Population mixture in evolutionary and medical genetics

描述(申请人提供)：种群之间的混合是形成生物学、遗传变异和疾病风险的基本过程。尽管混合物很重要，但可用于在全基因组范围内研究混合物的分析方法是有限的。这使得开发能够在大型数据集中分析这一历史的方法成为当务之急，这些数据集现在可以实际生成。目前没有联邦拨款支持这种方法的开发。这笔赠款建议开发研究混合物的方法和软件。其目的是：(1)开发基于等位基因频率和单倍型频率差异对混合物进行推断的工具。(2)开发基于混合连锁不平衡和遗传分化数据估计混合日期的工具。我们预计这笔赠款将在三个方面具有价值。(A)它将支持开发对进化和医学遗传学具有重要意义的方法和用户友好的软件。(B)它将支持将产生有关在人类种群中发现最近或以前混合的疾病基因的洞察力的工作。(C)它将导致对人类历史以及其他生物体的历史有新的见解。与医学遗传学的联系尤为重要。我们实验室过去在种群进化史方面的工作与我们在疾病基因图谱方面的工作交织在一起，我们在这两个领域开发的方法是协同的。特别是，我们利用人类种群中混合的历史来进行新的基因发现，并了解不同种群之间疾病风险的差异。我们希望能够通过开发复杂的方法来理解和模拟种群混合，从而在进化和医学遗传学之间建立进一步的联系。 公共卫生相关性：人口混杂的历史对公共卫生很重要，因为它决定了个人和人口继承的基因变异，这反过来又使一些人或多或少容易患上疾病。在过去的十年里，已经很明显，许多人类人口是具有不同祖先的人口混合的结果：不仅是非洲裔美国人和拉丁裔，而且还有南亚人和所有非非洲人(他们拥有尼安德特人的遗传物质)。例如，我们团队开发了研究人群混合的方法，并直接应用于发现非裔美国人前列腺癌的遗传风险因素。这笔赠款建议开发复杂的方法，利用现代基因组数据来理解和量化人类种群中的混合物。我们预计，对人类群体混合的更深入了解将有助于开发更强大的方法来发现疾病的遗传风险因素。

DESCRIPTION (provided by applicant): Mixture between populations is a fundamental process that shapes biology, genetic variation, and the risk for disease. Despite its importance, the analytical methods that are available to study mixture on a genome-wide scale are limited. This makes it a priority to develop methods that can analyze this history in the large data sets that are now practical to generate. No federal grant currently supports the development of such methods. This grant proposes to develop methods and make software available for studying mixture. The Aims are: (1) To develop tools that make inferences about mixture based on allele frequency and haplotype frequency differences. (2) To develop tools that estimate dates of mixture based on admixture linkage disequilibrium and genetic divergence data. We expect that this grant will be of value in three areas. (a) It will support the development of methods and user-friendly software that will be important for evolutionary and medical genetics. (b) It will support work that will result in insights relevant to finding disease genes in human populations that are recently or anciently admixed. (c) It will lead to new insights about human history as well as the history of other organisms. The connection to medical genetics is particularly important. Our laboratory's past work on the evolutionary history of populations has been intertwined with our work on disease gene mapping, and the approaches that we developed in both areas were synergistic. In particular, we have leveraged the history of admixture in human populations to make new gene discoveries and to understand variation in disease risk across populations. We expect to be able to make further connections between evolutionary and medical genetics by developing sophisticated approaches for understanding and modeling population mixture. PUBLIC HEALTH RELEVANCE: The history of population mixture is of importance to public health because it determines the genetic variants that individuals and populations inherit, which in turn make some people more or less susceptible to disease. In the last decade, it has become clear that many human populations are the result of mixtures of populations with divergent ancestries: not only African Americans and Latinos, but also South Asians and all non-Africans (who have Neandertal genetic material). For example, our group has developed methods for studying population mixture and directly applied them to discover genetic risk factors for prostate in African Americans. This grant proposes to develop sophisticated methods to understand and quantify mixture in human populations using modern genomic data. We anticipate that a deeper understanding of human population mixture will assist in the development of more powerful methods to discover genetic risk factors for disease.