAGCAAUGGAGAA NM_006447
2914 USP16 AAGAUAAAGCUGAAGAAGA NM_006447
2915 USP16 AGAGAGAAAAGAAGGAAAA NM_006447
2916 USP16 GAAAGAUAAAGCUGAAGAA NM_006447
2917 USP16 CGAAUAAACUGCUUUGUGA NM_006447
2918 USP16 CUGUAAGACUGACAAUAAA NM_006447
2919 USP18 GAAGAAGACCCGUGGGAAA NM_017414
2920 USP18 GGACAGACCUGCUGCCUUA NM_017414
2921 USP18 CUGCAUAUCUUCUGGUUUA NM_017414
2922 USP18 ACAUGAAGAUGGAGUGCUA NM_017414
2923 USP18 CCAUAUGAAUCAAGUGUUU NM_017414
2924 USP18 GCAUGGCGCUUGAGAGAUU NM_017414
2925 USP18 GGAAUGCUGUGGAUGGAAA NM_017414
2926 USP18 UCCAUAAGAUAGUGUGAUA NM_017414
2927 USP18 AGAAGGAAGAAGACAGCAA NM_017414
2928 USP18 GGAAACAGGUCUUGAAGCU NM_017414
2929 USP18 GGAAUUCACAGACGAGAAA NM_017414
2930 USP18 UAAACACGGUCAUGAAUAA NM_017414
2931 USP18 CCCAAAACCUUCAGAGAUU NM_017414
2932 USP18 GGAAAAUGGUCUUGCUUCA NM_017414
2933 USP18 ACAGCAACAUGAAGAGAGA NM_017414
2934 USP18 GGGAAGACAUCCAGUGUAC NM_017414
2935 USP18 GACAUUAGCCCUUUAGUUA NM_017414
2936 USP18 GGAAAAUGGUUCUGCUUCA NM_017414
2937 USP18 GCUGACGAGCAGAGGAGAA NM_017414
2938 USP18 AAGAAAAGAAGGAAGAAGA NM_017414
2939 USP18 CCAGGAUAUUGAAGAGGAU NM_017414
2940 USP18 UGAUAAACACGGUCAUGAA NM_017414
2941 USP18 CCAACAUGAUGCUGCCCAA NM_017414
2942 USP18 GGAGAAGCAUUGUUUUCAA NM_017414
2943 USP18 CCAGGGAGUUAUCAAGCAA NM_017414
2944 USP18 AGGAAUUCACAGACGAGAA NM_017414
2945 USP18 GGGAAGAAGACCCGUGGGA NM_017414
2946 USP18 GAGAAGCAUUGUUUUCAAA NM_017414
2947 USP18 UCGUAAUGAAUGUGGACUU NM_017414
2948 USP18 AGGAUAUUGAAGAGGAUCA NM_017414
2949 USP2 CGACAGAUGUGGAGAAAAU NM_004205
2950 USP2 CUGAAUACCUGGUCGACUA NM_004205
2951 USP2 AGACCCAGAUCCAGAGAUA NM_004205
2952 USP2 UCGACUACCUGGAGAACUA NM_004205
2953 USP2 CCAAAGAGGAUGUGCUUGA NM_004205
2954 USP2 GAAGGGACAUCUUUGGAAA NM_004205
2955 USP2 GGGAAGAGACGGCAUGAAU NM_004205
2956 USP2 ACACAAACCUGACAAGAGA NM_004205
2957 USP2 CGAGAAAGGCCGACAGAUG NM_004205
2958 USP2 CUGCAGUGCCUGAGCAACA NM_004205
2959 USP2 GCAUGAGGCUCUUCACCAA NM_171997
2960 USP2 ACACAGCCCUCGUGGAAGA NM_004205
2961 USP2 GACCUGGACUUAAGAGAAU NM_004205
2962 USP2 GGAAGAGACGGCAUGAAUU NM_004205
2963 USP2 AGGAUGUGCUUGAUGGAGA NM_171997
2964 USP2 CGGCAUGAAUUCUAAGAGU NM_004205
2965 USP2 CUGAAGCGCUACACAGAAU NM_004205
2966 USP2 GAAAAUAUCUAGAACGGGA NM_004205
2967 USP2 UCGCUGACGUGUACAGAUU NM_004205
2968 USP2 UGACAUUAAUGGACUGCAU NM_004205
2969 USP2 ACAAACCUGACAAGAGAAA NM_004205
2970 USP2 GGCAGAAAACGGUGUAUAA NM_004205
2971 USP2 UAACUAAAGUGUUCAGACU NM_004205
2972 USP2 CAUCUGAGUUCAAGACCCA NM_004205
2973 USP2 GCCGACAGAUGUGGAGAAA NM_004205
2974 USP2 GGAUGUGCUUGAUGGAGAU NM_004205
2975 USP2 ACACACAGCCCUCGUGGAA NM_171997
2976 USP2 AGAAAACGGUGUAUAAAGA NM_171997
2977 USP2 CGAGGUGAACCGAGUGACA NM_171997
2978 USP2 UCAACAAAGCCAAGAAUUC NM_171997
2979 USP20 GGACAAUGAUGCUCACCUA NM_006676
2980 USP20 CUGAUGAGUUAAAGGGUGA NM_006676
2981 USP20 GGUCAAAGGAAGCGGCCAU NM_006676
2982 USP20 CCAUAGGAGAGGUGACCAA NM_006676
2983 USP20 UCAAGAAAGCCCAGGUAUU NM_006676
2984 USP20 GGGAGUAGCUGCUGCUUCA NM_006676
2985 USP20 GUACAAACUCGGAGCAAGU NM_006676
2986 USP20 GAAAGGAGGACCUGGCCAA NM_006676
2987 USP20 AGUUAAAGGGUGACAACAU NM_006676
2988 USP20 AUGAGAAACGGGAGGGUGA NM_006676
2989 USP20 GAGUGACACGGAUGAGAAA NM_006676
2990 USP20 GCAUGAAGAACCUCGGGAA NM_006676
2991 USP20 CGCCAGAGCCGGACAAUGA NM_006676
2992 USP20 CGUCGUACGUGCUCAAGAA NM_006676
2993 USP20 GGUGUAAGAAGCUGCGGAA NM_006676
2994 USP20 GGUACGAGUUUGAUGACCA NM_006676
2995 USP20 UGCAGAACGCCGAGGGCUA NM_006676
2996 USP20 GGGCAGAUUUCGGAGGAGA NM_006676
2997 USP20 GUAAAGAGGCAGAAAAGUU NM_006676
2998 USP20 CCUGUGAGAAGGAGGUAUU NM_006676
2999 USP20 GGAACCGGAUGAUGAAACA NM_006676
3000 USP20 GGACCAAACCUAUGGGCCU NM_006676
3001 USP20 CCAUUCAUGCACAGGCAAA NM_006676
3002 USP20 UCUGAAAGCUGUUCCUAUU NM_006676
3003 USP20 AAGCACAACUUGACCGUGA NM_006676
3004 USP20 ACGAGACGGUGGUGCAGAA NM_006676
3005 USP20 CUGCUCAAAUCUAAGGGAA NM_006676
3006 USP20 GAGCUGAUGCUAAAGAAGA NM_006676
3007 USP20 CGAGUGACACGGAUGAGAA NM_006676
3008 USP20 UCUCUGAGGUCUGGCAUAA NM_006676
3009 USP21 GCUAGAAGAACCUGAGUUA NM_012475
3010 USP21 GAGCUGUCUUCCAGAAAUA NM_012475
3011 USP21 GAGCCAACCUAAUGUGGAA NM_016572
3012 USP21 GUGCCAGGCCUGUGGGUAU NM_012475
3013 USP21 AAGAAGAGCUAGAGUCGGA NM_016572
3014 USP21 GUUUCAACCUUUUCACUAA NM_012475
3015 USP21 GGUUGUAGCUCCAUUAUUU NM_016572
3016 USP21 CACUAAGGAAGAAGAGCUA NM_012475
3017 USP21 CUAAGGAAGAAGAGCUAGA NM_016572
3018 USP21 CGGCAGAAAACUCGAAGUA NM_012475
3019 USP21 GUACAAAGAUUCCCUCGAA NM_012475
3020 USP21 UGAUGAACGGCUCAAGAAA NM_012475
3021 USP21 CCACCCACUUUGAGACGUA NM_012475
3022 USP21 GCGAGAGGACAGCAAGAUU NM_016572
3023 USP21 CUGUGAAGCCCUUUAAACA NM_012475
3024 USP21 GUUAAGUGAUGAUGACCGA NM_016572
3025 USP21 GAGCGAGAGGACAGCAAGA NM_012475
3026 USP21 CCUCAGAGACGUCUAUUUU NM_012475
3027 USP21 GCAGCAAGGAGCGCAGAAA NM_012475
3028 USP21 GCGCAGAAACCCAGCCUCU NM_012475
3029 USP21 UAGAAGAACCUGAGUUAAG NM_012475
3030 USP21 CUUCGAAACCUGGGAAACA NM_012475
3031 USP21 GAACCUGAGUUAAGUGAUG NM_012475
3032 USP21 UGGCAUCCAGCGAGGGCUA NM_012475
3033 USP21 AGUUGACAGUACAAAGAUU NM_016572
3034 USP21 UUCAGUAGGUGUAGACUUU NM_016572
3035 USP21 GCAGGAUGCCCAAGAGUUC NM_012475
3036 USP21 CGGGAUUGUUUCAACCUUU NM_016572
3037 USP21 CUGAUGAACGGCUCAAGAA NM_016572
3038 USP21 AUGAACGGCUCAAGAAACU NM_016572
3039 USP22 CUGCAAAGGUGAUGACAAU XM_042698
3040 USP22 CCAAGGAGGAGCAGCGAAA XM_042698
3041 USP22 UGACAAAGACAUGGAAAUA XM_042698
3042 USP22 GGACUACAUCUAUGACAAA XM_042698
3043 USP22 CCACAAAGCAGCUCACUAU XM_042698
3044 USP22 CAGCGAAAAGCUUGGAAAA XM_042698
3045 USP22 GCAAACCGGUUCAGUGCUA XM_042698
3046 USP22 AUGACAAAGACAUGGAAAU XM_042698
3047 USP22 GCGAGGGCAACGUGGUAAA XM_042698
3048 USP22 AGGACUACAUCUAUGACAA XM_042698
3049 USP22 CAACAAUGACAACAAGUAU XM_042698
3050 USP22 ACUGAGAGCCUAUGACAAU XM_042698
3051 USP22 CAACCAAACGGGAGCUUGA XM_042698
3052 USP22 CCGAAAAGGAGAAAGAUCA XM_042698
3053 USP22 GGAGAAAGAUCACCUCGAA XM_042698
3054 USP22 GUGGACAACUGGAAGCAGA XM_042698
3055 USP22 AGCAAAGAGAGCAGGAUGA XM_042698
3056 USP22 GCAAAGAGAGCAGGAUGAA XM_042698
3057 USP22 GCAGCAGCGCCAAGAUCAA XM_042698
