Vast diversity of prokaryotic virus genomes encoding double jelly-roll major capsid proteins uncovered by genomic and metagenomic sequence analysis
Analysis of metagenomic sequences has become the principal approach for the study of the diversity of viruses. Many recent, extensive metagenomic studies on several classes of viruses have dramatically expanded the visible part of the virosphere, showing that previously undetected viruses, or those that have been considered rare, actually are important components of the global virome.
We investigated the provenance of viruses related to tail-less bacteriophages of the family Tectiviridae by searching genomic and metagenomics sequence databases for distant homologs of the tectivirus-like Double Jelly-Roll major capsid proteins (DJR MCP). These searches resulted in the identification of numerous genomes of virus-like elements that are similar in size to tectiviruses (10–15 kilobases) and have diverse gene compositions. By comparison of the gene repertoires, the DJR MCP-encoding genomes were classified into 6 distinct groups that can be predicted to differ in reproduction strategies and host ranges. Only the DJR MCP gene that is present by design is shared by all these genomes, and most also encode a predicted DNA-packaging ATPase; the rest of the genes are present only in subgroups of this unexpectedly diverse collection of DJR MCP-encoding genomes. Only a minority encode a DNA polymerase which is a hallmark of the family Tectiviridae and the putative family "Autolykiviridae". Notably, one of the identified putative DJR MCP viruses encodes a homolog of Cas1 endonuclease, the integrase involved in CRISPR-Cas adaptation and integration of transposon-like elements called casposons. This is the first detected occurrence of Cas1 in a virus. Many of the identified elements are individual contigs flanked by inverted or direct repeats and appear to represent complete, extrachromosomal viral genomes, whereas others are flanked by bacterial genes and thus can be considered as proviruses. These contigs come from metagenomes of widely different environments, some dominated by archaea and others by bacteria, suggesting that collectively, the DJR MCP-encoding elements have a broad host range among prokaryotes.
The findings reported here greatly expand the known host range of (putative) viruses of bacteria and archaea that encode a DJR MCP. They also demonstrate the extreme diversity of genome architectures in these viruses that encode no universal proteins other than the capsid protein that was used as the marker for their identification. From a supposedly minor group of bacterial and archaeal viruses, these viruses are emerging as a substantial component of the prokaryotic virome.
The last several years have witnessed major advances in our understanding of the diversity of the global virome (the entirety of viruses in the biosphere) and the evolutionary relationships among viruses and virus-like mobile genetic elements (MGE). As of late, the principal methodology for discovery of new viruses has dramatically changed: instead of the traditional virus isolation and cultivation, the great majority of new viruses are now discovered through metagenomic sequence analysis [1, 2, 3, 4, 5, 6, 7]. Some of these studies drastically change the existing knowledge on the virome compositions in various habitats. One of the most striking cases in point is the discovery of crAssphage, by far the most abundant virus in the human intestine and generally, in the human-associated virome that remained unknown until the advent of metagenomics [8, 9, 10]. At the time of the initial discovery, most of the crAssphage genes remained uncharacterized, and no related viruses have been identified, so that, despite its ubiquity and high abundance in humans, this virus remained completely enigmatic and recalcitrant to further investigation . However, a follow up study taking advantage of expanded databases and sensitive homology detection methods has led to the identification of an expansive family of bacteriophages all of which are predicted to infect bacteria of the phylum Bacteroidetes . The main structural and replication genes of these viruses have been identified, making them amenable to experimental characterization.
Metagenomic sequence mining has led to the discovery of previously unrecognized groups of viruses that apparently infect uncultivated bacteria and archaea, and are likely to be important ecological players. An example is a novel family of viruses associated with uncultivated Group II marine archaea, where both the hosts and the viruses appear to be among the most common members of the ocean that would remain obscure without the metagenomic effort [12, 13]. Other metagenomic studies have drastically changed the status of certain groups of viruses that previously have been considered minor components of the virosphere. In particular, metagenomic analyses have revealed enormous, unsuspected diversity and abundance of single-stranded (ss) DNA viruses [14, 15, 16, 17, 18]. These are only a few of the metagenomic discoveries which collectively indicate that traditional methods for virus isolation have only scratched the surface of the virosphere, whereas the actual diversity and structure of the global virome can be characterized only by comprehensive metagenomic analyses. In recognition of this sea change in virus research, the International Committee for Taxonomy of Viruses (ICTV) is now accepting proposals for new virus species and higher taxa on the basis of metagenomic sequences alone .
