Global phylogeography and ancient evolution of the widespread human gut virus crAssphage

Edwards, Robert A.; Vega, Alejandro A.; Norman, Holly M.; Ohaeri, Maria; Levi, Kyle; Dinsdale, Elizabeth A.; Cinek, Ondřej; Aziz, Ramy K.; McNair, Katelyn; Barr, Jeremy J.; Bibby, Kyle; Brouns, Stan J. J.; Cazares, Adrián; Jonge, Patrick A. de; Desnues, Christelle; Díaz‐Muñoz, Samuel L.; Fineran, Peter C.; Kurilshikov, Alexander; Lavigne, Rob; Mazankova, Karla; McCarthy, David Thomas; Nóbrega, Franklin L.; Reyes, Alejandro; Tapia, German; Trefault, Nicole; Tyakht, Alexander V.; Vinuesa, Pablo; Wagemans, Jeroen; Zhernakova, Alexandra; Aarestrup, Frank Møller; Ahmadov, Gunduz; Alassaf, Abeer; Antón, Josefa; Asangba, Abigail E.; Billings, E; Cantu, Adrian; Carlton, Jane M.; Cazares, Daniel; Cho, Gyu-Sung; Condeff, Tess; Cortés, Pilar; Cranfield, Mike; Cuevas, Daniel A.; Iglesia, Rodrigo De la; Decewicz, Przemysław; Doane, Michael P.; Dominy, Nathaniel J.; Dziewit, Łukasz; Elwasila, Bashir Mukhtar; Eren, A. Murat; Franz, Charles M. A. P.; Fu, Jingyuan; García-Aljaro, Cristina; Ghedin, Elodie; Gulino, Kristen M.; Haggerty, John M.; Head, Steven R.; Hendriksen, René S.; Hill, Colin; Hyöty, Heikki; Ilina, Elena N.; Irwin, Mitchell T.; Jeffries, Thomas C.; Jofre, Juan; Junge, Randall E.; Kelley, Scott T.; Mirzaei, Mohammadali Khan; Kowalewski, Martín M.; Kumaresan, Deepak; Leigh, Steven R.; Lipson, David A.; Lisitsyna, Eugenia S.; Llagostera, Montserrat; Maritz, Julia M.; Marr, Linsey C.; McCann, A.; Molshanski-Mor, Shahar; Monteiro, Sílvia; Moreira‐Grez, Benjamin; Morris, Megan M.; Mugisha, Lawrence; Muniesa, Maite; Neve, Horst; Nguyen, Nam; Nigro, Olivia D.; Nilsson, Anders S.; O’Connell, Taylor; Odeh, Rasha; Oliver, Andrew; Piuri, Mariana; Prussin, Aaron J.; Qimron, Udi; Quan, Zhe; Rainetová, Petra; Rojas, Adán Andrés Ramírez; Raya, Raúl R.; Reasor, Kim; Rice, Gillian A.O.; Rossi, Alessandro; Santos, Ricardo; Shimashita, John; Stachler, Elyse; Stene, Lars C.; Strain, Ronan; Stumpf, Rebecca M.; Torres, Pedro J.; Twaddle, Alan; Ibekwe, Mary Ann Ugochi; Villagra, Nicolás A.; Wandro, Stephen; White, Bryan A.; Whiteley, Andrew S.; Whiteson, Katrine; Wijmenga, Cisca; Zambrano, María Mercedes; Zschach, Henrike; Dutilh, Bas E.

doi:10.1038/s41564-019-0494-6

Cited by 201 publications

(197 citation statements)

References 80 publications

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“…1C-D), consistent with the previously reported individuality of the human gut viromes [2,7,11]. A notable exception are the crAss-like phages [59] that recruit at least one read from about one-third of the viromes (Q1 -Q3, 9-28%), in agreement with previous reports of their cosmopolitan distribution [60,61]. One uncharacterized Caudovirales genome was frequently observed in the collection of human gut viromes (54%, Fig.…”

Section: Selection Of Candidate Families For Comparative Genomicssupporting

confidence: 90%

“…Regardless, both groups encompass abundant members of the human gut virome. Predictably, the hosts of these phages include Bacteroides spp., which are some of the most dominant bacterial taxa of the human gut [106] and serve as hosts for other common human gut phages [61,107]. Much of the uncharacterized "dark matter" in these phage genomes is likely to be dedicated to preventing superinfection of the Bacteroides host cells by such phages and to counter the host defenses.…”

Section: Discussionmentioning

confidence: 99%

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Thousands of Previously Unknown Phages Discovered in Whole-community Human Gut Metagenomes

