Identification and spatio-temporal tracking of ubiquitous phage families in the human microbiome

Abstract

Viruses are a major component of the human microbiome, yet their diversity, lifestyles, spatiotemporal dynamics, and functional impact are not well understood. Elucidating the ecology of human associated phages may have a major impact on human health due to the potential ability of phages to modulate the abundance and phenotype of commensal bacteria. Analyzing 690 Human Microbiome Project metagenomes from 103 subjects sampled across up to 18 habitats, we found that despite the great interpersonal diversity observed among human viromes, humans harbor distinct phage families characterized by their shared conserved hallmark genes known as large terminase subunit (TerL) genes. Phylogenetic analysis of these phage families revealed that different habitats in the oral cavity and gut have unique phage community structures. Over a ~7-month timescale most of these phage families persisted in the oral cavity and gut, however, presence in certain oral habitats appeared to be transitory, possibly due to host migration within the oral cavity. Interestingly, certain phage families were found to be highly correlated with pathogenic, carriage and disease-related isolates, and may potentially serve as novel biomarkers for disease. Our findings shed new light on the core human virome and offer a metagenomic-independent way to probe the core virome using widely shared conserved phage markers.

Machine learning models can identify individuals based on a resident oral bacteriophage family

“…We will demonstrate that at high resolution, the mutant spectrum derived from members of just a single phage terminase family can already serve as a fingerprint, or a "phageprint" -highly unique to an individual. Phageprints were not observable through our earlier study of metagenomic datasets 35 demonstrate the power of combining metagenomic mining with targeted sequencing to put a spotlight on uncharacterized phage families and their sequence diversity in their native contexts.…”

“…a) Streptococcus oralis ATCC 49296 phage genome containing HA terminase homolog. Figure adopted from our previous study 35 b) Rhodococcus equi ReqiPepy6 phage adopted from Summer et al 64 . The red arrows point to the position of the large terminase in these phage genomes.…”

“…To test whether we were successful in identifying terminase families that were prevalent enough in the human phageome to be practical experimental targets, we searched for them across hundreds of metagenomic samples from the Human Microbiome Project (HMP) 45 spanning ∼100 individuals and 18 body sites 35 . Remarkably, we showed that despite the individual-specific nature of the human virome and the small number of individuals from which these terminase families were originally identified, they are prevalent across the HMP cohort.…”

“…Towards this goal, we first developed and benchmarked Metagenomic Clustering by Reference Library or MCRL, which is an algorithm for the identification of non-redundant gene families within a metagenome 32 . In a previous study, we then applied MCRL to oral metagenomes of seven individuals from two studies conducted in two different continents 33,34,35 . By focusing the search on the terminase (large subunit) gene families, we were able to narrow down the search from thousands of viral gene families to seven non-homologous terminase families that were shared across individuals in these two studies 35 .…”

“…In a previous study, we then applied MCRL to oral metagenomes of seven individuals from two studies conducted in two different continents 33,34,35 . By focusing the search on the terminase (large subunit) gene families, we were able to narrow down the search from thousands of viral gene families to seven non-homologous terminase families that were shared across individuals in these two studies 35 .…”