Insights from ancient and recent population mixture relevant to medical genetics

描述(申请人提供)：非洲裔美国人和西班牙裔/拉美裔美国人--美国最大的两个少数群体--是有多个祖先的混血群体。这项提案概述了几种使用混合种群的种群遗传学方法，这将促进医学遗传学。第一种提议的方法试图改进对非洲人和欧洲人混杂产生非裔美国人人口的时间进程的估计。描绘混合物中的迁徙浪潮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，从而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在混合个体的局部祖先估计中精细地映射祖先断裂点。这种方法可以提高祖先的分辨率，并可以将本地祖先估计扩展到具有较老混合的种群，增加了可用于混合映射的种群数量。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基因图谱。这项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的变异对健康的影响。由基因流引入的新的遗传变异，从一个种群进入另一个种群，具有适应能力或对特征产生影响的潜力。该提案的这一目的将探索古代混合物是否引入了经过正向选择的变异，或与身高、体重或疾病有关的变异。特别是，这项建议将检查最近发现的从尼安德特人进入非非洲人口的基因流，以检查高度分化的尼安德特人变体是否具有适应性并经历了正向选择，或者这些变体是否与形态表型或疾病有关。

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.