High-throughput characterization of cis-acting polymorphisms in the human genome

描述（由申请人提供）：人类遗传学研究的一个主要目标是对人类基因组中的多态性进行功能表征。最近的两个项目——HapMap和1000基因组计划——在构建不同种群中常见变异和连锁不平衡的目录方面取得了巨大成功。事实上，HapMap数据促进了全基因组关联研究（GWAS）的发展，该研究已经发现了与多种疾病相关的2000多个基因座。到本项目资助期开始时，“千人基因组计划”将基本上确定人类所有的约107种常见多态性（约1%的次要等位基因频率）。有了这个目录在手，该领域的下一个巨大挑战将是功能性地描述这一巨大的遗传变异景观。很有可能，这107种变异几乎都没有可检测到的功能后果——尽管不管哪一部分有功能影响，确定影响表型的特定变异将是未来十年人类遗传学研究的一个重要目标。我们的目标是开发一种实验和计算工具的结合，允许对数千种人类多态性的功能结果进行高通量分配，包括许多与GWAS有关的多态性。通过对标准染色质免疫沉淀和测序（“ChIP-seq”）方法的简单修改，涉及样本池，我们将能够将分子特征遗传映射到单核苷酸水平，与其他方法相比，效率和成本效益提高约100倍。将所得到的功能多态性图谱与eSNP和GWAS结果相结合，将使许多影响基因表达或疾病风险的多态性同时得到精确定位和功能表征。

DESCRIPTION (provided by applicant): A major goal of research in human genetics is to functionally characterize polymorphisms in the human genome. Two recent projects - the HapMap and the 1000 Genomes Project - have achieved tremendous success in constructing a catalog of common variants and linkage disequilibrium in diverse populations. Indeed, the HapMap data allowed the development of genome-wide association studies (GWAS), which have already implicated over two thousand loci associated with a wide range of diseases. By the beginning of this project's funding period, the 1000 Genomes Project will have identified essentially all ~107 common (>1% minor allele frequency) polymorphisms in humans. With this catalog in hand, the next great challenge for the field will be to functionally characterize this vast landscape of genetic variation. It is quite possible that nearly all of these 107 variants will have no detectable functional consequences - though regardless of what fraction have functional effects, identifying the specific variants that do affect phenotypes will be a significant goal for human genetics research in the coming decade. Our objective is to develop a combination of experimental and computational tools that will allow the high-throughput assignment of functional consequences to thousands of human polymorphisms, including many of those implicated by GWAS. With a simple modification to standard chromatin immunoprecipitation and sequencing ("ChIP-seq") methods involving pooling of samples, we will be able to genetically map molecular traits down to the level of single nucleotides with ~100-fold gains in efficiency and cost-effectiveness compared to alternative methods. Integrating the resulting functional polymorphism maps with eSNP and GWAS results will allow many polymorphisms affecting gene expression or disease risk to be simultaneously pinpointed and functionally characterized.