Integrative Genomics of Body Size and Metabolism in Ethnically Diverse Africans

不同种族非洲人体型和代谢的综合基因组学

• 批准号: 9014550
• 负责人: Sarah Anne Tishkoff
• 金额: $ 60.64万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-15 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9014550
• 关键词: Address; Affect; Africa; African; African American; Biological; Biological Assay; Biomedical Research; Body Size; Cameroon; Carbohydrates; Cardiovascular Diseases; Cell Line; Communities; Complex; Custom; DNA; Data; Diabetes Mellitus; Disease; Environment; Etiology; European; Exhibits; Fatty acid glycerol esters; Gene Expression; Genes; Genetic; Genetic Variation; Genomic Segment; Genomic approach; Genomics; Genotype; Goals; Growth; Growth Factor Gene; Health; Height; Hormonal; Hormones; Human; Immunity; In Vitro; Individual; Insulin; Knowledge; Length; Leukocytes; Light; Limb structure; Linear Regressions; Linkage Disequilibrium; Lipids; Longevity; Malignant Neoplasms; Maps; Metabolic; Metabolic syndrome; Metabolism; Modeling; Natural Selections; Nucleic Acid Regulatory Sequences; Pathway interactions; Pattern; Phenotype; Plasma; Play; Population; Population Heterogeneity; Recording of previous events; Reporter; Reproduction; Research; Resources; Role; SNP array; Sampling; Seasons; Shapes; Signal Pathway; Site; Somatotropin; Structure; Testing; Tissue-Specific Gene Expression; Variant; Weight; Work; admixture mapping; base; carbohydrate metabolism; diabetes risk; ethnic diversity; farmer; field study; functional genomics; genetic association; genetic variant; genome sequencing; genome wide association study; genome-wide; genomic variation; human genomics; hypothalamic-pituitary-thyroid axis; life history; lipid metabolism; lymphoblastoid cell line; metabolic phenotype; novel; phenotypic data; pituitary gland development; pleiotropism; response; trait; whole genome

 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.

 描述（由申请人提供）：阐明基因型到表型图谱是人类基因组学研究的主要目标，然而，关于非洲基因组和表型变异的知识存在根本差距，导致这些人群的生物医学研究滞后。非洲人群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体型、脂质和碳水化合物代谢，部分原因是对不同环境的适应。我们将采用综合进化基因组学方法，从喀麦隆身材矮小的俾格米狩猎采集者和邻近的讲班图语的高个子农民那里收集新的生物样本以及详细的人体测量和代谢特征表型数据。和基因表达数据，以更好地了解这些代表性不足的多样化非洲人的复杂适应性特征的遗传基础，包括体型和新陈代谢。具体来说，我们将使用高覆盖率的全基因组来识别新的遗传变异。我们还将使用全基因组 SNP 阵列来识别这些人群中自然选择的目标，并在俾格米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。方法来识别新的候选基因座，并使用高通量检测报告基因在适当的细胞系中研究候选可变位点对体外基因表达的影响，这些数据将使我们能够检验身材矮小的假设。俾格米人可能是对代谢、繁殖和免疫具有多效性影响的基因进行选择的副产品。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，我们的数据将产生更深入的了解。非洲基因组多样性、种群结构和连锁不平衡模式的研究对于非洲人后裔群体基因组范围关联研究的成功应用和解释至关重要。此外，这项研究将对理解非洲人后裔复杂性状的遗传基础产生重要影响。非洲人，身材矮小的病因学以及受 GH/IGF1 通路影响的其他特征和疾病，如代谢综合征、糖尿病、心血管疾病、长寿和癌症最后，我们的研究将揭示人类进化历史和塑造模式的进化力量。不同种族人类的基因组变异。