Human gut microbial communities are among the most complex and diverse known, yet the contributionofdifferences in the composition of these communities to human health remains largely unexplored. Culture-independent 16S rRNA surveys have revealed large differences in the microbial communities amonghealthyadults. However, the strong selective pressure and influx of heterogeneous DNA in the gut provides anunparalleled opportunity for lateral gene transfer, so 16S rRNA may not tell us the whole story. Thus,understanding patterns of gene flow in the gut and relating 16S rRNA gene sequences to the rest of thegenome is critical. In Project 3, we develop powerful new statistical tools for relating microbial communitiesin terms of the species, genes, transcripts, and metabolites they contain, and use these tools to provide thefirst quantitative estimates of the effects of host genetics and obesity to the composition of the humanmicrobial community. Specifically, we will place species and genes in the human gut in context by relatingthem to the gut communities of a wide range of other mammals, and to community samples from hundredsof different physical environments ranging from oceans to soils. We will then use the distribution of speciesand genes related to those in the human gut to understand how the variability and diversity of gutcommunities within and between individuals relates to patterns observed in other species andenvironments. We will test the following two hypotheses. (1)There are systematic differences in human gutcommunities related to host genetics and to obesity. (2)The strong selective pressure in the gut environmentresults in adaptation through the acquisition of genes with specific functions, such as carbohydratemetabolism, through lateral gene transfer. We will examine these hypotheses by developing powerful newmethods to detect lateral gene transfer, and by combining these methods with UniFrac,our tool for relatingmicrobial communities. This project will utilize the community samples from monozygotic and dizygotictwins and their mothers from Project 1, and the pan-genome sequences of B. thetaiotaomicron and M. smithiifrom Project 2, to determine the relative contributions of genetic relatedness and obesity to the genes andspecies present in the gut communities ofindividual adult humans.
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