Extensive Unexplored Human Microbiome Diversity Revealed by Over 150,000 Genomes from Metagenomes Spanning Age, Geography, and Lifestyle

Edoardo Pasolli,Francesco Asnicar,Serena Manara,Moreno Zolfo,Nicolai Karcher,Federica Armanini,Francesco Beghini,Paolo Manghi,Adrian Tett,Paolo Ghensi,Maria Carmen Collado,Benjamin L Rice,Casey Dulong,Xochitl C Morgan,Christopher D Golden,Christopher Quince,Curtis Huttenhower,Nicola Segata

doi:10.1016/j.cell.2019.01.001

Abstract

SummaryThe body-wide human microbiome plays a role in health, but its full diversity remains uncharacterized, particularly outside of the gut and in international populations. We leveraged 9,428 metagenomes to reconstruct 154,723 microbial genomes (45% of high quality) spanning body sites, ages, countries, and lifestyles. We recapitulated 4,930 species-level genome bins (SGBs), 77% without genomes in public repositories (unknown SGBs [uSGBs]). uSGBs are prevalent (in 93% of well-assembled samples), expand underrepresented phyla, and are enriched in non-Westernized populations (40% of the total SGBs). We annotated 2.85 M genes in SGBs, many associated with conditions including infant development (94,000) or Westernization (106,000). SGBs and uSGBs permit deeper microbiome analyses and increase the average mappability of metagenomic reads from 67.76% to 87.51% in the gut (median 94.26%) and 65.14% to 82.34% in the mouth. We thus identify thousands of microbial genomes from yet-to-be-named species, expand the pangenomes of human-associated microbes, and allow better exploitation of metagenomic technologies.

Highlights

Despite extensive recent studies of the human microbiome using a variety of culture-independent molecular technologies (HumanMicrobiome Project Consortium, 2012; Qin et al, 2010; Quince et al, 2017a; Rinke et al, 2013), most characterization of these ecosystems is still focused on microbes that are cultivable, when those with sequenced isolate genomes are considered
Culture-independent genomic approaches that are scalable to large cohorts (Human Microbiome Project Consortium, 2012; Qin et al, 2010; Quince et al, 2017a) have facilitated access to an expanded set of isolation-recalcitrant members of the microbiome, but they suggested the presence of a large fraction of still unexplored diversity (Nielsen et al, 2014; Rinke et al, 2013)
Otherstudieshave succeeded in reconstructing microbial genomes by metagenomic assembly on single human cohorts (Bäckhed et al, 2015; Brooks et al, 2017; Ferretti et al, 2018; Human Microbiome Project Consortium, 2012; Raveh-Sadka et al, 2015; Sharon et al, 2013), but systematic cross-study cataloging of metagenomically assembledgenomesfocusedsofaronnon-humanenvironments(Oyama et al, 2017; Parks et al, 2017)

Summary

Introduction

Despite extensive recent studies of the human microbiome using a variety of culture-independent molecular technologies (HumanMicrobiome Project Consortium, 2012; Qin et al, 2010; Quince et al, 2017a; Rinke et al, 2013), most characterization of these ecosystems is still focused on microbes that are cultivable, when those with sequenced isolate genomes are considered. Otherstudieshave succeeded in reconstructing microbial genomes by metagenomic assembly on single human cohorts (Bäckhed et al, 2015; Brooks et al, 2017; Ferretti et al, 2018; Human Microbiome Project Consortium, 2012; Raveh-Sadka et al, 2015; Sharon et al, 2013), but systematic cross-study cataloging of metagenomically assembledgenomesfocusedsofaronnon-humanenvironments(Oyama et al, 2017; Parks et al, 2017) Complementary techniques, such as co-abundance of gene groups (Nielsen et al, 2014), can identify genomic bins without reference, but these techniques do not account for sample-specific strains and strain-level differences in the sequence reconstruction and require downstream single-nucleotide variation analysis on specific genomic regions to uncover strain variability (Quince et al, 2017b; Truong et al, 2017)

Methods

Results

Conclusion