Integrative Genomics of Body Size and Metabolism in Ethnically Diverse Africans

 描述(申请人提供)：阐明基因到表型的图谱是人类基因组研究的主要目标。然而，关于非洲基因组和表型变异的知识存在着根本性的差距，导致这些人群的生物医学研究滞后。非洲人口蕴藏着巨大的遗传多样性，并表现出大量的表型差异，包括与糖尿病和心血管疾病风险相关的体型、脂肪和碳水化合物代谢，部分原因是对不同环境的适应。在这里，我们建议进行实地研究，从喀麦隆身材矮小的俾格米人狩猎采集者和邻近身材高大的说班图语的农民那里收集新的生物样本以及关于人体测量和代谢特征的详细表型数据。我们将应用整合基因组、代谢和基因表达数据的综合进化基因组学方法，更好地了解这些种族多样性不足的非洲人复杂适应特征的遗传基础，包括身体尺寸和新陈代谢。具体地说，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阵列来确定这些种群中自然选择的目标，并寻找与俾格米人狩猎采集者和班图农民的人体测量学、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方法来识别新的候选基因座，并在适当的细胞系中使用高通量报告分析来研究候选可变点对基因表达的影响。这些数据将使我们能够检验这样的假设，即俾格米人身材矮小可能是受代谢、生殖和免疫多效性基因影响的性状选择的副产品。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，我们的数据将加深对非洲基因组多样性、种群结构和连锁不平衡模式的理解，这些对于在非洲裔人口中成功应用和解释全基因组关联研究至关重要。此外，这项研究将对了解非洲人复杂性状的遗传基础、矮小的病因以及受GH/IGF1途径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史和塑造不同种族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.