3058 USP22 GACAAAGACAUGGAAAUAA XM_042698
3059 USP22 UCACAAAGAAGCAUAUUCA XM_042698
3060 USP22 CGGACAGUCUCAACAAUGA XM_042698
3061 USP22 GCAAGGCGUUGGAGAGAAG XM_042698
3062 USP22 GCAGCUUCAAGGUGGACAA XM_042698
3063 USP22 CCUCACUGUUUCAGGAGUU XM_042698
3064 USP22 AAAUAAUCGCCAAGGAGGA XM_042698
3065 USP22 GCAUCAUAGACCAGAUCUU XM_042698
3066 USP22 UCAACAAUGACAACAAGUA XM_042698
3067 USP22 GAAGCAUAUUCACGAGCAU XM_042698
3068 USP22 GAGCGAGGGCAACGUGGUA XM_042698
3069 USP24 CCAACUACUUCAUGAAAUA XM_165973
3070 USP24 CCUCAUGAGUUAAAGAAUA XM_165973
3071 USP24 CUAUAGAGGCUCACAGUAA XM_165973
3072 USP24 UGACACAGUUAUAGAAGAA XM_165973
3073 USP24 GAACAAAUCCUUACAGUGA XM_165973
3074 USP24 GAAUGUUGCUCCUGGCAUA XM_165973
3075 USP24 GGACGAGAAUUGAUAAAGA XM_165973
3076 USP24 GAGAUUACUUGGCUGGAUA XM_165973
3077 USP24 GAGAACAGCAGGAUGCAUA XM_165973
3078 USP24 GCCAAAUCCUUCUGUGAAA XM_165973
3079 USP24 GGGAGUAGCCAGCCAAUUA XM_165973
3080 USP24 GGAUGAAUACCUCAAGAAA XM_165973
3081 USP24 AAAGCAAGCUGCAGUACUA XM_165973
3082 USP24 GAAAAUGCCUGCUCGAAUA XM_165973
3083 USP24 CUACGAUGCUUGAAGAUGA XM_165973
3084 USP24 GAAUAGAGAUGUAUACAGU XM_165973
3085 USP24 AGAAGAAGAUGUCAGAACA XM_165973
3086 USP24 GGAAAUGCUUGGUUCAUCA XM_165973
3087 USP24 GGGAAUCUGUGUUCGACAA XM_165973
3088 USP24 CAACUUGAUUCUUUAGGAA XM_165973
3089 USP24 UUGAUCAGAUGGAUGAAUA XM_165973
3090 USP24 UGACAGUAAUGAAACCAUA XM_165973
3091 USP24 GUUCUAAGCUCCAAACUCA XM_165973
3092 USP24 CGAAACAGACUCAGCAGUU XM_165973
3093 USP24 GAAAAGGACCUGUAUUAAA XM_165973
3094 USP24 AAACAAACCCAUACACUGA XM_165973
3095 USP24 GAAAAGAGAAUAACAGUGA XM_165973
3096 USP24 AGGGAAACCUUACCUGUUA XM_165973
3097 USP24 CCACAGCUUUGUUGAAUGA XM_165973
3098 USP24 UUACCAAGGAGUUUGAUUA XM_165973
3099 USP25 GCACAGAAACAGAGAAAUA NM_013396
3100 USP25 UGGAAUAACUGAUGAGGAA NM_013396
3101 USP25 GGGAAGAGCUAGUGAGGGA NM_013396
3102 USP25 GGGAGUACUUGAAGGUAAA NM_013396
3103 USP25 CUGUAGAAGAUAUGAGAAA NM_013396
3104 USP25 GGGAAGAGAUCAAGAGACU NM_013396
3105 USP25 GCUAAAGAAUGUUGGCAAU NM_013396
3106 USP25 GAAAGUUGCUCAAGCCAAA NM_013396
3107 USP25 GAUAAAACCUGAAGAAGUA NM_013396
3108 USP25 AACAAAGGCUAGAAAGAUA NM_013396
3109 USP25 GGCAAUACUUGUUGGUUUA NM_013396
3110 USP25 UAUAGGAAAUUCAGGGAAA NM_013396
3111 USP2S CAUCAGGAUUAUAGGAAAU NM_013396
3112 USP25 CAUUAUUACUGGUGGAUGA NM_013396
3113 USP25 CAGAAAGCUUUGCAGGAAA NM_013396
3114 USP25 ACAGAUACAUGCACAGAAA NM_013396
3115 USP25 GCAGAUGGAUGAAGUACAA NM_013396
3116 USP25 GCAUCAGGAUUAUAGGAAA NM_013396
3117 USP25 GGACAGAAAUAGAAAAUGA NM_013396
3118 USP25 CCAGCAUAGCAGAGAAUAA NM_013396
3119 USP25 GGUAAAUCCAGGAGUGUAU NM_013396
3120 USP25 UGGAGAGGAUCGAGAAGUA NM_013396
3121 USP25 UGGGAGUACUUGAAGGUAA NM_013396
3122 USP25 CCACCGGAUUUGAGAGAUU NM_013396
3123 USP25 CGUGAAAGCAGAUGGAUGA NM_013396
3124 USP25 GAGCAUUGGUUUACUGAAU NM_013396
3125 USP25 GGAAUUUGCCUCAAGUAAA NM_013396
3126 USP25 AGGCAAUUAAGUUGGAAUA NM_013396
3127 USP25 GAACCAGGCACCAAAGAAA NM_013396
3128 USP25 GAGCAAUUGCCUUGAGUUU NM_013396
3129 USP26 CCACAAAGCUGGAGGUAAA NM_031907
3130 USP26 CCACAAAGUUGAUGAGAAA NM_031907
3131 USP26 CAGAAGAGCUUGAGUAUAA NM_031907
3132 USP26 AAGCUAUAAUCGAGAGAAA NM_031907
3133 USP26 ACAAAGGAAUCCAAAGAUA NM_031907
3134 USP26 GAACGAUGCUCAUGAGUUU NM_031907
3135 USP26 GAGUGAGGAUGGAGAAAUU NM_031907
3136 USP26 GGUUACACAAAGUGGGAUA NM_031907
3137 USP26 UAUCAGAAUUCCAGAAAGA NM_031907
3138 USP26 GCACAACACAGAAGGAAAU NM_031907
3139 USP26 CCUAUGACUUUGAGAAACA NM_031907
3140 USP26 GCAAAAGUACCUUGGAAAA NM_031907
3141 USP26 ACACAAAGUGGGAUAAAUU NM_031907
3142 USP26 CAGCACAAGAAGAGGAAAA NM_031907
3143 USP26 CCAAUAAGAAUCCAAGAAA NM_031907
3144 USP26 CCACAGAUGCUGAACAAUU NM_031907
3145 USP26 GCUAUAAUCGAGAGAAACA NM_031907
3146 USP26 UUGAAGCAGUGGAAAGAAA NM_031907
3147 USP26 CCUAAGACCUACAAAAUUA NM_031907
3148 USP26 CUGAAAGAUAACAUGGAAA NM_031907
3149 USP26 CAGAGAUGAAUGAGGAAUU NM_031907
3150 USP26 GAGAAAUCAAGUAGCAAAU NM_031907
3151 USP26 GAAAUGAUGAUAAGGGAGA NM_031907
3152 USP26 GAGAGAAACAAUUGAAGUU NM_031907
3153 USP26 UGGAAAGAAAGAAGAAAGA NM_031907
3154 USP26 CAACAAAGGAAUCCAAAGA NM_031907
3155 USP26 CUGUUUAGAUCAACUGAAA NM_031907
3156 USP26 GAGCAGAAGAGCUUGAGUA NM_031907
3157 USP26 CCGAAAAUCCAAAACGAAA NM_031907
3158 USP26 GCAGAAGACAGCAGCAAAA NM_031907
3159 USP28 GGGAAGAAGUUGAAAGAGA NM_020886
3160 USP28 CCAUUGAGGUCAUGAGAAA NM_020886
3161 USP28 GGACAAGAGCGUUGGUUUA NM_020886
3162 USP28 UGGAAAGGUAUGUGAAAUA NM_020886
3163 USP28 UCACAGAUGAGGAGAUAAA NM_020886
3164 USP28 AAGCGAAACUGAAGGAAAU NM_020886
3165 USP28 GCAAGGAGCUUAUUCGAAA NM_020886
3166 USP28 GGCAAUACAUGUUGGUUUA NM_020886
3167 USP28 GGAACAGUUUGCAGAUAAA NM_020886
3168 USP28 GAAGGUGGCUCAAGCGAAA NM_020886
3169 USP28 GAAAUAAGAGAGAGUGUAU NM_020886
3170 USP28 CUGUGGAACUCAAGCAUUA NM_020886
3171 USP28 GAAAGUUGAAGGAGGAAAU NM_020886
3172 USP28 GGAAGAAGUUGAAAGAGAU NM_020886
3173 USP28 GGCAGAAAGCAGUGUAUUA NM_020886
3174 USP28 AGUUGAAGGAGGAAAUAAA NM_020886
3175 USP28 GACCAGACAUCCAAGGAAA NM_020886
3176 USP28 ACAAGGAAGUAUUAGCAAA NM_020886
3177 USP28 AGAAGUGGCAUGAAGAUUA NM_020886
3178 USP28 GAGAGAAAUCACAGGCAUU NM_020886
3179 USP28 UGUCGAAGUCAUACAGAAA NM_020886
3180 USP28 CAAGCGAAACUGAAGGAAA NM_020886
3181 USP28 CAGCAAGAUGUGAGUGAAU NM_020886
3182 USP28 UGGAACAGUUUGCAGAUAA NM_020886
3183 USP28 GAUUAUAGUUUGUUCCGAA NM_020886
3184 USP28 UGAAUAUGGAAGAGUACAA NM_020886
3185 USP28 CUAAACGCUCAAAGAGAAA NM_020886
3186 USP28 GGAGUGAGAUUGAACAAGA NM_020886
3187 USP28 AAUUCAAGCUGAUGGAAGA NM_020886
3188 USP28 GCAACUUAGACGAGUGUUU NM_020886
3189 USP29 GUACAAAGAUCAAGAGAGA NM_020903
3190 USP29 GGAAUAUGCUGAAGGAAAU NM_020903
3191 USP29 AGGAAUAUGCUGAAGGAAA NM_020903
3192 USP29 AGACAGAUUCCUUGAAAUA NM_020903
3193 USP29 ACAAAGAUCAAGAGAGAAU NM_020903
3194 USP29 AUACAAAGCAAUAGGAAGA NM_020903
3195 USP29 CCAAGGAACUAACAAGAAA NM_020903
3196 USP29 CAUCAAGUUUAGAGGAUUU NM_020903
3197 USP29 CAUGAAAGUUUGAAGAACA NM_020903
3198 USP29 GGAUGAAAUCUCAAUGAAA NM_020903
3199 USP29 UGAAAGAAGACAUGGAAAA NM_020903
3200 USP29 GAUGAUAUCUCUAAAGGUA NM_020903
