Abstract: While SNP-based marker sets and population-level DNA repositories are approaching sufficient size for whole-genome association studies, individual genotyping remains very costly. Pooled DNA tests are a less costly alternative, but uncertainty about loss of power due to allele frequency measurement error and population stratification hinder their use. Here we describe how to optimize pooled tests as an explicit function of measurement error, and we present family-based tests that eliminate stratification effects. We show that identification of functional genetic variants and linked markers may be feasible with current-day instruments.

Abstract: Disclosed herein are methods and apparatuses for sequencing a nucleic acid. These methods permit a very large number of independent sequencing reactions to be arrayed in parallel, permitting simultaneous sequencing of a very large number (>10,000) of different oligonucleotides.

Abstract: Identifying the genetic determinants for disease and disease predisposition remains one of the outstanding goals of the human genome project. When large patient populations are available, genetic approaches using single nucleotide polymorphism markers have the potential to identify relevant genes directly. While individual genotyping is the most powerful method for establishing association, determining allele frequencies in DNA pooled on the basis of phenotypic value can also reveal association at a much-reduced cost. Here we analyze pooling methods to establish association between a genetic polymorphism and a quantitative phenotype. Exact results are provided for the statistical power for a number of pooling designs where the phenotype is described by a variance components model and the fraction of the population pooled is optimized to minimize the population requirements.

Abstract: Identifying the genetic components of complex diseases is one of the most important goals of the human genome project. These diseases and their underlying risk factors are often better described by quantitative phenotypes than by an arbitrary distinction between affected and unaffected individuals. Association studies are able to identify genetic loci contributing to these quantitative trait loci directly at the cost of requiring large population sizes. Studies of sib pair populations have been suggested to increase power when populations are stratified, and tests on pooled DNA may reduce the experimental burden, but these approaches have been analyzed primarily in the context of affected/unaffected disease phenotypes. Disclosed herein are efficient methods for QTL mapping using DNA pooled from sib pairs. A preferred test using a single set of pools is to select unrelated sibs with extreme phenotypic values, requiring a population size approximately 1.5× larger than for individual genotyping.

Abstract: The present invention provides novel methods to identify, classify, quantify and compare nucleic acids and polypeptides.

Abstract: The invention relates to a method of identifying genetic regions related to disease and to predicting the response to therapeutic agents. The invention provides a method of identifying a genetic region associated with a disease and/or associated with responsiveness to a therapeutic agent.

Abstract: Risk assessment and diagnosis of a complex disorder often requires measuring an underlying quantitative phenotype. Association studies in unrelated populations can implicate genetic factors contributing to disease risk, and experiments using pooled DNA provide a less costly but necessarily less powerful alternative to methods based on individual genotyping. Although the sample sizes required for pooling and individual genotyping studies have been compared in certain instances, general results have not been reported in the context of association studies, nor have there been clear comparisons of pooling based on quantitative and qualitative (affected/unaffected) phenotypes. Here we use exact numerical calculations and analytical approximations to examine the sample size requirements of association tests for quantitative traits and affected-unaffected studies using pooled DNA.

Abstract: Disclosed are methods of selectively analyzing a nucleic acid in a sample. The methods allow for selective identification of a target sequence in a population of nucleic acids. For example, the methods allow for confirmation of the identity of a nucleic acid tentatively identified in a quantitative expression analysis (QEA) assay.

Abstract: Disclosed herein are methods and apparatuses for sequencing a nucleic acid. These methods permit a very large number of independent sequencing reactions to be arrayed in parallel, permitting simultaneous sequencing of a very large number (>10,000) of different oligonucleotides.

Abstract: Disclosed herein are methods and apparatuses for sequencing a nucleic acid. The method includes annealing a population of circular nucleic acid molecules to a plurality of anchor primers linked to a solid support, and amplifying those members of the population of circular nucleic acid molecules which anneal to the target nucleic acid, and then sequencing the amplified molecules by detecting the presence of a sequence byproduct.

Abstract: Disclosed herein are methods and apparatuses for sequencing a nucleic acid. The method includes annealing a population of circular nucleic acid molecules to a plurality of anchor primers linked to a solid support, and amplifying those members of the population of circular nucleic acid molecules which anneal to the target nucleic acid, and then sequencing the amplified molecules by detecting the presence of a sequence byproduct.

Abstract: This invention relates to a method and device for separating charged particles according to their diffusivities in a separation medium by means of a spatially and temporally varying electric potential. The method is particularly suited to sizing and separating DNA fragments, to generating DNA fragment length polymorphism patterns, and to sequencing DNA through the separation of DNA sequencing reaction products. The method takes advantage of the transport of charged particles subject to an electric potential that is cycled between an off-state (in which the potential is flat) and one or more on-states, in which the potential is preferably spatially periodic with a plurality of eccentrically shaped stationary potential wells. The potential wells are at constant spatial positions in the on-state. Differences in liquid-phase diffusivities lead to charged particle separation. A preferred embodiment of the device is microfabricated. A separation medium fills physically defined separation lanes in the device.

Abstract: This invention includes methods for analyzing data generated by various solid-state NMR experiments, including rotational echo double resonance (REDOR), transferred echo double resonance (TEDOR), dipolar recoupling at the magic angle (DRAMA), dipolar recoupling with a windowless sequence (DRAWS), and melding of spin-locking and DRAMA (MELODRAMA). The methods are based alternately on a new analytical transform or the maximum entropy method and their multi-dimensional extensions. They permit simultaneous, multiple distance measurements of high accuracy and precision, even from nuclei with identical chemical shifts. By providing high quality easily obtained distance measurement from disordered solid state materials, this invention also improves drug discovery and design through fast determination of structures of pharmaceutical lead compounds, drug molecules, or their targets.

Abstract: This invention relates to a method and device for separating charged particles according to their diffusivities in a separation medium by means of a spatially and temporarily varying electric potential. The method is particularly suited to sizing and separating DNA fragments, to generating DNA fragment length polymorphism patterns, and to sequencing DNA through the separation of DNA sequencing reaction products. The method takes advantage of the transport of charged particles subject to an electric potential that is cycled between an off-state (in which the potential is flat) and one or more on-states, in which the potential is preferably spatially periodic with a plurality of eccentrically shaped stationary potential wells. The potential wells are at constant spatial positions in the on-state. Differences in liquid-phase diffusivities lead to charged particle separation. A preferred embodiment of the device is microfabricated. A separation medium fills physically defined separation lanes in the device.