Population Genomics of Host-Microbiome Interactions There is wide variation in the composition of the microbial communities that colonize the human body across individuals and populations, and this variation has been associated with numerous host traits and diseases. Understanding the factors that influence this variation, and the mechanism by which this variation affects host traits, is of central goal in human disease research. Although some of the variation in the microbiome is controlled by host genetics, we know very little about the genomic factors that control the interaction between humans and the microbiome and their effect on complex human disease. Disentangling genetic from environmental effects on the microbiome is challenging, and the microbiome is usually profiled in a single time point, which doesn’t account for microbiome longitudinal variation. Moreover, most of our knowledge on host-microbiome interactions consists of correlational associations, and we do not know how inter-individual and inter-population variation in microbiome composition affects host gene regulation. My laboratory’s research aims 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. My lab’s research program for the next five years is designed to answer fundamental questions about the genomic basis of host-microbiome interactions via three broad, complementary Project Areas, aiming to: (1) develop computational techniques to integrate microbiome and host genomic data, and apply these methods to achieve a systems-level understanding of host-microbiome interactions across populations and disease states; (2) characterize the heritability of functional components of the microbiome (microbial genes, strains, and pathways) and assess the effect of life-long longitudinal microbiome dynamics on host physiology in a primate model system; and (3) use novel in-vitro and ex-vivo systems to understand the causal effect of inter-individual and 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 factors in the gut across populations, environments, and diseases; a characterization of how microbiome longitudinal dynamics, as well as genes, pathways, and strains are controlled by host genetic; and a description of the mechanism with which 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 enable development of microbiome-based therapeutics and diagnostics that improve h...