3201 USP29 CAAUCAGUCUACAGAAUUA NM_020903
3202 USP29 GGUGAAGAAUAACGAGCAA NM_020903
3203 USP29 GUGCAAAGACAAAAGGAAA NM_020903
3204 USP29 UUGAGGAGCUGUUAAGAAA NM_020903
3205 USP29 GCUAGGGACUGAUUAGAAA NM_020903
3206 USP29 GCUGAAGGAAAUUGACAAA NM_020903
3207 USP29 GAAACAGUGCAAAGACAAA NM_020903
3208 USP29 GGUUGCUGGUGAAGAAUAA NM_020903
3209 USP29 AAGAAGAAGAGCUUGAAUA NM_020903
3210 USP29 UUGUAAAGCUUGUGGUCAU NM_020903
3211 USP29 AGAAGAAGAGCUUGAAUAU NM_020903
3212 USP29 GAGAGAAUUACUUGGGAAU NM_020903
3213 USP29 GUAUGAAGAUGGAGGGAAG NM_020903
3214 USP29 CUUUAAAGAAGAAGAGCUU NM_020903
3215 USP29 CCAGAGAGACUGUGGAGAU NM_020903
3216 USP29 CAGAAGAUGCCUUUGUUUA NM_020903
3217 USP29 CUGAAAGAAGACAUGGAAA NM_020903
3218 USP29 GGAAAAUGGCUCUGCACUA NM_020903
3219 USP3 GUAGAAGAGUUUAGAAAGA NM_006537
3220 USP3 GGAGUUAAGGAAUGGGAAA NM_006537
3221 USP3 GUGAUGAUUUUGUGGUUAA NM_006537
3222 USP3 UGGUAGAAGAGUUUAGAAA NM_006537
3223 USP3 GGACAGCAUAUUUAAGAAA NM_006537
3224 USP3 AGAAGAACUUGAUGAGACA NM_006537
3225 USP3 GGGACAGAAUCUAGAAAGU NM_006537
3226 USP3 CACAAUGACUGCUGAGGAA NM_006537
3227 USP3 UAACAAAGGGCAUCAUUAA NM_006537
3228 USP3 CCAAGUCAGUUCAGAAGUA NM_006537
3229 USP3 CCACAAAAUUUCACAAUGA NM_006537
3230 USP3 GGCCAAAGCUGGAUCGGAU NM_006537
3231 USP3 CUAGAAAGUUUGAUCCAUU NM_006537
3232 USP3 GACAGAAUCUAGAAAGUUU NM_006537
3233 USP3 GAGAACACUUACAGAACUU NM_006537
3234 USP3 GCUCUAAGAAUCAAGAAAA NM_006537
3235 USP3 ACUCAACACUAAACAGCAA NM_006537
3236 USP3 GGCUAUAUUCGGAGGCAUU NM_006537
3237 USP3 AGACUGUGGUGAAGGCGAA NM_006537
3238 USP3 CCAUGAAUUCAAUGCGCUA NM_006537
3239 USP3 GGGAUAACAAUGUGUCUUU NM_006537
3240 USP3 AGAAGAGUUUAGAAAGACA NM_006537
3241 USP3 UUGCAUAAAUGGAGCAUCU NM_006537
3242 USP3 ACGAGGAGACUGUGGUGAA NM_006537
3243 USP3 GUACAGAAAGUCAGAGAAC NM_006537
3244 USP3 UUGAUGAGACAGAGUUAUA NM_006537
3245 USP3 GCUGAAAGCAAGAUGUGUU NM_006537
3246 USP3 ACACUAAACAGCAAGUUAU NM_006537
3247 USP3 CCAAAGCUGGAUCGGAUAA NM_006537
3248 USP3 CGUAGAAUUUCCACUGAGA NM_006537
3249 USP30 GUACAAAGAUUGAAGCCAA NM_032663
3250 USP30 GAAAUAACUCCCAAACAAA NM_032663
3251 USP30 GGGAGUUAUAGGUGGAAUU NM_032663
3252 USP30 CAUUGGAAGAUGAGCGAGA NM_032663
3253 USP30 GGACAUAAACCUAGUCAAC NM_032663
3254 USP30 ACAGAAAGAAAGAAGCGUA NM_032663
3255 USP30 CAUCAGAAUCAGUGCGGGA NM_032663
3256 USP30 GCGCCUACCUGCUGUUCUA NM_032663
3257 USP30 GAACAAGAACCCAGGGCCU NM_032663
3258 USP30 UGAUGGACAUUUACAAGUA NM_032663
3259 USP30 UGUUGGAUGUCUUAAGAAU NM_032663
3260 USP30 AAGAAAGAAGCGUAGAAAA NM_032663
3261 USP30 AGAAAGAAGCGUAGAAAAG NM_032663
3262 USP30 GCCAAGAAGUUACUGAUGA NM_032663
3263 USP31 GGAUAAAGGAAAAGCAAAA NM_032236
3264 USP31 GUGCAAGAUUUUAGAAAGA NM_032236
3265 USP31 CAAAUUUGUUCCAGGAUAA NM_032236
3266 USP31 GGACAAGGAAGAAGCUAAA NM_032236
3267 USP31 GAAGAAGGGUUUAAAGGUA NM_032236
3268 USP31 GAAAAGAAGAGGAGGAAUU NM_032236
3269 USP31 CAGUAAAGGGCGAUGGAUU NM_032236
3270 USP31 GCAGGAUGCUCAAGAAUUU NM_032236
3271 USP31 CCAAAUUUGUUCCAGGAUA NM_032236
3272 USP31 CCAUAAAGUUGUGGAUAAU NM_032236
3273 USP31 GCAAACUGGACAUAAGAAA NM_032236
3274 USP31 GUUUAAAGGUACUGGUCUU NM_032236
3275 USP31 AAGAAGAGGAGGAAUUAAA NM_032236
3276 USP31 CUGAAACAGAGGAGGACAA NM_032236
3277 USP31 GGCGGAAAUUUGUUAGAAA NM_032236
3278 USP31 AGUAGAACGUUGUCGCAUA NM_032236
3279 USP31 ACAGCAAGUCUGAGGACAA NM_020718
3280 USP31 AUGCAAAUACAACGGGAAA NM_020718
3281 USP31 CUUCAAGACUAUUGUGUCA NM_020718
3282 USP31 UGUCAGAAACAGAGCAACA NM_020718
3283 USP31 UCGUAGAUACACAGAGCAA NM_020718
3284 USP31 CAAAGAAACCAGAGAGCAC NM_020718
3285 USP31 UUGUAAAUACUGAGGAUGA NM_020718
3286 USP31 AUUUAGGCCUGAAGGAAUU NM_020718
3287 USP32 AGGCAAAGAUGAAGAGAAA NM_032582
3288 USP32 GGAGAUAUCCUGUGGGUUA NM_032582
3289 USP32 GUAAAUGGUCGGUGGAUAA NM_032582
3290 USP32 GAUCAAUUGUUGUGGAUUU NM_032582
3291 USP32 GGACAAAUUAUUAGAGGAU NM_032582
3292 USP32 GGAAGAAGAAGGACAAAUU NM_032582
3293 USP32 GAAUACUACAGAAGAGAAA NM_032582
3294 USP32 GCAUUAAAGAGGAAGAUAU NM_032582
3295 USP32 CAGCUAAGAUCUCAAGUAA NM_032582
3296 USP32 GCAUAUAAGUGUCCGAUUU NM_032582
3297 USP32 GGACAAAUCCCAUUGGUAU NM_032582
3298 USP32 GUACAUGGUUCCAACAUAA NM_032582
3299 USP32 GAGAAACGCUAUUGGUUAU NM_032582
3300 USP32 AGUAAAGGCUACAUCAUUA NM_032582
3301 USP32 UGGCAAGGGAGGUGAAGAA NM_032582
3302 USP32 UGGCAACAGUGGAAAGAAU NM_032582
3303 USP32 ACUAGAAGGAGGACGAUUA NM_032582
3304 USP32 GAACUAUGUUAUACGGGAA NM_032582
3305 USP32 UCACAAAUGGAAUGGUUAA NM_032582
3306 USP32 UAUCAAACAUCCCAGGAAA NM_032582
3307 USP32 CAGUAUGGAUGAAGACUUU NM_032582
3308 USP32 GGACAACCAUCUAAGAAGA NM_032582
3309 USP32 GUGGAAAGAAUAUGUCAAA NM_032582
3310 USP32 UGAUAUUGUAGAAGGCAUA NM_032582
3311 USP32 AUGCAGACCAUCAAGGAAA NM_032582
3312 USP32 ACGAUUUGAUUUAGAGACA NM_032582
3313 USP33 CAGCAGAGCUUCAGAAUAU NM_015017
3314 USP33 UUUUGAAAGUCUUGGGAAA NM_015017
3315 USP33 CAACAGUGAUAGAGCAGAA NM_015017
3316 USP33 AAAGAGAAGAUGUGCAAUA NM_015017
3317 USP33 AGACAAUGGAAGAAGACAA NM_015017
3318 USP33 AGACAUAUUUGAUGGAACA NM_015017
3319 USP33 GGAAAUACUUGUUACAUGA NM_015017
3320 USP33 CAGCUCAAAUUGUGACAUA NM_015017
3321 USP33 UGGAAUAUGUGAAGAGGUU NM_015017
3322 USP33 AGUCAUGGAAGUAGAAGAA NM_015017
3323 USP33 AAAGAGAGGAGAAGGAUAU NM_015017
3324 USP33 UCAGAAAUGUCAAAGGAUU NM_015017
3325 USP33 AGUAAAUUCUGAAGGCGAA NM_015017
3326 USP33 CGACAGUGGCUUAAUAAAU NM_015017
3327 USP33 CUGAAACAGUCGACUUAAA NM_015017
3328 USP33 GGACUAGCUCGAACAGAUA NM_015017
3329 USP33 GGGCAUGUCUGGAGAAUAG NM_015017
3330 USP33 UCAUGGAAGUAGAAGAAGA NM_015017
3331 USP33 GGAGAAGGAUAUCAAAUUU NM_015017
3332 USP33 UCAUGUUGAUCCAGAUAUA NM_015017
3333 USP33 UGGAAGAAGACAAGAGCCA NM_201624
3334 USP33 AUAUAGAAGCGGAUGAAGA NM_015017
3335 USP33 GGAAACUGUCAAAGUGCAA NM_201624
3336 USP33 GAUCAUGUGGCGAAGCAUA NM_015017
3337 USP33 CAAUGUUAAUUCAGGAUGA NM_015017
3338 USP34 GGAUAUAGUCCAAGAUGAA NM_014709
3339 USP34 GCGGAAAGCCAUAGGAAAA NM_014709
3340 USP34 CUACAAAGCUAGUGCCCUA NM_014709
3341 USP34 CAGGUUAAGUUUAGAGCAA NM_014709
3342 USP34 AUAGAAAGUUAGAGAGUCA NM_014709
3343 USP34 GGGAAGAAGAAGAGGAGGA NM_014709
3344 USP34 GGGCAUGUUUUAAGAAAUU NM_014709
