Metagenomic deconvolution and species discovery in microbiomes using contact probability maps. J. N. Burton, I. Liachko, M. J. Dunham, J. Shendure Department of Genome Sciences, University of Washington, Seattle, WA.

   Every surface of the human body and digestive tract hosts a microbial community, i.e., a microbiome, consisting of bacterial, archaeal, and eukaryotic species in varying abundances. It has become increasingly clear that the human microbiomes play crucial roles in human health and disease. However, most microbial species cannot be cultured independently of their native communities, and thus are difficult to study even if they are abundant. Microbiomes are often analyzed through metagenomic shotgun sequencing. With this approach, the library construction step removes long-range contiguity information; thus shotgun sequencing and de novo assembly of a metagenomic sample typically yields a collection of contigs that derive from many different species in the sample and cannot readily be grouped by species. To enable whole-genome assembly from metagenomic samples, we have adapted the Hi-C technique, which creates a map of interactions between spatially adjacent DNA regions. When applied to a mixed cell population, Hi-C produces paired-end reads which connect intracellular sequences. Our method, which we call MetaPhase, exploits this signal to reconstruct the individual genomes of microbial species in a mixed sample, including unculturable and previously unknown species. MetaPhase can also use the Hi-C signal to create scaffolded genome assemblies of individual eukaryotic species within the microbial community and model the 3-dimensional architecture of these newly assembled genomes. We have applied MetaPhase to several synthetic metagenome samples containing up to 18 species of bacteria, archaea, and fungi, successfully clustering their genome content with over 99% agreement with published reference genomes. We are also applying it to samples of vaginal microbiomes from individuals with bacterial vaginosis (BV), a disease characterized by an increase in the species diversity of the vaginal microbiome. Lastly, we are applying MetaPhase to the microbial communities living inside sputum from patients with cystic fibrosis, with the goal of understanding the species responsible for opportunistic lung infections in these patients.

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