Lost-of-function variants in the 1000 genomes data set and implications to GWAS

描述（由申请人提供）： 千人基因组计划是一个国际研究联盟，其目标是制作人类遗传变异的详细地图，以支持主要测序工作的疾病研究。该项目涉及对来自世界各地的至少1000人的基因组进行测序，以促进发现和理解遗传变异，如单核苷酸多态性和结构变异。该项目产生的数据将有助于发现基因组中含有与人类疾病风险相关的遗传变异的区域，如HapMap项目等先前的努力。然而，在这些数据的分析、注释和应用中存在重大挑战，以指导与疾病和各种性状相关的变异的鉴定。在本申请中，我们将重点关注功能丧失变异，因为它们代表了可能涉及复杂性状的主要一类遗传变异，我们相信这些变异的全面表征并将所获得的知识提供给一般研究界将有助于识别涉及复杂性状的基因。为了实现这一目标，我们将开发一个生物信息学管道，从1000个基因组数据中识别功能丧失的变体，将它们与文献和公共数据库中积累的其他类型的信息相关联，例如基因本体论，蛋白质相互作用，表达谱，研究在人群样本中获得这些变体基因型的最佳方法，并开发统计方法来结合注释结果，以增加识别影响复杂性状的功能丧失变体的统计能力。我们将通过一个专注于功能丧失变体的独立应用程序以及通过与UCSC基因组浏览器团队合作向公众传播方法和结果，以在其浏览器上添加有关这些功能丧失变体的不同类型信息的跟踪。我们相信，这个拟议的项目将为科学界提供非常宝贵的资源，可以大大提高我们对人类功能丧失变异的理解，并利用这些知识更有效地改善人类健康。相关性：该研究提案旨在为科学界提供非常宝贵的资源，可以显着提高我们对人群中功能丧失变异的理解，并利用这些知识更有效地改善人类健康。

DESCRIPTION (provided by applicant): The 1000 Genomes Project is an international research consortium whose aim is to produce a detailed map of human genetic variation to support disease studies with major sequencing effort. This project involves sequencing the genomes of at least a thousand people from around the world to facilitate the discovery and understanding of genetic variants such as single nucleotide polymorphisms and structural variants. The data generated from this project will help in the discovery of regions in the genome containing genetic variations associated with risk of human diseases as previously attempted by efforts such as the HapMap Project. However, there are significant challenges in the analysis, annotation, and applications of these data to guide the identifications of variants associated with diseases and various traits. In this application, we will focus on loss-of-function variants because they represent a major class of genetic variations that are potentially involved in complex traits, and we believe a comprehensive characterization of these variants and making the knowledge gained available to the general research community will facilitate the identifications of genes involved in complex traits. To accomplish this objective, we will develop a bioinformatics pipeline to identify loss-of-function variants from the 1000 genome data, associate them with other types of information accumulated in the literature and public databases, such as gene ontology, protein interactions, expression profiles, investigate the best approaches to attain the genotypes of these variants in population samples, and develop statistical methods to incorporate the annotation results to increase the statistical power to identify loss of function variants affecting complex traits. We will disseminate the methods and results to the public both through a stand-alone application focusing of loss of function variants as well as through collaboration with the UCSC Genome Browser team to add tracks on their browser to different types of information on these loss of function variants. We believe that this proposed project will generate very valuable resources to the scientific community that can significantly enhance our understanding of loss of function variants in human populations and use such knowledge to more effectively improve human health. RELEVANCE: The research proposal is developed to generate very valuable resources to the scientific community that can significantly enhance our understanding of loss of function variants in human populations and use such knowledge to more effectively improve human health.