3345 USP34 CAAGCUAAUAGGAGGGAAA NM_014709
3346 USP34 GCAUGGAACCAGAGGAAGA NM_014709
3347 USP34 GGUUCAAAGUCAAGUGUUU NM_014709
3348 USP34 GGGAAAGAGUGAGAGGAAA NM_014709
3349 USP34 GAAGAAAGUACGAGCUGAA NM_014709
3350 USP34 CGGAAUAGAAAGUUAGAGA NM_014709
3351 USP34 GAGCAAGAAGCCAAAGAAA NM_014709
3352 USP34 CCUAAUAUGUUGAUGGCAU NM_014709
3353 USP34 GCAUAUAAUCCUAGACCUU NM_014709
3354 USP34 GGAUAUGGGAGGUGAUUGA NM_014709
3355 USP34 UGGGAAAGAGUGAGAGGAA NM_014709
3356 USP34 GAGAAGAAGAAUUAGAAGA NM_014709
3357 USP34 AUUAAAGCACUGUGGAAUA NM_014709
3358 USP34 CAUAUUUAAUGGAGAGUGA NM_014709
3359 USP34 GAACCAAACAUGUGCAACA NM_014709
3360 USP34 AGAUAUGAGAGAAGAAGAA NM_014709
3361 USP34 CAAAAGACUCAGAGAGCUA NM_014709
3362 USP34 CAGAAAGGCAUUUGACAUU NM_014709
3363 USP34 GAGCUUACGAUGUGAAGAA NM_014709
3364 USP34 CAUCUGAGACAGUGGCAAA NM_014709
3365 USP34 CCAAGUAUUCAGAGGAUAU NM_014709
3366 USP34 GGAAAGAGUGAGAGGAAAG NM_014709
3367 USP34 UCUCAUGGUUAUAGAAAGA NM_014709
3368 USP35 GGAUAGAGAGGGAGGAAGA XM_290527
3369 USP35 AAGAAGAGAAGGUGGAGAA XM_290527
3370 USP35 AGGAAAGGAUAGAGAGGGA XM_290527
3371 USP35 GUGGAGAAGGAGACAGAAA XM_290527
3372 USP35 UGGAAGAGGAAGAAGAGAA XM_290527
3373 USP35 AAGAGAAGGUGGAGAAGGA XM_290527
3374 USP35 AAGACAAGGAUGAGGAUGA XM_290527
3375 USP35 GGAAGGAGAGAGGGAGAAA XM_290527
3376 USP35 AGAAAGAGGAGGAGGUGGA XM_290527
3377 USP35 GGAAAGCACCAGAGGGGAA XM_290527
3378 USP35 GUUAAGAAGUUCAGCAUCU XM_290527
3379 USP35 GGGAGAAAGAGGAGGAGGU XM_290527
3380 USP35 AAGGAGAGAGGGAGAAAGA XM_290527
3381 USP35 CCGAGAAGGUGGUGGAGCU XM_290527
3382 USP35 AAGAGGAGGAGGUGGAAGA XM_290527
3383 USP35 GCUCGGAGUAUCUGAAGUA XM_290527
3384 USP35 AGAGCGAGCUGGCGGGUUU XM_290527
3385 USP35 AGGAAGAAGGGAAGGAGGA XM_290527
3386 USP35 GGAGGAGGUGGAAGAGGAA XM_290527
3387 USP35 AGGAGGAGGUGGAAGAGGA XM_290527
3388 USP35 AGAGGGAGGAAGAAGGGAA XM_290527
3389 USP35 AGGAAGAAGAGAAGGUGGA XM_290527
3390 USP35 AGGAGGUGGAAGAGGAAGA XM_290527
3391 USP35 AGACAAGGAUGAGGAUGAA XM_290527
3392 USP35 GGAAGAGGAAGAAGAGAAG XM_290527
3393 USP35 AGAGAACGGAGAAGGAAGA XM_290527
3394 USP35 GAGAAGGUGGAGAAGGAGA XM_290527
3395 USP35 AGACAGAAAAGGAGGCUGA XM_290527
3396 USP35 AGGUGGAGAAGGAGACAGA XM_290527
3397 USP35 AGGUGGAAGAGGAAGAAGA XM_290527
3398 USP36 GGGAAGAGGAAGAGGAAGA NM_025090
3399 USP36 GGAAGAGUCUCCAAGGAAA NM_025090
3400 USP36 UGAUAAAGCUUACGGGAGA NM_025090
3401 USP36 CGUAUAUGUCCCAGAAUAA NM_025090
3402 USP36 GGAAGAGGAAGAAGAAGAA NM_025090
3403 USP36 CUGGAAAGAAGGUGAAGAA NM_025090
3404 USP36 AGGAAGAGGAAGAAGAAGA NM_025090
3405 USP36 AAAGAAAGCAGGAGACACA NM_025090
3406 USP36 GGACUGAGACCGUGGUUGA NM_025090
3407 USP36 GCACACCACUGAAGAGAUU NM_025090
3408 USP36 UGUCCUGAGUGGAGAGAAU NM_025090
3409 USP36 GUGCUAAAUGCAAGAAGAA NM_025090
3410 USP36 AAGAGAGAGAAGAGGAGAA NM_025090
3411 USP36 GGGAAGGAAAAGAAAAUUA NM_025090
3412 USP36 AGAGAGAAGAGGAGAAACU NM_025090
3413 USP36 CCAAGAAGAACAUCGGCAA NM_025090
3414 USP36 GGAAAGGAGCAGAAGGUCU NM_025090
3415 USP36 GGACAGUGGUACCAGAUGA NM_025090
3416 USP36 CACCAAGGAUGUAGGCUAU NM_025090
3417 USP36 GAAAGGAGCAGAAGGUCUU NM_025090
3418 USP36 AGCAGAAGGUCUUGGUGAA NM_025090
3419 USP36 UCACCAAGGAUGUAGGCUA NM_025090
3420 USP36 AGAGAGAGAAGAGGAGAAA NM_025090
3421 USP36 AGAGGAAGAGGAAGAAGAA NM_025090
3422 USP36 GAGGAGGAAAGGAGCAGAA NM_025090
3423 USP36 CGACAAGACUCUGGGACGA NM_025090
3424 USP36 CUCAAAUACUCAUCUGAUA NM_025090
3425 USP37 CUACAAUACUGGAGGAAUU NM_020935
3426 USP37 GAAGAUUACCCUAAGGAAA NM_020935
3427 USP37 CAAAAGAGCUACCGAGUUA NM_020935
3428 USP37 GAAAAGAAAUGCUGAGACA NM_020935
3429 USP37 GCUCAGAAUUGAAUGAAGA NM_020935
3430 USP37 AAGUAAGGAUGCAGAGGAA NM_020935
3431 USP37 GCGUGAAAGGGAAGAGCAA NM_020935
3432 USP37 GUGAAAGGGAAGAGCAAGA NM_020935
3433 USP37 GUAAGGAUGCAGAGGAAAU NM_020935
3434 USP37 GGAAAUACCUGCUAUAUGA NM_020935
3435 USP37 CCGAAGAACUGGAGUAUUC NM_020935
3436 USP37 GAAAAGAGGAAAAGAAUGA NM_020935
3437 USP37 GAGAAAAGCAGCUGAGUUU NM_020935
3438 USP37 CUGAAAGAAGAUAUGGAAA NM_020935
3439 USP37 GAUUAAGACUGUAGCAGGA NM_020935
3440 USP37 UCGAAAAGUUCUUGGUAAU NM_020935
3441 USP37 CAGCUAAGUCAUAACAUUA NM_020935
3442 USP37 GAAGAAAAUUCACCAGAUA NM_020935
3443 USP37 ACUCAGGAUUUGACAGAAU NM_020935
3444 USP37 AGAUCAGGGUUGCUAGAAA NM_020935
3445 USP37 GAAACAGUCAGAAGAGAAU NM_020935
3446 USP37 GGGCCGAAGAACUGGAGUA NM_020935
3447 USP37 UGACAGAAUGAGCGAAGAA NM_020935
3448 USP37 AGCCAGAGACUUUGUGAAA NM_020935
3449 USP37 GAGAUAAGUAAGAGAGAUG NM_020935
3450 USP37 GGGAACAGAAAGAAGAUGA NM_020935
3451 USP37 CUGAGGAACUGAAAAGAAA NM_020935
3452 USP37 GGAGGAAUUCCAAGGAUAU NM_020935
3453 USP37 UGUAGCAGGAAGUGGAAUA NM_020935
3454 USP37 GAAUAGGACAUCAGGGCUU NM_020935
3455 USP38 GCAUAGUACUAAUGGUUUA NM_032557
3456 USP38 CAGAAGAACCAGUAGUUUA NM_032557
3457 USP38 ACACAAGCCUUCUGAAAUU NM_032557
3458 USP38 GGAAGUAGCUAGUAAAGCA NM_032557
3459 USP38 GAAAGAGAGCUGCGGGAAU NM_032557
3460 USP38 CAGCAAGACUGUUCUGAAU NM_032557
3461 USP38 ACUAAUGGUUUAAGUGGUA NM_032557
3462 USP38 UCAGAAACCAGGAGGUGAA NM_032557
3463 USP38 GGUAAUUGCACUCCUGAAA NM_032557
3464 USP38 GUAACUUGCUGCAGAACAU NM_032557
3465 USP38 GAGUUUUACUGUUCUGAAA NM_032557
3466 USP38 CUGGAUAAAUGGAGACCCA NM_032557
3467 USP38 GUAUCAUGUGAGAAGGAAA NM_032557
3468 USP38 UUUAAUGACAGUAGAGUGA NM_032557
3469 USP38 AGGUAGAGGUGUUACGGAU NM_032557
3470 USP39 UGAAUAACAUAAAGGCCAA NM_006590
3471 USP39 GAGAAUACUUGUCUGAAGA NM_006590
3472 USP39 CCAUGAGGAUCUUCACUAA NM_006590
3473 USP39 GCAUCACUGAGAAGGAAUA NM_006590
3474 USP39 ACGAGUACCAGGAGACAAU NM_006590
3475 USP39 CAAAUGUGGAUCUGAGAGA NM_006590
3476 USP39 UCACUGAGAAGGAAUAUAA NM_006590
3477 USP39 AGACUUACAAGGAGAACUU NM_006590
3478 USP39 CUGAAUAACAUAAAGGCCA NM_006590
3479 USP39 GGGUAUUGUGGGACUGAAU NM_006590
3480 USP39 UGGCUAAGUUCAAUGGCAU NM_006590
3481 USP39 UCUUCAACAUCCUGGCUAA NM_006590
3482 USP4 CCAAAUGGAUGAAGGUUUA NM_003363
3483 USP4 AGAACAAACUGAAUGGUAA NM_003363
3484 USP4 GAACAAACUGAAUGGUAAA NM_003363
3485 USP4 GGAACAAAUACAUGAGCAA NM_199443
3486 USP4 AGGAAGAAAUGGAGCAUCA NM_003363
3487 USP4 GGAAGAAGUAUGUGGGCUU NM_003363
3488 USP4 GAGAAGAUGAGGAAGAAAU NM_003363
