Population genetics to improve homozygosity mapping and mapping in admixed groups

群体遗传学是促进医学遗传学和疾病基因定位研究的重要工具。这一建议概述了两种新的群体遗传技术，每一种技术都以不同的方式促进疾病基因定位。首先，它描述了一种基于SNP阵列数据检测个体可能具有的纯合子比例的概率技术。这有助于对疾病病例样本个体进行全基因组测序和随后的纯合性定位，以确定隐性疾病基因。这样的工具对于像欧美人这样的大型近交群体很有用，因为纯合区域很可能很短，因此无法使用现有的SNP阵列数据技术明确地检测到。我将把这种纯合子优先排序方案应用于自闭症患者的数据集，以确定对重排序最有信息的个体，并将在序列数据上执行纯合子映射，以定位隐性疾病基因。第二个目标是开发方法，以允许拉丁美洲人的组合外加剂作图和全基因组关联（GWA），目前的外加剂作图方法失败的人口。拉丁美洲人的混合图谱是具有挑战性的，因为缺乏合适的参考单倍型，因为现有的技术不能模拟他们复杂的三向混合。我将探索三种对拉丁美洲人进行混合映射的方法，包括使用美洲原住民参考单倍型集合的线性组合，以及利用拉丁美洲人自身存在的美洲原住民变异信息。为了证明我的方法在实践中是有效的，我将应用这个工具来研究2型糖尿病的遗传学，这是一种在拉丁美洲人中发病率较高的疾病。

Population genetics is a crucial tool for facilitating medical genetics and disease gene mapping studies. This proposal outlines two novel population genetic techniques that each facilitate disease gene mapping in different ways. First, it describes a probabilistic technique for detecting the proportion of homozygosity an individual is likely to have based on SNP array data. This is useful for prioritizing disease case sample individuals for whole genome sequencing and subsequent homozygosity mapping to identify recessive disease genes. Such a tool is useful for large outbred populations such as European Americans for which homozygous regions are likely to be short and therefore cannot be unambiguously detected using existing techniques for SNP array data. I will apply this homozygosity prioritization scheme to a dataset of individuals with autism to identify individuals that will be most informative to resequence and will perform homozygosity mapping on the sequence data to locate recessive disease genes. The second aim is to develop methods to permit combined admixture mapping and genome-wide association (GWA) of Latinos, a population for which current admixture mapping methods fail. Latino admixture mapping is challenging because suitable reference haplotypes for their Native American ancestry are lacking, and because existing techniques cannot model their complex three-way admixture. I will explore three methods for performing admixture mapping of Latinos, including using linear combinations of collections of Native American reference haplotypes and utilizing the information about Native American variation present in the Latinos themselves. To show that my approach works in practice, I will apply this tool to study the genetics of type 2 diabetes, a disease with higher prevalence among Latinos. PUBLIC HEALTH RELEVANCE: Insights from population genetics and statistical methods grounded in medical genetics have been very important in facilitating medical genetics and disease gene mapping studies. This pro- posal describes novel population genetic techniques with direct application to disease gene mapping, both in populations that have experienced founder events and in U.S. Latino populations that are admixed. The technology that I develop will be widely applicable to many disease gene mapping studies, but I will focus as proof-of-principle on two diseases: autism and type 2 diabetes.