Population Genomics of Host-Microbiome Interactions

寄主-微生物组相互作用的群体基因组学 寄生在人体内的微生物群落的组成千差万别。 它与许多寄主特征和疾病有关。尽管 微生物群受环境因素的影响，寄主遗传因素也有望控制 人类与微生物群之间的相互作用。理解遗传和环境的相对作用 宿主-微生物组相互作用的因素是人类疾病研究的中心目标。然而，我们非常清楚 关于控制人类与微生物群相互作用的基因组因素及其影响的研究很少 关于复杂的人类疾病。通常很难区分遗传和环境对人类健康的影响 微生物组，研究只考虑单个时间点的微生物组，这可能是有问题的 微生物群可能在日常生活中和在个人的一生中发生巨大变化。此外，就像大多数人一样 微生物组研究确定了相关性，我们不知道个体间和种群间的差异是如何在 微生物群的组成影响寄主生理。 在这项提案中，我概述了一项长期研究战略，以解决这些关键的知识差距。研究 在我的实验室里是基于这样的假设，即微生物群可以被认为是数量性状，因此我们可以 直接定位宿主基因组中控制微生物组变异的因素，以及识别单个宿主 受微生物组调控的基因和途径。在这里，我概述一下我的实验室的研究计划 未来五年，旨在回答有关宿主-微生物组遗传基础的基本问题 通过三个广泛的、互补的项目领域进行互动，旨在：(1)收集和整合东道主和 微生物组基因组数据，以实现对宿主-微生物组分子相互作用的系统水平的理解 (2)描述灵长类动物模型中终生纵向微生物组动力学的遗传力 系统；以及(3)使用新的体外和体外系统来了解种群间变异对 阐述了微生物组对宿主基因的调控及其潜在的调控机制。 拟议的研究计划将提供寄主之间分子相互作用的系统级视图 肠道中的基因和微生物分类群、基因和途径；微生物组动态和 分类群由寄主遗传变异控制；以及对微生物 调节寄主基因。这些结果将改变我们对人类基因组之间相互作用的理解 和微生物组，解释这种相互作用如何影响疾病，并将使微生物组的发展- 改善人类健康的基础疗法和诊断学。

Population Genomics of Host-Microbiome Interactions The composition of the microbial communities that colonize the human body varies widely across individuals and populations, and has been associated with numerous host traits and diseases. Although the microbiome is influenced by environmental factors, a strong host genetic factor is also expected to control the interaction between humans and the microbiome. Understanding the relative role of genetic and environmental factors in host-microbiome interactions is a central goal in human disease research. However, we know very little about the genomic factors that control the interaction between humans and the microbiome and their effect on complex human disease. It is often difficult to disentangle genetic from environmental effects on the microbiome, and studies only consider the microbiome in a single time point, which could be problematic given the microbiome can vary dramatically day-to-day and throughout an individual’s life. Moreover, as most microbiome studies identify correlations, we do not know how inter-individual and inter-population variation in microbiome composition affects host physiology. In this proposal, I outline a long-term research strategy to address these critical gaps in knowledge. Research in my lab is based on the hypothesis that the microbiome can be considered a quantitative trait, and thus we can directly map host genomic factors controlling the variation in the microbiome, as well as identify individual host genes and pathways that are regulated by the microbiome. Here, I outline my lab’s research program for the next five years, designed to answer fundamental questions about the genetic basis of host-microbiome interactions via three broad, complementary Project Areas, aiming to: (1) collect and integrate host and microbiome genomic data to achieve a systems-level understanding of host-microbiome molecular interactions in the colon; (2) characterize the heritability of life-long longitudinal microbiome dynamics in a primate model system; and (3) use novel in vitro and ex vivo systems to understand the effect of inter-population variation in the microbiome on host gene regulation and describe the underlying regulatory mechanism. The proposed research program will provide a systems-level view of the molecular interactions between host genes and microbial taxa, genes, and pathways in the gut; a characterization of how microbiome dynamics and taxa are controlled by host genetic variation; and a description of the mechanism with which the microbes regulate host genes. These results would transform our understanding of the interplay between human genomics and the microbiome, explain how this interaction affects disease, and would enable development of microbiome- based therapeutics and diagnostics that improve human health.