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: 9360249
• 负责人: Sarah Anne Tishkoff
• 金额: $ 28.94万
• 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/9360249
• 关键词: Address; Affect; Africa; African; African American; Anatomy; 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; Height; Hormonal; Hormones; Human; Immunity; In Vitro; Individual; Insulin; Knowledge; Length; Leukocytes; Light; Limb structure; Linear Models; Linear Regressions; Linkage Disequilibrium; Lipids; Longevity; Malignant Neoplasms; Maps; Metabolic; Metabolic syndrome; Metabolism; Modernization; Natural Selections; Nucleic Acid Regulatory Sequences; Pathway interactions; Pattern; Phenotype; Plasma; Play; Population; Recording of previous events; Reporter; Reproduction; Research; Role; SNP array; Sampling; Seasons; Shapes; Signal Pathway; Site; Somatotropin; Structure; Testing; Tissue-Specific Gene Expression; Variant; Weight; Work; admixture mapping; base; biomedical resource; 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; public health relevance; 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（通过应用程序提供）：阐明基因型到表型图是人类基因组学研究的主要目标。但是，关于非洲基因组和表型变异的知识的根本差距，导致这些人群的生物医学研究滞后。非洲人口具有巨大的遗传多样性，并暴露了大量的表型变异，包括身体大小，脂质和碳水合物代谢，这与患有糖尿病和心血管疾病的风险有关，部分原因是适应了对潜水环境的适应性。在这里，我们建议进行现场研究，以收集新的生物学样本，以及有关人体测量和代谢特征的详细表型数据，这些数据来自喀麦隆的侏儒猎人 - 采集者，以及邻近的高个子班图说话的农民。我们将采用结合基因组，代谢和基因表达数据的综合进化基因组学方法，以更好地了解这些不足代表性的种族多样性的非洲人中复杂自适应特征（包括体型和代谢）的遗传基础。具体而言，我们将使用高覆盖范围的整个基因组测序来鉴定新的遗传变异。我们还将使用全基因组的SNP阵列来识别这些人群中自然选择的靶标，并在侏儒猎人 - 采集者和班图族农民中寻找与人体测量，荷尔蒙和心脏代谢性状的遗传关联。我们将使用功能性基因组学方法来识别新的候选局部局部局部，并使用适当的细胞系中的高通量记者测定法研究候选变量位点对基因表达的影响。这些数据将使我们能够检验以下假设：pygmies中的矮小身材可能是受到对代谢，繁殖和免疫学影响基因影响的特征的选择的副产品。收集的生物样品和数据将是生物医学研究界的重要资源。此外，我们的数据将对非洲基因组多样性，人群结构和连锁二动型的模式产生更深入的了解，这对于在非洲衰老人群中成功应用和解释广泛的基因组关联研究至关重要。此外，这项研究将对理解非洲人的复杂性状，病因以及受GH/IGF1途径影响的其他特征和疾病的遗传基础具有重要意义，例如代谢综合征，糖尿病，心血管疾病，长寿，长寿和癌症。最后，我们的研究将阐明人类的进化史和进化力，塑造了种族多元化人类基因组变异的模式。