A role for host-bacteria interactions in shaping patterns of genetic variation across human populations. R. Blekhman1,2, J. K. Goodrich1,3, K. Huang4, Q. Sun5, R. Bukowski5, J. T. Bell6, T. D. Spector6, A. Keinan7, R. E. Ley1,3, D. Gevers4, A. G. Clark1 1) Molecular Biology and Genetics, Cornell University, Ithaca, NY; 2) Neurology and Neuroscience, Weill Cornell Medical College, New York, NY; 3) Microbiology, Cornell University, Ithaca, NY; 4) 4.Genome Sequencing and Analysis Program, The Broad Institute of MIT and Harvard, Cambridge, MA; 5) Computational Biology Service Unit, Cornell University, Ithaca, NY; 6) Twin Research & Genetic Epidemiology, Kings College London, U.K; 7) Biological Statistics and Computational Biology, Cornell University, Ithaca, NY.

   The composition of bacteria in and on the human body varies widely across human individuals, and has been associated with multiple health conditions. While host genetic factors are expected to control the human microbiome through the immune system and metabolic pathways, elucidation of the genetic influence on microbiome composition has proven to be a challenge. Here, we present a genome-wide association study aimed at identifying human genetic variation associated with microbial diversity in multiple body sites. By mining the shotgun metagenomic data from the Human Microbiome Project for incidental host DNA reads, we gathered information on host genetic variation for 93 individuals for whom bacterial abundance data are also available. Using a two-stage discovery and validation approach, we identified 26 candidate human genes that are associated with microbiome composition in 15 host body sites. These genes are significantly enriched in immunity functional categories, and form an interaction network highly enriched with immunity-related functions. To investigate the evolutionary history of bacteria-associated host genes, we used available sequencing data from the 1000 Genomes Project, and find that these genes show a significant excess of highly differentiated allele frequencies among human populations. Moreover, these genes are over-represented with genes that have been identified in recent genome scans for positive selection and balancing selection. Combined, these results highlight the role of host immunity in determining bacteria levels across the body, and underline a possible role for the microbiome in driving the evolution of bacteria-associated host genes.