3489 USP4 CUGCAUAUGCGAAGAACAA NM_003363
3490 USP4 CCUCAGAAGAAGAAGAAGA NM_003363
3491 USP4 AACAGAUACUGGAGGGAUA NM_003363
3492 USP4 GCAAAUGGUGAUAGCACUA NM_003363
3493 USP4 GGGAAGAUGAGCCAGGAAA NM_003363
3494 USP4 CCUACGAGCAGUUGAGCAA NM_003363
3495 USP4 GAACAGCUGUGAAGGAGAA NM_003363
3496 USP4 GGAAAUUGCAGAAGCCUAU NM_003363
3497 USP4 GGAAGAUGAGCCAGGAAAU NM_003363
3498 USP4 AAGGAGAAGAUGAGGAAGA NM_199443
3499 USP4 GGGAUAAGCUCGACACAGU NM_003363
3500 USP4 GCAUCAGGAAGAAGGCAAA NM_003363
3501 USP4 GGGAAAUUGCAGAAGCCUA NM_199443
3502 USP4 ACGAGAAGCAUGUGAGCAU NM_003363
3503 USP4 CAGAUGCGGUGGUGGCAAA NM_003363
3504 USP4 GAGAGGAAGUCCAGGCCAU NM_003363
3505 USP4 GCAAAGUCGAGGUGUAUUU NM_003363
3506 USP4 GAAGAAAGAUCGAGUUAUG NM_003363
3507 USP4 ACUGCAAAGUCGAGGUGUA NM_003363
3508 USP4 GCAAAGGAAGCCUGGGAGA NM_003363
3509 USP4 GAACUGAAGCUCUGUGAGA NM_003363
3510 USP4 UGAAGGAGAAGAUGAGGAA NM_003363
3511 USP4 CAGAAGAAGAAGAAGACCA NM_199443
3512 USP40 GGGAAGAAAUUAAAGACUA NM_018218
3513 USP40 GCUUUUAAUUGAAGGACAA NM_018218
3514 USP40 CAAAUAACCAAGAGGAAAA NM_018218
3515 USP40 GGAAAAGGGAAGAAAUUAA NM_018218
3516 USP40 AAACAAUAUCUGUGAGAGA NM_018218
3517 USP40 AGGAUAAACCCGAUGCAAA NM_018218
3518 USP40 CCAAGGAAGACAUGAGGAA NM_018218
3519 USP40 CAAUCUUAUUAGAGGAGAA NM_018218
3520 USP40 GCUCAGAAAUGGAAGCUCA NM_018218
3521 USP40 AGUUAGAAUCUGAAGAGAA NM_018218
3522 USP40 ACAAAUAACCAAGAGGAAA NM_018218
3523 USP40 GGACCAGUAAUGAGGAAAU NM_018218
3524 USP40 CUGAAGAGAAGCAAGUUAA NM_018218
3525 USP40 CCAGAGUGAAGAAGAGAUU NM_018218
3526 USP40 AAGGAAGACAUGAGGAAGA NM_018218
3527 USP40 UGAAAUUGCUGAUGGGGAA NM_018218
3528 USP40 UGUAAGAACGUUAGCGAGA NM_018218
3529 USP40 UGGAAAUCGUAGUAGAAGA NM_018218
3530 USP40 CUAUGAAGCUGGAGAGCCU NM_018218
3531 USP40 GGGACUGUGUCUUGGAAAA NM_018218
3532 USP40 AAGUAAACCAGAUGUGAAU NM_018218
3533 USP40 CCUGGACGGUGGAGAGGAA NM_018218
3534 USP40 GGAUUAAUCUCAAGCCCUU NM_018218
3535 USP40 CUGAUAUGUUCUGGAGAUA NM_018218
3536 USP40 GCAGAAUUGAAGAUGGGAA NM_018218
3537 USP40 AGUUAAUGCUGAAGAAAUC NM_018218
3538 USP40 AAUCAUCCCUUUACAGUUA NM_018218
3539 USP40 GGGAAAAGGAUAUUGAACA NM_018218
3540 USP40 AUGUUGAUCAUUUGGGAAA NM_018218
3541 USP40 CGGAGAUACUAUUGGUGUU NM_018218
3542 USP42 CGGAACAGCUUGAUGGAGA XM_374396
3543 USP42 GGGCAAGGAGAAUGGGAUU XM_374396
3544 USP42 CUAGAAGAGCCUAAAGCAA XM_374396
3545 USP42 UCUGAAACGUUUUGCAAAU XM_376571
3546 USP42 GGAGCAAGACUGAGGGCCA XM_374396
3547 USP42 CAGCAAUAAAUUAGACAGA XM_376571
3548 USP42 CAUAGUAAUUCUUUGGAGA XM_376571
3549 USP42 CAAGAAAAUCAGAGGACUU XM_376571
3550 USP42 AGUCAAAGGGGCUGGGCAA XM_374396
3551 USP42 CUGAAAGGCUCGACGGAUG XM_374396
3552 USP42 GCUUCAAAGAGGUUCACUA XM_374396
3553 USP42 CAGUCAUGUUGAAAAGAAA XM_374396
3554 USP42 CUUGAAUGGCAGCAAUAAA XM_374396
3555 USP42 GCUCCCAGCCCGUGAUGAA XM_374396
3556 USP42 CAGUGAUAUUAGAUCGGUA XM_374396
3557 USP42 CCAAAGACAAACACCGAGA XM_374396
3558 USP42 GUGCAGACAGCGACAGUGA XM_374396
3559 USP42 ACAAAAGGAUCAAGCCCUA XM_374396
3560 USP42 CUCCAGAAUUUGGGCAAUA XM_376571
3561 USP42 GCAACAAACUGAAAGGCUC XM_376571
3562 USP42 CCUGGAACGUACAGCUCUA XM_376571
3563 USP42 GCUUAGCAACAAACUGAAA XM_374396
3564 USP42 UCAACAAGGCAUUGGAGCA XM_374396
3565 USP42 CUUCAGGCUUAGCAACAAA XM_374396
3566 USP42 GGCCAUUACUUCUGCUACA XM_374396
3567 USP42 AAACACUUACGGAUGGAAA XM_376571
3568 USP42 CUAAAGCAAAGAAGCACAA XM_376571
3569 USP42 GGAAAGUCCCGGAAACGGA XM_374396
3570 USP42 CACUCUUGUUUGUCAGAUA XM_374396
3571 USP42 CAGUCUACCUCGAACGCAU XM_374396
3572 USP43 GCCAUGAACUGGAAGGAGA XM_371015
3573 USP43 GCUUGAAGAACCACGGCAA XM_371015
3574 USP43 GCUCUCAGUUCCAAGGCAA XM_371015
3575 USP43 AGACGAGGUUCUUGAGUGU XM_371015
3576 USP43 GCGCUCAGGGCUUGAAGAA XM_371015
3577 USP43 GGAAGAUGGUUGCAGAGGA XM_371015
3578 USP43 CGGAAGAAGGAGAACAGGA XM_371015
3579 USP43 GAGAUAAUGUGUAUGCCUU XM_371015
3580 USP43 GUGCAGUGUCUCAGCAACA XM_371015
3581 USP43 CAGCAAAGACAGUCGCCGA XM_371015
3582 USP43 AUACCAUCGCAGAGGGAGA XM_371015
3583 USP43 UGAACUGGAAGGAGAGCUU XM_371015
3584 USP43 GAGGAUGAGAAGUCAGCAU XM_371015
3585 USP43 CAGGUGGGCGAGAGAAGAA XM_371015
3586 USP44 GUAACAGGAUUGAGAAAUU NM_032147
3587 USP44 AAGCAGAAUUGGAAAGUAU NM_032147
3588 USP44 GAUUGAGAAAUUUGGGAAA NM_032147
3589 USP44 GUAUCAAGUUAAAGCAGAA NM_032147
3590 USP44 GUGUAACAGGAUUGAGAAA NM_032147
3591 USP44 GGAAAUACUUGCUAUAUGA NM_032147
3592 USP44 AAACUAAGCAUGUGCACUA NM_032147
3593 USP44 ACUAAGUGGUGGAGCAUCA NM_032147
3594 USP44 UCUUAAACAUGGAGCCCUA NM_032147
3595 USP44 AUGAAUGAAUGUCAGGAAA NM_032147
3596 USP44 CUGAAGCUUUAGAAGGAAA NM_032147
3597 USP44 GGUAAAAUCUUUCGAACAU NM_032147
3598 USP44 GAAUUGGAGUAUCAAGUUA NM_032147
3599 USP44 CUGAAAUGUUGGCCAAAUU NM_032147
3600 USP44 GCUCUUUGGCACAGGAGAA NM_032147
3601 USP44 CCAUGUUGCCUGUGGAAGA NM_032147
3602 USP44 GGACGUAAUAACCGAGAGA NM_032147
3603 USP46 CAGAAAAGGAUGAGGGUAA NM_022832
3604 USP46 CAGCAAAAGAAGAAGGAAA NM_022832
3605 USP46 UGAUGACAUUGUAGAGAAA NM_022832
3606 USP46 CCAAAGAAGUUCAUUUCAA NM_022832
3607 USP46 CUAUCAGUCAAGAGAGUAA NM_022832
3608 USP46 GAGGAGAAGAAACAGGAAA NM_022832
3609 USP46 AGCAAAAGAAGAAGGAAAA NM_022832
3610 USP46 GGUCAAUUUUGGAAACACA NM_022832
3611 USP46 AGGAGAAGAAACAGGAAAA NM_022832
3612 USP46 CUAAGAGACUUCAGCAACA NM_022832
3613 USP46 CAUACAAGGCCCAGCAAAA NM_022832
3614 USP47 GAACAGAAAUGGAAGCAAA NM_017944
3615 USP47 GAAAGCAAAUGAAGGGAAA NM_017944
3616 USP47 CCUGAAAGCUGAAGGAUUU NM_017944
3617 USP47 GCGCAAUACAUGCAAGAUA NM_017944
3618 USP47 GCUUAUAAGAUGAUGGAUU NM_017944
3619 USP47 AGGAAUGACUGUACGGCAA NM_017944
3620 USP47 CAGCAAAAGUACUGAGACA NM_017944
3621 USP47 GAAAAGAGACAACGAGAAA NM_017944
3622 USP47 GGAUAUUAUUCUAGUGCUU NM_017944
3623 USP47 GCUCCGAGACUUUGGAUUA NM_017944
3624 USP47 CGCAAUACAUGCAAGAUAA NM_017944
3625 USP47 UGACAGAUGAGCAAAGAAA NM_017944
3626 USP47 GUGAAUAAUGACAGGAGUA NM_017944
3627 USP47 GGAUAACACAAGAGGACAU NM_017944
3628 USP47 AGAGAGAGUUGGAAGAACA NM_017944
3629 USP47 GCAUUAUAUAAGUGGGAAU NM_017944
3630 USP47 GGAUGAUGACUGUGAAAGA NM_017944
3631 USP47 AAGGCAAGCUGAAGGACUA NM_017944
3632 USP47 AAAGGAGAAUACAGAGUUA NM_017944
