Insights from ancient and recent population mixture relevant to medical genetics

描述（由申请人提供）：非洲裔美国人和西班牙裔/拉丁美洲人-美国最大的两个少数民族群体-是来自多个祖先群体的混合人口。该提案概述了几种使用混合群体的群体遗传学方法，这将有助于医学遗传学。第一个提出的方法，旨在提高估计的时间过程中的非洲人和欧洲人的混合引起的非裔美国人的人口。描述混合物中的迁移波将提高对非裔美国人复杂结构的理解，并可能为如何更好地设计混合物研究提供见解，这些研究可能提高检测与疾病相关的变异的能力。第二种方法将利用序列数据来精细绘制混合个体的局部祖先估计中的祖先断点。这种方法可以导致增加的分辨率的祖先，并可以扩展当地的祖先估计人口与较老的混合物，增加人口的数量，可以用于混合物映射。它还可以在没有家族或谱系数据的情况下构建精细的人类遗传图谱。该提案中概述的第三种方法将检查通过古代混合物引入现代人群的变异对健康的影响。通过基因流动从一个种群引入另一个种群的新的遗传变异具有适应性或对性状产生影响的潜力。该提案的目的是探索古代混合物是否引入了经历过积极选择或与身高，体重或疾病相关的变异。特别是，该提案将研究最近发现的从尼安德特人到非非洲人群的基因流，以研究高度分化的尼安德特人变体是否具有适应性并经历了正选择，或者这些变体是否与形态学表型或疾病相关。 公共卫生相关性：医学遗传学利用群体遗传学方法进行混合作图以发现疾病基因。该提案概述了三种新的群体遗传学方法，旨在研究混合人群（具有多个祖先人群祖先的人群，如非洲裔美国人），这将为改善混合物映射研究设计提供见解，将混合物映射扩展到具有较老混合物的人群，并检查混合物对人类疾病风险的影响。

DESCRIPTION (provided by applicant): African Americans and Hispanic/Latinos - two of the largest minority groups in the U.S. - are admixed populations with ancestry from multiple ancestral populations. This proposal outlines several population genetic methods using admixed populations that will facilitate medical genetics. The first proposed method seeks to improve estimation of the time course of admixture of Africans and Europeans giving rise to African American populations. Delineating the waves of migration in the admixture will improve understanding of the complex structure of African Americans and may provide insights into how to better the design of admixture studies that may boost power to detect variants associated with disease. The second proposed method will leverage sequence data to fine map ancestry breakpoints in local ancestry estimation of admixed individuals. This method can lead to an increased resolution of ancestry, and can extend local ancestry estimation to populations with older admixture, increasing the number of populations that can be utilized for admixture mapping. It may also allow the construction of a fine- scale human genetic map without family or pedigree data. The third method outlined in this proposal will examine the health impact of variants introduced into modern human populations through ancient admixture. The new genetic variants introduced by gene flow, from one population into another, have the potential to be adaptive or to have an impact on traits. This aim of the proposal will explore whether ancient admixture introduced variants that have undergone positive selection or that are associated with height, weight, or disease. In particular, this proposal will examine the recently discovered gene flow from Neandertals into non-African populations, to examine whether the highly-diverged Neandertal variants were adaptive and have undergone positive selection, or whether these variants are associated with morphometric phenotypes or disease. PUBLIC HEALTH RELEVANCE: Medical genetics leverages population genetic methods to perform admixture mapping to find disease genes. This proposal outlines three new population genetic methods, designed for studying admixed populations (populations with ancestry from multiple ancestral populations, such as African Americans), that will provide insights to improve admixture mapping study design, expand admixture mapping to populations with older admixture, and examine the impact of admixture on human disease risk.