Population Genomics of Geographically and Ethnically Diverse Africans

描述（由申请人提供）：拟议的研究项目涉及未充分研究的生活在不同环境和不同饮食中的种族和地理不同的非洲人的全基因组变异的详细特征。该数据集代表了迄今为止在代表性不足的非洲人口中创建的最详细的基因组变异目录。种群遗传分析将使我们能够识别在适应不同环境中发挥作用的潜在功能变异，并推断种群的人口历史。尽管存在大量的遗传变异和重大的公共卫生挑战，但非洲人类遗传学在很大程度上尚未得到充分研究。重要的是，基因组学和遗传医学的最新进展不能忽视非洲人口。利用高覆盖全基因组测序，我们将分析多个非洲人群中多个个体的全基因组序列，以推断非洲最近和古代的人口历史，并确定人类基因组中自然选择的目标。现有的统计群体遗传学方法将被应用，新的理论方法将被开发来分析群体基因组学数据集，使用计算机模拟和数学建模的结合。全基因组序列还将与基因分型阵列产生的数据相结合，以评估SNP确定偏差对不同非洲人口的影响。生活在不同气候和不同饮食条件下的非洲人口（农人、牧民和狩猎采集者）中存在的基因组变异与高血压和糖尿病等现代疾病有关。此外，遗传变异的发现将有助于非洲人群的全基因组关联研究。本研究也与美国国立卫生研究院的非洲人类遗传与健康项目（H3Africa）高度相关，该研究项目将为博士后培养做出重大贡献。最后，为非洲人口开发的分析方法也将对利用下一代测序技术的其他研究有用。

DESCRIPTION (provided by applicant): The proposed research project involves detailed characterization of whole genome variation in understudied ethnically and geographically diverse Africans living in distinct environments and with distinct diets. The dataset represents the most detailed catalog of genomic variation in under-represented African populations created to date. Population genetic analyses will enable us to identify potential functional variants that play a role in adaptation to diverse environments and to infer the demographic history of populations. Despite immense amounts of genetic variation and significant public health challenges, African human genetics has largely been understudied. It is important that recent advances in genomics and genetic medicine do not ignore Africa populations. Using high-coverage whole genome sequencing we will analyze whole genome sequences of multiple individuals in multiple African populations in order to infer both recent and ancient demographic history in Africa and to identify targets of natural selection in the human genome. Existing statistical population genetics approaches will be applied, and novel theoretical approaches will be developed to analyze population genomics datasets using a combination of computer simulations and mathematical modeling. Whole genome sequences will also be combined with data generated from genotyping arrays to assess the impact of SNP ascertainment bias on diverse African populations. Genomic variation present in African populations living in diverse climates and with diverse diets (agriculturalists, pastoralists and hunter- gatherers) is relevant o diseases of modernity, such as hypertension and diabetes. In addition, genetic variation found will be useful for genome-wide association studies of African populations. This proposed study is also highly relevant to the NIH's Human Heredity and Health in Africa Project (H3Africa), and this research project will contribute substantially to postdoctoral training. Finally, analytic approaches developed for African populations will also be useful to other studies that utilize next-generation sequencing technology.