Integrative Genomics of Body Size and Metabolism in Ethnically Diverse Africans

 描述（由申请人提供）：阐明基因型-表型图谱是人类基因组学研究的主要目标。然而，在非洲基因组和表型变异方面存在着根本性的知识空白，导致这些人群的生物医学研究滞后。非洲人口拥有大量的遗传多样性，并表现出大量的表型变异，包括与糖尿病和心血管疾病风险相关的身体大小，脂质和碳水化合物代谢，部分原因是适应不同的环境。在这里，我们建议进行实地研究，收集新的生物样本，以及详细的表型数据的人体测量和代谢特征，从矮身材俾格米人的狩猎采集者在喀麦隆和邻近的高身材班图语农民。我们将采用整合进化基因组学方法，结合基因组，代谢和基因表达数据，以更好地了解这些代表性不足的种族多样性非洲人的复杂适应性特征的遗传基础，包括体型和代谢。具体来说，我们将使用高覆盖率的全基因组测序来识别新的遗传变异。我们还将使用全基因组SNP阵列来确定这些人群中自然选择的目标，并在俾格米人狩猎采集者和班图农民中寻找与人体测量，激素和心脏代谢特征的遗传关联。我们将使用功能基因组学的方法来确定新的候选位点，并研究候选可变位点对基因表达的影响，在适当的细胞系中使用高通量的报告分析体外。这些数据将使我们能够测试的假设，身材矮小的俾格米人可能是一个副产品的选择性状的基因与多效性影响代谢，生殖和免疫。收集的生物样本和数据将成为生物医学研究界的重要资源。此外，我们的数据将产生更深入的了解非洲的基因组多样性，人口结构和模式的连锁不平衡，这是成功的应用和解释基因组广泛的关联研究在非洲裔人口的关键。此外，这项研究将对了解非洲人复杂性状的遗传基础、身材矮小的病因以及受GH/IGF 1通路影响的其他性状和疾病（如代谢综合征、糖尿病、心血管疾病、长寿和癌症）具有重要意义。最后，我们的研究将揭示人类进化历史和形成种族多样性人类基因组变异模式的进化力量。

 DESCRIPTION (provided by applicant): Elucidating the genotype-to-phenotype map is a primary goal of human genomics research. However, a fundamental gap in knowledge exists regarding African genomic and phenotypic variation, resulting in a lag in biomedical research in these populations. African populations harbor immense amounts of genetic diversity and exhibit substantial amounts of phenotypic variation, including body size, lipid and carbohydrate metabolism that are associated with risk for diabetes and cardiovascular disease, partly due to adaptation to diverse environments. Here, we propose to perform field studies to collect novel biological samples as well as detailed phenotypic data on anthropometric and metabolic traits from short statured Pygmy hunter-gatherers in Cameroon and neighboring tall-statured Bantu-speaking farmers. We will apply an integrative evolutionary genomics approach incorporating genomic, metabolic, and gene expression data to better understand the genetic basis of complex adaptive traits, including body size and metabolism, in these under-represented ethnically diverse Africans. Specifically, we will identify novel genetic variants using high coverage whole genome sequencing. We will also use genome-wide SNP arrays to identify targets of natural selection in these populations and to look for genetic associations with anthropometric, hormonal, and cardio-metabolic traits in Pygmy hunter-gatherers and Bantu farmers. We will use functional genomics approaches to identify new candidate loci and to study the impact of candidate variable sites on gene expression in vitro using high-throughput reporter assays in appropriate cell lines. These data will enable us to test the hypothesis that short stature in Pygmies may be a byproduct of selection for traits influenced by genes with pleiotropic effects on metabolism, reproduction, and immunity. The biological samples and data collected will be an important resource for the biomedical research community. In addition, our data will generate a deeper understanding of African genomic diversity, population structure, and patterns of linkage disequilibrium which are critical for the successful application and interpretation of genome wide association studies in African-descent populations. Furthermore, this study will have important implications for understanding the genetic basis of complex traits in Africans, etiology of short stature as well as other traits and diseases influenced by the GH/IGF1 pathway, such as metabolic syndrome, diabetes, cardiovascular disease, longevity, and cancer. Lastly, our study will shed light on human evolutionary history and evolutionary forces shaping patterns of genomic variation in ethnically diverse humans.