Hi-C deconvolution of a human gut microbiome yields high-quality draft genomes and reveals plasmid-genome interactions

Abstract

T he assembly of high-quality genomes from mixed microbial samples is a long-standing challenge in genomics and metagenomics. Here, we describe the application of ProxiMeta, a Hi-C-based metagenomic deconvolution method, to deconvolve a human fecal metagenome. This method uses the intra-cellular proximity signal captured by Hi-C as a direct indicator of which sequences originated in the same cell, enabling culture-free de novo deconvolution of mixed genomes without any reliance on a priori information. We show that ProxiMeta deconvolution provides results of markedly high accuracy and sensitivity, yielding 50 near-complete microbial genomes (many of which are novel) from a single fecal sample, out of 252 total genome clusters. ProxiMeta outperforms traditional contig binning at high-quality genome reconstruction. ProxiMeta shows particularly good performance in constructing high-quality genomes for diverse but poorly-characterized members of the human gut. We further use ProxiMeta to reconstruct genome plasmid content and sharing of plasmids among genomes-tasks that traditional binning methods usually fail to accomplish. Our findings suggest that Hi-C-based deconvolution can be useful to a variety of applications in genomics and metagenomics.

Evolutionary dynamics of bacteria in the gut microbiome within and across hosts

“…Future efforts to combine metagenomic-and isolate-based approaches, e.g. by incorporating long-range linkage information [41,88,89], will be crucial for building a more detailed understanding of these evolutionary processes.…”

Nanopore sequencing enables high-resolution analysis of resistance determinants and mobile elements in the human gut microbiome

“…These two strains exhibited very different correlation patterns with the abundance of the IMP plasmid, identifying strain L as the likely host (Pearson correlation 0.94 versus 0.07 for strain H; Figure 4F). By isolating the CRE strain from stool samples for this subject and sequencing its genome we were also able to confirm the correctness of this association (Methods), suggesting that this approach could complement existing Hi-C sequencing based techniques to link plasmids and their host genomes in metagenomic data 41 .…”

bin3C : Exploiting Hi-C sequencing data to accurately resolve metagenome-assembled genomes (MAGs)

“…The richness of information captured in Hi-C experiments is such that the technique has subsequently been applied to a wide range of problems in genomics, such as: genome reassembly [21] , haplotype reconstruction [22,23] , assembly clustering [24] , centromere prediction [25] . The potential of Hi-C (and other 3C methods) as a means to cluster or deconvolute metagenomes into genome bins has been demonstrated on simulated communities [26][27][28] and real microbiomes [29,30] .…”

“…Most recently, commercial Hi-C products ranging from library preparation kits through to analysis services [30,31] have been announced. These products aim to lessen the experimental challenge in library preparation for non-specialist laboratories, while also raising the quality of data produced.…”

“…These products aim to lessen the experimental challenge in library preparation for non-specialist laboratories, while also raising the quality of data produced. In particular, one recently introduced commercial offering is a proprietary metagenome genome binning service called ProxiMeta, which was demonstrated on a real human gut microbiome, yielding state of the art results [30] .…”