Characterizing the Global Architecture of Genomic Diversity

描述(由申请人提供)：NIH主任早期独立奖的这项提案旨在通过更全面地了解人类基因组多样性的全球架构，实现基因组学改善所有人健康的承诺。这将通过在人类人口历史的背景下描述全球基因组多样性，包括序列和结构变异来实现。为了实现这一目标，我们提出了三个具体目标：(1)改进对人类人口历史和全球多样性的描述；(2)评估人口历史对功能变异的影响，以及推断古代对人类变异的贡献；(3)发展利用短读测序对基因组结构变异进行基因分型的方法。拟议的研究将提供有关未充分查明的变异类型的全球流行和特征的基本信息，阐明人类种群历史的重要特征，并确定这一历史对与现有种群相关的变异的持久影响，包括其基因组包括来自不同大陆祖先的片段的混合或世界性种群。了解这些全球多样性模式，包括序列和结构变异，对于正确执行和解释旨在阐明不同人类群体疾病易感性的遗传基础的研究至关重要。 与公共卫生相关：一些基因变异在改变人类疾病的易感性方面发挥着重要作用。这些变异既包括基因组序列的变化，也包括基因组结构的变化，众所周知，这些变化在全球种群中是不同的。更全面地了解全球遗传多样性模式的性质将有助于研究人员识别与当今人口中的疾病风险相关的遗传变异。

DESCRIPTION (provided by applicant): This proposal for the NIH Director's Early Independence Award is designed to realize the promise of genomics for improving health of all people by achieving a more complete understanding of the global architecture of human genomic diversity. This will be achieved by characterization global genomic diversity, including sequence and structural variation, in the context of the demographic history of human populations. To achieve this objected we propose three specific aims: (1) improve description of human demographic history and global diversity, (2) assess impact of demographic history on functional variation and inferences of archaic contributions to human variation and (3) develop methods to genotype genomic structural variation using short-read sequencing. The proposed research will provide essential information concerning the global prevalence and characteristics of under-ascertained variant types, clarify important characteristics of human population history, and define the lasting effects of this history on variation that is relevant for extant populations, including admixed or cosmopolitan populations whose genomes include segments from diverse continental ancestries. Understanding these global patterns of diversity, including sequence and structural variants, will be critical for proper execution and interpretation of studies designed to elucidate the genetic basis for disease susceptibility in diverse human populations. PUBLIC HEALTH RELEVANCE: Some genetic variants play an important role in altering susceptibility to human disease. These variants include both changes to the sequence and to the structure of genomes, and are known to vary across global populations. A more comprehensive understanding the nature of global patterns of genetic diversity will aid researchers in the identification of genetic variants relevant to disease risk in populations today.