African Odyssey: An Integrative Genomics Analysis of Complex Physiologic Traits

描述 摘要 后基因组时代的主要挑战之一是理解持续性状变异背后的遗传、发育、生理和环境相互作用的复杂网络，包括对疾病的易感性。虽然孟德尔性状的定位已经取得了显著的成功，但在解剖涉及多个基因座和环境因素的复杂性状的遗传结构方面却相对较少。我们对非洲复杂性状变异的遗传学了解更少，而非洲是一个在人类遗传学研究中代表性不足的地区。高通量基因分型、基因表达和测序技术的最新进展现在促进了将来自数千个个体的数千个基因座的基因和基因表达数据结合在一起的方法。系统生物学方法结合了关于遗传相互作用和转录网络的信息，并专注于自然发生的遗传变异如何扰乱这些网络，在剖析复杂变量特征的遗传结构和识别功能变异方面可能比传统方法更成功。同样重要的是了解这些分子网络如何受到包括饮食、生活方式和传染病状况在内的环境因素的影响。出于这些原因，我计划使用一种新的综合基因组学方法，结合从生活在不同环境中的不同基因、种族和地理多样性的非洲人获得的基因组、转录和代谢数据。这些数据将首次提供关于遗传和文化多样性的非洲人的比较生理学的详细知识，以及对非洲人类进化史的详细了解。我将使用系统和进化生物学的方法来确定影响这些人群中复杂生理特征(包括疾病易感性)的遗传和环境因素。

DESCRIPTION Abstract One of the major challenges in the post-genomic era is understanding the complex web of genetic, developmental, physiological, and environmental interactions underlying continuous trait variation, including susceptibility to disease. Although there have been notable successes in mapping Mendelian traits, there have been relatively few successes in the dissection of the genetic architecture of complex traits involving multiple loci and environmental factors. We know even less about the genetics of complex trait variability in Africa, a region that had been under-represented in human genetics studies. Recent advances in the development of high-throughput genotyping, gene expression, and sequencing technologies now facilitate approaches that incorporate genotype and gene expression data from thousands of loci in thousands of individuals. A systems biology approach, which incorporates information about genetic interactions and transcription networks, and focuses on how naturally occurring genetic variants perturb these networks, may be more successful than traditional approaches for dissecting the genetic architecture of complex variable traits and for identifying functional variants. Equally important is understanding how these molecular networks are influenced by environmental factors including diet, lifestyle, and infectious disease status. For these reasons, I plan to use a novel integrative genomics approach, incorporating genomic, transcriptomic, and metabolomic data obtained from genetically, ethnically and geographically diverse Africans living in distinct environments. These data will provide, for the first time, a detailed knowledge of the comparative physiology of genetically and culturally diverse Africans and a detailed understanding of human evolutionary history in Africa. I will use a systems and evolutionary biology approach to identify genetic and environmental factors that influence complex physiologic traits, including disease susceptibility, in these populations.