3633 USP47 AGUAGAAGAACGAAAGCAA NM_017944
3634 USP47 GUAUAAAGUCAUUCAGUGA NM_017944
3635 USP49 GGGCAAGAGUGUUCAGCAA NM_004275
3636 USP49 GAGAAUGGCCCUUGCCUUA NM_004275
3637 USP49 GGGCAGAGAAGCAAGGAAC NM_004275
3638 USP49 GUGUGGACUGUGAGACUUA NM_004275
3639 USP49 UCGAGUUCCUACAGAGUUU NM_004275
3640 USP49 GGCAAGAGUGUUCAGCAAA NM_004275
3641 USP5 CCACAGAGAAGGUGAAGUA NM_003481
3642 USP5 UGGAUAAGCUGGAGAAGAU NM_003481
3643 USP5 UCAACAUGGUGGAGAGGAA NM_003481
3644 USP5 AGAGGAAGUAUGUGGAUAA NM_003481
3645 USP5 UGACUGAGUUGGAGAUAGA NM_003481
3646 USP5 AAGAGGAGCUUCUGGAGUA NM_003481
3647 USP5 GAGCAGAGGGGCAGCGAUA NM_003481
3648 USP5 GGAUGGUCCUGGAAAGUAU NM_003481
3649 USP5 UGGAGUACGAGGAGAAGAA NM_003481
3650 USP5 CGAGGAGAAGUUUGAAUUA NM_003481
3651 USP5 GGAUGCAGCCCUUAACAAA NM_003481
3652 USP5 AGAGAGAACCUGUGGCUCA NM_003481
3653 USP5 AGGAGAAGUUUGAAUUAGA NM_003481
3654 USP5 GAGCUGACGUGUACUCAUA NM_003481
3655 USP5 CAGAGGAAGUAUGUGGAUA NM_003481
3656 USP5 GCCUCAAGCAGUUGGACAA NM_003481
3657 USP5 GUGGAGAGACAUUUCAAUA NM_003481
3658 USP5 CAUCAAGAAAGAAGGCAGA NM_003481
3659 USP5 AAAGAAGGCAGAUGGGUGA NM_003481
3660 USP5 GCGAGGAGAAGUUUGAAUU NM_003481
3661 USP5 UGGAGAGACAUUUCAAUAA NM_003481
3662 USP5 AACAGUAUGUGGAGAGACA NM_003481
3663 USP5 CAAAAUACACGAUGUGAAU NM_003481
3664 USP5 CAGACAAGACGAUGACUGA NM_003481
3665 USP5 AAGUGUGACAUGAGAGAGA NM_003481
3666 USP5 AGUUGGAGAUAGACAUGAA NM_003481
3667 USP5 AAGCCGAAGAGGAGAAGAU NM_003481
3668 USP5 GAUCUACAAUGACCAGAAA NM_003481
3669 USP5 CCAAGUGUGACAUGAGAGA NM_003481
3670 USP5 GCUUCUUGGUGGAGGAAAG NM_003481
3671 USP52 GCAGAAAGAUGGACUGGAA NM_014871
3672 USP52 GGGAAAUCUCCAAGAACAA NM_014871
3673 USP52 GAGUCAAGUUUGUGGGUCA NM_014871
3674 USP52 UGGAAAUACCACAGGCUUA NM_014871
3675 USP52 CCAUUGAGGAGUUGAAGAA NM_014871
3676 USP52 AGAACAACCUCAAGUAUAU NM_014871
3677 USP52 UGGAUGAGAAUGAGGAUAU NM_014871
3678 USP52 GCACGGAAGCAGCGGAAAA NM_014871
3679 USP52 CCAUGAAGAAGGUGGGCUU NM_014871
3680 USP52 CCUUCAAGAUGGCAGUAAA NM_014871
3681 USP52 GCACUGAGCCUGAGUCUUU NM_014871
3682 USP52 CAUCAAAGUUGGAGAGACC NM_014871
3683 USP52 GUGUAUGACCUGAUGGCUA NM_014871
3684 USP52 GGGUCUGGAUGCUGAGUUU NM_014871
3685 USP52 GGGAAACCCAUGACAGUAU NM_014871
3686 USP53 CCUAAGAACUGUUGGGUUA XM_052597
3687 USP53 GCAAUGAGGUUGAAAGAAU XM_052597
3688 USP53 GGAAGAGAGUGAACAGUAA XM_052597
3689 USP53 CAGCAUAGUCCAAGACAUA XM_052597
3690 USP53 CAGGCAAAGCAGAGAGAAA XM_052597
3691 USP53 GAUUGGAACUAGAUGGAAA XM_052597
3692 USP53 CGACGAAGCUUGCGGGUUU XM_052597
3693 USP53 GGAUAUCAGUGGUGUUAAA XM_052597
3694 USP53 UGGAAAAGGAGCAGAGAAA XM_052597
3695 USP53 AGCCAAGAUUCUAGGGAUA XM_052597
3696 USP53 GAUAAUUGGCAGAUGCAAA XM_052597
3697 USP53 ACAGAUGACUAUAGGAAAU XM_052597
3698 USP53 CCAUAAUGCAAGAGAACAU XM_052597
3699 USP53 GUUGAAAGAAUGUUGGAAA XM_052597
3700 USP53 GUUAAAUGAACCAGGACAA XM_052597
3701 USP53 UGGAAACCUAUGAGAGAAA XM_052597
3702 USP53 UUACAGAAUUUGUGCGGUA XM_052597
3703 USP53 GGAAAGAUGUUGUCUCCAA XM_052597
3704 USP53 GGGAAGAGAGUGAACAGUA XM_052597
3705 USP53 ACGGAAACCUGGUGGCAAU XM_052597
3706 USP53 GAUGAAAUGAAGCAGGAAA XM_052597
3707 USP53 CGACAAGCAACCUAAAUAA XM_052597
3708 USP53 GGGACAAAGAAAAGAUUUA XM_052597
3709 USP53 UGAAGACAAUGGAAAGUUA XM_052597
3710 USP53 GAUCAAAGGGAAAAGAUAA XM_052597
3711 USP53 GCAUAGUCCAAGACAUAAA XM_052597
3712 USP53 UGACAAUGGCACUGGAUAU XM_052597
3713 USP53 CAACAGAUGACUAUAGGAA XM_052597
3714 USP53 GGGAAAAGAUAAAAGACAU XM_052597
3715 USP53 UCACAUUGAUCAAAGGGAA XM_052597
3716 USP54 ACAAGAAGGAAGAGGCAUU NM_152586
3717 USP54 AGGAAGAGGCAUUGCUCAA NM_152586
3718 USP54 CUCACAGGGUCAAGAGAAA NM_152586
3719 USP54 GGACAGAGGCAGUGAGGAG NM_152586
3720 USP54 CCACAAGAAGGAAGAGGCA NM_152586
3721 USP54 AGUACAGUGCAGAGAAUUU NM_152586
3722 USP54 CAAUAGACUCCCAGGAACU NM_152586
3723 USP54 GGCCAUGGGCAAAGCAACA NM_152586
3724 USP54 GGUGUCUCCAUGAGGGAUA NM_152586
3725 USP54 GUGAGAGAUGUUAGGUCUA NM_152586
3726 USP54 AUUCAUCAAACGUGAGGAA NM_152586
3727 USP54 AGAGAGCAGAUCAGGGCUA NM_152586
3728 USP6 AGGAAAGGGUUGUAGAUAA NM_004505
3729 USP6 GUAAAUGAUCAGUGGAUAA NM_004505
3730 USP6 GCUAAGAUCUCAAGUCAAA NM_004505
3731 USP6 GCGGAGAGGUUCACAACAA NM_004505
3732 USP6 GGAUGGAAAUGCUGGGAGA NM_004505
3733 USP6 CGAAGAAACUAACAAGGAA NM_004505
3734 USP6 GAACAAAUAUGUAGUGAGU NM_004505
3735 USP6 GUACAUGAUUCCAACAUAA NM_004505
3736 USP6 CAAGAGAGGUGAAGAAAGU NM_004505
3737 USP6 GGAGAAUGGGAGACAUAUA NM_004505
3738 USP6 GCACAGGAGCGGAAGGACA NM_004505
3739 USP6 GGAGAAAGCAAGAUCAUGA NM_004505
3740 USP6 GGGCAGUUGUGGAAAGUGA NM_004505
3741 USP6 GGAUGGACAUGGUAGAGAA NM_004505
3742 USP6 ACGAGCAAGUGGAUGGAAA NM_004505
3743 USP6 UGGGAGAAUGGGAGACAUA NM_004505
3744 USP6 CCAUUAGCCUGUAAACAAA NM_004505
3745 USP6 GGAAAGGGUUGUAGAUAAG NM_004505
3746 USP6 GCUAAAUGCUAUGGUGAUU NM_004505
3747 USP6 GGACCUACCCAAACCAAUA NM_004505
3748 USP6 GCUCUAAGGGCUAUAAAUU NM_004505
3749 USP6 CAACAAAGAAGCUGGAUCU NM_004505
3750 USP6 GUCCAGAUAUGAACAAAUA NM_004505
3751 USP6 GCACAGUAGCAAACUCAUA NM_004505
3752 USP6 AGACAGCACUGAUGACCAA NM_004505
3753 USP6 CCAUGUGGCAUCAGGACAA NM_004505
3754 USP7 GGAGAAAGCAUCAGGGAAA NM_003470
3755 USP7 GGACAUAGACAAAGAGAAU NM_003470
3756 USP7 UGAUAAACCUGUAGGAACA NM_003470
3757 USP7 GCGAUUACAAGAAGAGAAA NM_003470
3758 USP7 GAGAAGUGAUGAAGCGAAU NM_003470
3759 USP7 UGAUAAAGCCCUUGAUGAA NM_003470
3760 USP7 CGAAUUUAACAGAGAGAAU NM_003470
3761 USP7 GGUUCAUAGUGGAGAUAAU NM_003470
3762 USP7 CAGAGAAAGGUGUGAAAUU NM_003470
3763 USP7 GUGUAAAGAAGUAGACUAU NM_003470
3764 USP7 CAGAGAGAAUUCAGGACUA NM_003470
3765 USP7 GGGCAUAUCUACACACCAA NM_003470
3766 USP7 AGAAGGAGUUUGAGAAGUU NM_003470
3767 USP7 GAGAACAGGCGAAGUUUUA NM_003470
3768 USP7 CAGCAAUGUUAGAUAAUGA NM_003470
3769 USP7 GAAUUACAGCAUAGUGAUA NM_003470
3770 USP7 GGUAAUCCUCUUAGACAUA NM_003470
3771 USP7 AAACUUAGGCUGCUAGAAA NM_003470
3772 USP7 ACAUAAAUGAAGACGAGUA NM_003470
3773 USP7 ACAUAGACAAAGAGAAUGA NM_003470
3774 USP7 AGAUAAUCAUGGUGGACAU NM_003470
3775 USP7 CUACAACUGAUGAGAUUUA NM_003470
3776 USP7 CUUACAGGAAGCAGAGAAA NM_003470
3777 USP7 GGAAAUAACACUAUAUCCA NM_003470
