Integrative Genomic Analyses of Human Evolution and Adaptation in Africa

非洲人类进化和适应的综合基因组分析

• 批准号: 10561604
• 负责人: Sarah Anne Tishkoff
• 金额: $ 53.43万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10561604
• 关键词: Africa; African; African ancestry; Biological; Biological Assay; Biological Models; Biomedical Research; CRISPR/Cas technology; Cell Line; Cells; Communities; Complex; Data; Diet; Evolution; Gene Expression; Genetic; Genomic approach; Genomics; Human; Immune; In Vitro; Knowledge; Linkage Disequilibrium; Luciferases; Metabolic; Modernization; Natural Selections; Pattern; Persons; Phenotype; Population; Recording of previous events; Reporter; SNP array; Sampling; Shapes; Site; Source; Structure; Variant; biomedical resource; cardiometabolism; epigenomics; ethnic diversity; field study; functional genomics; genetic association; genome sequencing; genome wide association study; genome-wide; genomic variation; gut microbiome; in vivo; in vivo Model; metabolome; metabolomics; microbiome; model organism; novel; phenotypic data; trait; transcriptomics; whole genome

Abstract Africa is the site of origin of modern humans, contains the greatest levels of human genomic variation, and is the source of the worldwide range expansion of modern humans in the past 100,000 years. However, a fundamental gap in knowledge exists regarding African genomic and phenotypic variation, resulting in a lag in biomedical research, not only in Africans, but also in people of recent African descent. We will apply an integrative evolutionary genomics approach incorporating genomic, metabolomic, microbiome, epigenomic, and transcriptomic data in combination with detailed phenotypic data to reconstruct African population history and better understand the genetic basis of adaptive traits in ethnically diverse African populations. Specifically, we will use genome-wide SNP arrays as well as high-coverage whole genome sequencing data to identify targets of natural selection in these populations and to look for genetic associations with gene expression as well as anthropometric, cardio-metabolic, and immune related traits. We will use functional genomics approaches to identify causal regulatory loci and to study their impact on gene expression in vitro using high-throughput luciferase reporter assays in appropriate cell lines. We will also use Crispr-Cas9 technology to validate and characterize the functional impact of potential casual variants in both human cells and in vivo in model systems. Lastly, we will characterize gut microbiome diversity and examine correlations with diet, genetic and environmental variation. Our data will generate a deeper understanding of African genomic diversity, population structure, and patterns of linkage disequilibrium that 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 intermediate phenotypes (gene expression and the metabolome) and of complex traits in Africans. In addition, the data collected will be an important resource for the biomedical research community. Lastly, our study will shed light on human evolutionary history and evolutionary forces shaping patterns of genomic variation in ethnically diverse humans.

抽象的 非洲是现代人类的起源地，拥有最高水平的人类基因组 变异，是过去现代人类在全球范围内扩张的根源 十万年。然而，关于非洲基因组和 表型变异，导致生物医​​学研究的滞后，不仅在非洲，而且在 近代非洲人后裔。我们将应用综合进化基因组学方法 将基因组、代谢组、微生物组、表观基因组和转录组数据纳入 结合详细的表型数据重建非洲人口历史并更好 了解非洲不同种族人群适应性特征的遗传基础。 具体来说，我们将使用全基因组 SNP 阵列以及高覆盖度全基因组 测序数据以确定这些群体中自然选择的目标并寻找遗传 与基因表达以及人体测量、心脏代谢和免疫的关联 相关特征。我们将使用功能基因组学方法来识别因果调控位点和 使用高通量荧光素酶报告基因检测研究它们对体外基因表达的影响 在适当的细胞系中。我们还将使用 Crispr-Cas9 技术来验证和表征 人类细胞和模型系统体内潜在偶然变异的功能影响。 最后，我们将描述肠道微生物组多样性的特征，并检查与饮食、遗传的相关性。 和环境变化。我们的数据将加深对非洲基因组的了解 多样性、人口结构和连锁不平衡模式对于 全基因组关联研究在非洲人后裔中的成功应用和解释 人口。此外，这项研究对于理解遗传因素也具有重要意义。 中间表型（基因表达和代谢组）和复杂性状的基础 非洲人。此外，收集到的数据将成为生物医学研究的重要资源 社区。最后，我们的研究将揭示人类进化历史和进化力量 塑造不同种族人类的基因组变异模式。