Metapangenomics of the Oral Microbiome

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Project Summary/Abstract The oral microbiome is a complex multispecies ecosystem. Deciphering the interactions of microbes with each other and their host habitats is essential for understanding the oral microbiome's role in health and disease and for developing preventive and therapeutic strategies. To successfully modulate the microbiome we need to understand the genomic drivers of bacterial site tropisms and community membership. Much of the molecular data needed to address these fundamental questions already exists in publicly available databases, but has not been analyzed within an ecologic framework using appropriate bioinformatic tools and in sufficient depth. While genome information exists for most bacterial species in the mouth, there has been no systematic analysis of what genes are core or accessory for the major species – information critical for assessing microbial function and for selecting strains for in vitro models. The scientific premise of our proposal is that the combination of pangenomic analysis with oral metagenomic information, hence metapangenomics, will test the site-specialist hypothesis and provide unique, gene-level insights into the function of the oral microbiome. We will construct pangenomes from high-quality genomes in the National Center for Biotechnology Information (NCBI) to identify core and accessory genes of oral species. We will map metagenomic data from the Human Microbiome Project (HMP), and other sources, onto the pangenomes to assess which genomes actually occur in the human mouth. Analysis by oral site will identify site-tropisms at the genomic level, thus evaluating the site- specialist hypothesis. We will determine which genes are unique to a species or strain occupying a particular oral niche, and we will identify candidate gene drivers of site tropism. The products of our analysis will be made available to the oral research community by expanding the Human Oral Microbiome Database (HOMD), developed by Dr. Dewhirst, a PI on this proposal. Pangenomes will be made available interactively via a new platform for Analysis and Visualization of Omics Information (Anvi'o) created by Dr. Eren, a PI on this proposal. The impact of the project is that it will establish a genomic, ecologic framework for understanding the oral microbiome. It will provide a detailed, species, strain- and gene-level analysis of the oral microbiome in the context of individual oral sites. It will identify key genes for follow-up mechanistic studies on site tropisms, niche adaptation, and pathogenesis. It will improve authentication and error-correction of key bacterial species and strains. The project builds on the existing strengths of HOMD, NCBI and HMP, makes available to researchers the results of cutting-edge genomic analysis, and lays the groundwork for propelling oral microbiome research into the pangenomic and metagenomic era.