3778 USP7 AGGAGGACAUGGAGGAUGA NM_003470
3779 USP7 GGGAGAAAGCAUCAGGGAA NM_003470
3780 USP7 GGAACAUGGCUUACAGGAA NM_003470
3781 USP7 GUGCAUCUGUUAAGGCAAA NM_003470
3782 USP7 CCAAUUUAGGGAAGAGGAA NM_003470
3783 USP7 UGACGUGUCUCUUGAUAAA NM_003470
3784 USP8 AAGAAGAAAUGGAGAAGAA NM_005154
3785 USP8 CGAAAGAAAUAAAGCUCAA NM_005154
3786 USP8 GGACAGGACAGUAUAGAUA NM_005154
3787 USP8 CCUGAAGAGCAUAGAAUAA NM_005154
3788 USP8 CUUUAAAGCUGCAGAACAU NM_005154
3789 USP8 AAAUAAAGCUCAACGAGAA NM_005154
3790 USP8 ACACAAUGAUGACGGAUAA NM_005154
3791 USP8 GAAAUGGAGAAGAAAGAAA NM_005154
3792 USP8 GAUAAUCGGAAGAGAUAUA NM_005154
3793 USP8 GUACAAACCAUGAGCAACA NM_005154
3794 USP8 GGAAACAGGAAGAGAGGAU NM_005154
3795 USP8 AGAAAGAGAAACUGAGGAA NM_005154
3796 USP8 GAAACAAGAAGCUGAAGAA NM_005154
3797 USP8 GAAGGAAGAACAAGAACAA NM_005154
3798 USP8 GCAAAGAGGGGCAAAGAAA NM_005154
3799 USP8 GGAAAGGGCCUAUGUACUA NM_005154
3800 USP8 CAAAGAAAUAACAGGAGUA NM_005154
3801 USP8 CCAAGAAAGAAGAUAAAGA NM_005154
3802 USP8 CUGAUAAUCGGAAGAGAUA NM_005154
3803 USP8 AGAAGUUAAACCAGAGAAA NM_005154
3804 USP8 ACAAGAAGCUGAAGAAAAU NM_005154
3805 USP8 GCAAUGAGCCUUUGGUUUU NM_005154
3806 USP8 GUGAACAGGCCAAGAAAGA NM_005154
3807 USP8 GGCCAAGAAAGAAGAUAAA NM_005154
3808 USP8 AGGCCAAGAAAGAAGAUAA NM_005154
3809 USP8 GAGCAAUGGUGAAAAGAAU NM_005154
3810 USP8 GAAGAGAAGAGGAAGCCAA NM_005154
3811 USP8 GAUUAAAGGACAACCAGAA NM_005154
3812 USP8 CAGACGAUACCGAAAGAAA NM_005154
3813 USP8 GGAAAGGCAGCAAGAGGAA NM_005154
3814 USP9X UGAGAGAAGUGUACGGAAA NM_021906
3815 USP9X CCUUAGAGAUGGAGCAAGA NM_004652
3816 USP9X ACAAAUGACAAAUGGGUUA NM_004652
3817 USP9X GGGAUGAUGUAUUUGGAUA NM_004652
3818 USP9X GUGGAGAUGGUGAGAGAAA NM_004652
3819 USP9X GAGAGAAAUCGCUGGUAUA NM_021906
3820 USP9X GAGCACAGCAAGAGAGAGA NM_004652
3821 USP9X GGGUCGUGAUUCAGAGUAA NM_004652
3822 USP9X AGACACAGCUUCUGAAAUU NM_021906
3823 USP9X CCAAGAUGCUCCAGAUGAA NM_004652
3824 USP9X GAACAAGUUAUGUGAAGAA NM_004652
3825 USP9X GGGAUGAGAAGCAGGACAA NM_004652
3826 USP9X CCAAAGGAAUGGUGGAGAU NM_004652
3827 USP9X CAGAAUGGAUACAGCAGAA NM_004652
3828 USP9X GCAAAGGUGUAUAUAGUAU NM_004652
3829 USP9X CCUCAAUGCUCUUAAAAUA NM_004652
3830 USP9X UGACAAAGACAGUGUUAAU NM_004652
3831 USP9X CUGCAGUAAUUCAGAGGAA NM_004652
3832 USP9X ACACGAUGCUUUAGAAUUU NM_021906
3833 USP9X AGGCACAGGUAGUGAUGUA NM_004652
3834 USP9X CAGAAAACCUUGUAACUUA NM_004652
3835 USP9X GGAAUGGCUUGGAGAUGAA NM_004652
3836 USP9X CUAUACAACUAAAGCGAUU NM_021906
3837 USP9X ACGAAUGGCAGAAUGGAUA NM_004652
3838 USP9X AGACUUAGAUCCUGAUAUU NM_004652
3839 USP9X GGACAAGAAGAAACUGUUA NM_004652
3840 USP9X UAUUAAACCAUUUGGGCAA NM_004652
3841 USP9X AGAAAUGGUUCCACAGUUU NM_004652
3842 USP9X GGUGGAUAGUUUAGAUGAA NM_004652
3843 USP9X GAUGAGGCUUCAAGAUAUA NM_021906
3844 USP9Y GGUGGUAACUUUUGAAUUA NM_004654
3845 USP9Y GGAAAGAGAAUGUGCAAUU NM_004654
3846 USP9Y UUUAAGAAGUGGAGAACUA NM_004654
3847 USP9Y ACAAAUGACAAGUGGGUAA NM_004654
3848 USP9Y CAGCAAGAGAGAAGGGUAA NM_004654
3849 USP9Y GAAAUAACUUCUUGCCAAA NM_004654
3850 USP9Y AGGCACAGGUAGUGAUUUA NM_004654
3851 USP9Y UCGAAUGGUUAGAGUAUUA NM_004654
3852 USP9Y GCAAUAAGCUGGAGGUGGA NM_004654
3853 USP9Y GAACUUAGCUUCAAGAAUU NM_004654
3854 USP9Y CCAAAUACAGAUAUGGAAA NM_004654
3855 USP9Y GCGAAUGGCAGAAUGGAUA NM_004654
3856 USP9Y GAGAGAGUGUAGUGAUUAA NM_004654
3857 USP9Y GGAAUGAAAUGCUUUGAAA NM_004654
3858 USP9Y GGUUAUAUCUAGUGUAUCA NM_004654
3859 USP9Y GAACAGUAUUCUUGCAAUU NM_004654
3860 USP9Y GCAGAGAGCUUGGAGAUAA NM_004654
3861 USP9Y CAGAAGAGGUGGUGGAAUG NM_004654
3862 USP9Y GUAUUUAAGAAGUGGAGAA NM_004654
3863 USP9Y GAGAUGAUGUAUUUGGAUA NM_004654
3864 USP9Y GGCAAAGAAUGAAGCCAAA NM_004654
3865 USP9Y AAUUAGGGCUAUACAGAAA NM_004654
3866 USP9Y UAACAGAGCUAUAGAUCUU NM_004654
3867 USP9Y AAACACAGCUUCUGAAAUU NM_004654
3868 USP9Y CAGCAUUAAUUGUGCAAGA NM_004654
3869 USP9Y GGACAAGAUGAGACUAUAA NM_004654
3870 USP9Y CCAAGUUACUCAUGAUCAA NM_004654
3871 USP9Y AGGCAAAGAAUGAAGCCAA NM_004654
3872 VCIP135 CAGAAGGACUGGAGUGAUA NM_025054
3873 VCIP135 GGGACAGACUUUAGUAAUA NM_025054
3874 VCIP135 GAUCCAAGAGCUAGGGAAA NM_025054
3875 VCIP135 GGAAGAGUGGUCAGAGAAA NM_025054
3876 VCIP135 CAGCAUGGCGACAGAAUUA NM_025054
3877 VCIP135 CGACAGAAUUACAAUAGAA NM_025054
3878 VCIP135 GCGAAAGGUCAGAGGAGAU NM_025054
3879 VCIP135 AGUAAUAGUUCCACCUAAA NM_025054
3880 VCIP135 AAACAGAAGUUGUGAGUUC NM_025054
3881 VCIP135 CAAUGAAACUUGUUACCAA NM_025054
3882 VCIP135 GGAUAAUCGCCUUCACAAA NM_025054
3883 VCIP135 GGUCAGAGAAACAGUAUAU NM_025054
3884 VCIP135 AGAGAAGUGCACUGGGAAA NM_025054
3885 VCIP135 CCUCAUAGAACCAGAGCAU NM_025054
3886 VCIP135 GACAGAAGUUUGCAAGAUA NM_025054
3887 VCIP135 GGUGAAUUUGGGAGUGAAA NM_025054
3888 VCIP135 UGGAGAUGUUCAAGGACAA NM_025054
3889 VCIP135 CAACAUUCCUCCAUAUUUA NM_025054
3890 VCIP135 UGGCAUGCCUUAAGAGAGA NM_025054
3891 VCIP135 GAAAGUAUAGCCAGAGAAU NM_025054
3892 VCIP135 GAGAAGAAGAUCCGAAUCA NM_025054
3893 VCIP135 UGGUUGAGGCCCAGCGAAA NM_025054
3894 VCIP135 CCGACAACUUCUAAGGAGA NM_025054
3895 VCIP135 GGUCAGAGGAGAUGGGUCU NM_025054
3896 VCIP135 CAGACUAUGGAAUGAGUAA NM_025054
3897 VCIP135 UUGAAGAGAUGGAUAGUCA NM_025054
3898 VCIP135 GAGUAGUAACAAUGAGAGA NM_025054
3899 VCIP135 GUGGAAGAGUGGUCAGAGA NM_025054
3900 VCIP135 GGAUGGUGGUUGUGUUAUU NM_025054
3901 VCIP135 AGGAGUUAAACAUGAGUAA NM_025054
3902 VDU1 CCUCAGAACAUUUGGGAUA NM_015017
3903 VDU1 UGAAAGUAGUAGUCAGAAA NM_015017
3904 VDU1 GAGAAGAUGUGCAAUAAGA NM_015017
3905 VDU1 GGAUGAAGAAGAUGAACUU NM_015017
3906 VDU1 GCUAAAGCAAUGUUGUUAA NM_015017
3907 ZA20D1 GAUCAUGAAUGGAGGAAUA NM_020205
3908 ZA20D1 GCAGCAAGCUCAAGAAGAA NM_020205
3909 ZA20D1 UGAAAGUACUUGAGGAUCA NM_020205
3910 ZA20D1 AGAAGGAGGCAGAGAGGAA NM_020205
3911 ZA20D1 AGGAAAUGAUCCAGCGCUA NM_020205
3912 ZA20D1 CGUUUGAACUGGUGGGUGA NM_020205
3913 ZA20D1 CCAGCAGAGUCGAGGGCAA NM_020205
3914 ZA20D1 CCAUGGAGCAGAAGGAGAA NM_020205
3915 ZA20D1 GCUGAAAGUACUUGAGGAU NM_020205
3916 ZA20D1 GGACAAGAAGAGAGCAGAU NM_020205
3917 ZA20D1 CAGCAGACACAGCAGAAUA NM_020205
3918 ZA20D1 ACUUACAGAUUCAGAGUAU NM_020205
3919 ZA20D1 GGGACAGGGUUGGGAGGAA NM_020205
3920 ZA20D1 CCAUAGUCGUCGUGGCAGA NM_020205