Benler

Yutin

Antipov

et al. 2020

Preprint

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Background: Double-stranded DNA bacteriophages (dsDNA phages) play pivotal roles in structuring human gut microbiomes; yet, the gut phageome is far from being fully characterized, and additional groups of phages, including highly abundant ones, continue to be discovered by metagenome mining. A multilevel framework for taxonomic classification of viruses was recently adopted, facilitating the classification of phages into evolutionary informative taxonomic units based on hallmark genes. Together with advanced approaches for sequence assembly and powerful methods of sequence analysis, this revised framework offers the opportunity to discover and classify unknown phage taxa in the human gut.Results:A search of human gut metagenomes for circular contigs encoding phage hallmark genes resulted in the identification of 3,738 apparently complete phage genomes that represent 451 putative genera. Several of these phage genera are only distantly related to previously identified phages and are likely to found new families. Two of the candidate families, “Flandersviridae” and “Quimbyviridae”, include some of the most common and abundant members of the human gut virome that infect Bacteroides, Parabacteroides and Prevotella. The third proposed family, “Gratiaviridae”, consists of less abundant phages that are distantly related to the families Autographiviridae, Drexlerviridae and Chaseviridae. Analysis of CRISPR spacers indicates that phages of all three putative families infect bacteria of the phylum Bacteroidetes. Comparative genomic analysis of the three candidate phage families revealed features without precedent in phage genomes. Some “Quimbyviridae” phages possess Diversity-Generating Retroelements (DGRs) that generate hypervariable target genes nested within defense-related genes, whereas the previously known targets of phage-encoded DGRs are structural genes. Several “Flandersviridae” phages encode enzymes of the isoprenoid pathway, a lipid biosynthesis pathway that so far has not been known to be manipulated by phages. The “Gratiaviridae” phages encode a HipA-family protein kinase and glycosyltransferase, suggesting these phages modify the host cell wall, preventing superinfection by other phages. Hundreds of phages in these three and other families are shown to encode catalases and iron-sequestering enzymes that can be predicted to enhance cellular tolerance to reactive oxygen species.Conclusions:Analysis of phage genomes identified in whole-community human gut metagenomes resulted in the delineation of at least three new candidate families of Caudovirales and revealed diverse putative mechanisms underlying phage-host interactions in the human gut. Addition of these phylogenetically classified, diverse and distinct phages to public databases will facilitate taxonomic decomposition and functional characterization of human gut viromes.

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Section: Selection Of Candidate Families For Comparative Genomicssupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Thousands of Previously Unknown Phages Discovered in Whole-community Human Gut Metagenomes

Benler

Yutin

Antipov

et al. 2020

Preprint

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“…The diversity generating benefits of such a stable core and pan-genome are particularly exemplified by the allelic variation present in Cryophage, an abundant, stable, Bacteroidetes phage found in every cryoconite metagenome. Cryophage draws many parallels with crAssphage, another highly stable, abundant, Bacteroidetes phage genome found globally in the majority of human gut microbiomes 59,60 . crAssphage also exhibit multiple MGIs across its genome between microbiomes 59 , suggesting the stability in the human gut microbiome is also maintained by recombination in specific genes from a constantly diverse phage population.…”

Section: Discussionmentioning

confidence: 99%

Flexible genes establish widespread bacteriophage pan-genomes in cryoconite hole ecosystems

et al. 2020

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Bacteriophage genomes rapidly evolve via mutation and horizontal gene transfer to counter evolving bacterial host defenses; such arms race dynamics should lead to divergence between phages from similar, geographically isolated ecosystems. However, near-identical phage genomes can reoccur over large geographical distances and several years apart, conversely suggesting many are stably maintained. Here, we show that phages with nearidentical core genomes in distant, discrete aquatic ecosystems maintain diversity by possession of numerous flexible gene modules, where homologous genes present in the pangenome interchange to create new phage variants. By repeatedly reconstructing the core and flexible regions of phage genomes from different metagenomes, we show a pool of homologous gene variants co-exist for each module in each location, however, the dominant variant shuffles independently in each module. These results suggest that in a natural community, recombination is the largest contributor to phage diversity, allowing a variety of host recognition receptors and genes to counter bacterial defenses to co-exist for each phage.

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“…The crAssphage is represented in about half of human gut metagenomes and in some of these accounts for up to 90% of the sequencing reads in the virus-like particle fraction. CrAssphage genome sequences have been detected in human gut metagenomes from diverse geographic locations, showing that crAssphage is not only the most abundant virus in some human gut microbiomes but is widely spread across human populations 2,[6][7][8][9][10] .…”

Section: Introductionmentioning

confidence: 99%

Unique genomic features of crAss-like phages, the dominant component of the human gut virome

Yutin¹,

Benler²,

Shmakov³

et al. 2020

Preprint

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CrAssphage is the most abundant virus identified in the human gut virome and the founding member of a large group of bacteriophages that infect bacteria of the phylum Bacteroidetes and have been discovered by metagenomics of both animal-associated and environmental habitats. By analysis of circular contigs from human gut microbiomes, we identified nearly 600 genomes of crAss-like phages. Phylogenetic analysis of conserved genes demonstrates the monophyly of crAss-like phages, which can be expected to become a new order of viruses, and of 5 distinct branches, likely, families within that order. Two of these putative families have not been identified previously. The phages in one of these groups have large genomes (145-192 kilobases) and contain an unprecedented high density of self-splicing introns and inteins. Many crAss-like phages encode suppressor tRNAs that enable readthrough of UGA or UAG stop-codons, mostly, in late phage genes, which could represent a distinct anti-defense strategy. Another putative anti-defense mechanism that might target an unknown defense system in Bacteroidetes inhibiting phage DNA replication involves multiple switches of the phage DNA polymerase type between A and B families. Thus, comparative genomic analysis of the expanded assemblage of crAss-like phages reveals several unusual features of genome architecture and expression as well as phage biology that were not apparent from the previous crAssphage analyses.

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Global phylogeography and ancient evolution of the widespread human gut virus crAssphage

Cited by 201 publications

References 80 publications

Thousands of Previously Unknown Phages Discovered in Whole-community Human Gut Metagenomes

Thousands of Previously Unknown Phages Discovered in Whole-community Human Gut Metagenomes

Flexible genes establish widespread bacteriophage pan-genomes in cryoconite hole ecosystems

Unique genomic features of crAss-like phages, the dominant component of the human gut virome

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