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/拉丁裔美国人是美国最大的两个少数民族，他们是来自多个祖先群体的混血儿。本提案概述了几种使用混合种群的种群遗传方法，这将促进医学遗传学。第一种提出的方法旨在改进对非洲人和欧洲人混合产生非裔美国人人口的时间进程的估计。描绘混血儿中的移民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血儿研究提供见解，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绘制祖先断点。该方法可以提高祖先的分辨率，并且可以将局部祖先估计扩展到具有较老外加剂的种群，从而增加可用于外加剂映射的种群数量。它还可以在没有家庭或系谱数据的情况下构建精细的人类遗传图谱。本提案中概述的第三种方法将检查通过古代混合引入现代人类种群的变异对健康的影响。基因流动带来的新基因变异，从一个种群进入另一个种群，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了正选择的变异，或者与身高、体重或疾病相关的变异。特别是，该提案将检查最近发现的从尼安德特人到非非洲人群的基因流，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积极的选择，或者这些变体是否与形态计量表型或疾病相关。

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. 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.