3921 ZA20D1 AGGAGAAGUCAAAGCGAGA NM_020205
3922 ZA20D1 GGGACUUGAUGCUGCGGAA NM_020205
3923 ZA20D1 GCAGCUUCAUAGAGAGAGA NM_020205
3924 ZA20D1 GGAGAAUACCAAGGAACAA NM_020205
3925 ZA20D1 AGGAGAAUACCAAGGAACA NM_020205
3926 RANGB1 GAACAAAUCCGGAGAGAGA NM_017580
3927 RANGB1 CCAAAGACCUAGUGGAACA NM_017580
3928 RANGB1 GAGAGGAAGAUGAGGAUGA NM_017580
3929 RANGB1 GCCCAAAGACCUAGUGGAA NM_017580
3930 RANGB1 ACAAAUCCGGAGAGAGAUA NM_017580
3931 RANGB1 GGAAGUUGCAGUAGUGGUA NM_017580
3932 RANGB1 GAGAGAAGAACAAUGGCAA NM_017580
3933 RANGB1 GGGGAGAAACUUUAGGAUA NM_017580
3934 RANGB1 GUAAUGAGGAACAGCAAGA NM_017580
3935 RANGB1 GCAGGAUAUGCUAGCAAUA NM_017580
3936 RANGB1 UGUCCAGACUCUAGUGCAA NM_017580
3937 RANGB1 CCUAAUAACAUUGAAGCAA NM_017580
3938 RANGB1 GGACUCAGUGCUUCGGAAA NM_017580
3939 RANGB1 GGAUGAUGAAGAUGAAUGA NM_017580
3940 RANGB1 CCGAGGUGCUGGUGCUAAU NM_017580
Thus, consistent with Example XVII, the present invention provides an siRNA that targets a nucleotide sequence for a deubiquitination enzymes, wherein the siRNA is selected from the group consisting of SEQ. ID NOs. 438-3940.
In another embodiment, an siRNA is provided, said siRNA comprising a sense region and an antisense region, wherein said sense region and said antisense region are at least 90% complementary, said sense region and said antisense region together form a duplex region comprising 18-30 base pairs, and said sense region comprises a sequence that is at least 90% similar to a sequence selected from the group consisting of: SEQ. ID NOs 438-3940.
In another embodiment, an siRNA is provided wherein the siRNA comprises a sense region and an antisense region, wherein said sense region and said antisense region are at least 90% complementary, said sense region and said antisense region together form a duplex region comprising 18-30 base pairs, and said sense region comprises a sequence that is identical to a contiguous stretch of at least 18 bases of a sequence selected from the group consisting of: SEQ. ID NOs 438-3940.
In another embodiment, an siRNA is provided wherein the siRNA comprises a sense region and an antisense region, wherein said sense region and said antisense region are at least 90% complementary, said sense region and said antisense region together form a duplex region comprising 19-30 base pairs, and said sense region comprises a sequence that is identical to a contiguous stretch of at least 18 bases of a sequence selected from the group consisting of: SEQ. ID NOs 438-3940.
In another embodiment, a pool of at least two siRNAs is provided, wherein said pool comprises a first siRNA and a second siRNA, said first siRNA comprises a duplex region of length 18-30 base pairs that has a first sense region that is at least 90% similar to 18 bases of a first sequence selected from the group consisting of: SEQ. ID NOs 438-3940 and said second siRNA comprises a duplex region of length 18-30 base pairs that has a second sense region that is at least 90% similar to 18 bases of a second sequence selected from the group consisting of: SEQ. ID NOs 438-3940 and wherein said first sense region and said second sense region are not identical.
In another embodiment, a pool of at least two siRNAs is provided, wherein said pool comprises a first siRNA and a second siRNA, said first siRNA comprises a duplex region of length 18-30 base pairs that has a first sense region that is identical to at least 18 bases of a sequence selected from the group consisting of: SEQ. ID NOs 438-3940 and wherein the second siRNA comprises a second sense region that comprises a sequence that is identical to at least 18 bases of a sequence selected from the group consisting of: SEQ. ID NOs 438-3940.
In another embodiment, a pool of at least two siRNAs is provided, wherein said pool comprises a first siRNA and a second siRNA, said first siRNA comprises a duplex region of length 19-30 base pairs and has a first sense region comprising a sequence that is at least 90% similar to a sequence selected from the group consisting of: SEQ. ID NOs 438-3940, and said duplex of said second siRNA is 19-30 base pairs and comprises a second sense region that comprises a sequence that is at least 90% similar to a sequence selected from the group consisting of: SEQ. ID NOs 438-3940.
In another embodiment, a pool of at least two siRNAs is provided, wherein said pool comprises a first siRNA and a second siRNA, said first siRNA comprises a duplex region of length 19-30 base pairs and has a first sense region comprising a sequence that is identical to at least 18 bases of a sequence selected the group consisting of: SEQ. ID NOs 438-3940 and said duplex of said second siRNA is 19-30 base pairs and comprises a second sense region comprising a sequence that is identical to a sequence selected from the group consisting of: SEQ. ID NOs 438-3940.
In each of the aforementioned embodiments, preferably the antisense region is at least 90% complementary to a contiguous stretch of bases of one of the NCBI sequences identified in Example XVII; each of the recited NCBI sequences is incorporated by reference as if set forth fully herein. In some embodiments, the antisense region is 100% complementary to a contiguous stretch of bases of one of the NCBI sequences identified in Example XVII.
Further, in some embodiments that are directed to siRNA duplexes in which the antisense region is 20-30 bases in length, preferably there is a stretch of 19 bases that is at least 90%, more preferably 100% complementary to the recited sequence id number and the entire antisense region is at least 90% and more preferably 100% complementary to a contiguous stretch of bases of one of the NCBI sequences identified in Example XVII.
While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departure from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth and as follows in the scope of the appended claims.
