Integrative Genomic Analyses of Human Evolution and Adaptation in Africa

摘要 非洲是现代人类的起源地，蕴藏着人类基因组水平最高的地区 变异，是过去现代人类在世界范围内扩张的根源。 十万年然而，在非洲基因组和 表型变异，导致生物医学研究的滞后，不仅在非洲，而且在非洲， 近代非洲人后裔。我们将应用综合进化基因组学方法 将基因组学、代谢组学、微生物组学、表观基因组学和转录组学数据整合到 结合详细的表型数据，重建非洲人口历史， 了解不同种族的非洲人群中适应性特征的遗传基础。 具体来说，我们将使用全基因组SNP阵列以及高覆盖率的全基因组 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、心脏代谢和免疫功能的相关性 相关特征。我们将使用功能基因组学的方法来确定因果调节基因座， 使用高通量荧光素酶报告基因分析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 在人细胞和模型系统中的体内潜在偶然变体的功能影响。 最后，我们将描述肠道微生物组多样性的特征，并研究与饮食、遗传、 和环境变化。我们的数据将使我们更深入地了解非洲的基因组 多样性，人口结构和模式的连锁不平衡，是至关重要的 全基因组关联研究在非洲裔人群中成功应用与解读 人口。此外，这项研究将对理解遗传学有重要意义。 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，收集的数据将是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的历史和进化的力量 在不同种族的人类中形成基因组变异的模式。

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.