Parallel to the advances in metagenomics, and in large part, fueled by metagenomic discoveries, there has been considerable progress in the reconstruction of virus evolution. The major emerging trend is the ultimate modularity of virus evolution whereby evolutionarily coherent structural and replication modules combine promiscuously with one another and with a variety of additional genes [19, 20, 21]. One of the most notable cases in point are the ssDNA viruses that appear to have evolved on multiple occasions via independent recombination events between a capsid protein gene derived from RNA viruses and a plasmid replication module [20, 22, 23]. A complete reconstruction of virus evolution is feasible only through phylogenomic analysis of both the structural and the replication modules, along with the recombination events . In practice, the structural module is often the best marker of virus evolution because the structural genes seem to be exchanged or eliminated less often than replication genes, and hence provide for unification of more diverse groups of viruses [25, 26].
The great majority of the double-stranded (ds) DNA viruses with moderate-sized and large genomes can be partitioned into two vast supergroups with distinct, unrelated structural modules . The robustness of the two groups has been validated quantitively by analysis of bipartite, gene-genome networks . The first supergroup includes most of the known head-tail bacteriophages (order Caudovirales), a variety of phage-like viruses infecting mesophilic archaea, and the animal viruses of the order Herpesvirales. All these viruses possess icosahedral particles formed by the so called HK97 fold (named after the eponymous bacteriophage) capsid protein and a two-subunit terminase that mediates ATP-dependent DNA packaging into the capsid. The second supergroup consists of two families of bacteriophages (Tectiviridae and Corticoviridae) , archaeal viruses of the family Turriviridae  and many diverse groups of eukaryotic viruses including giant eukaryotic viruses of the putative order “Megavirales” . All these viruses also possess icosahedral capsids that, however, are built of the double jelly-roll major capsid protein (DJR MCP [31, 32]) that is unrelated to the HK97 capsid protein, typically, accompanied by a single jelly roll minor capsid protein. Furthermore, these viruses employ a distinct ATPase that belongs to the FtsK-HerA superfamily of P-loop NTPases  and is unrelated to the terminase, for DNA packaging.
The two major supergroups of dsDNA viruses strongly differ with respect to the representation of viruses infecting prokaryotes and eukaryotes. The HK97 supergroup consists primarily of prokaryotic viruses, the tailed phages that represent a substantial majority among all known viruses. By contrast, viruses of eukaryotes are represented by a single, even if expansive, order Herpesvirales, with representatives so far detected only in animals. In contrast, viruses of the DJR MCP supergroup attained remarkable diversity in eukaryotes but are only sparsely represented among the known viruses of prokaryotes. We sought to explore the actual expanse of the DJR MCP group among prokaryotes by searching genomic and metagenomic databases for homologs of the tectivirus-like MCP using sensitive sequence analysis methods. In genomes and metagenomes from various environments, we discovered numerous, highly diverse DJR MCP-encoding sequences in variable genomic contexts. Analysis of these sequences revealed several groups of previously unknown viruses and proviruses that show extreme plasticity of gene repertoires and genome organizations.
Genomic and metagenomic database screening
-Enterobacteria phage PRD1 (NP_040692).
-Pseudoalteromonas phage PM2 (NP_049903).
-Bacillus phage Bam35c (NP_943764),
-Sulfolobus turreted icosahedral virus (YP_025022).
-Methanococcus voltae provirus (ADI36123).
-Thermococcus kodakarensis provirus (BAD85542).
-Flavobacterium phage FLiP (ASQ41214).
were used as queries for PSI-BLAST  searches against the GenBank non-redundant protein sequence database (nr) and for TBLASTN  searches against the metagenomic database (wgs) at the NCBI . The sequences of putative new MCPs retrieved in these searches were aligned with the original query sequences using MUSCLE . The newly detected sequences were validated as bona fide MCP homologs by inspection of the conserved structural elements and secondary structure prediction, and the multiple sequence alignments were used as queries for additional database searches using PSI-BLAST and HHpred ; the search procedure was iterated until convergence. In addition to the contigs from public databases, new contigs from Loki’s Castle (hydrothermal vent field on the Arctic Mid-Ocean Ridge from which diverse archaea have been isolated including the closest known archaeal relative of eukaryotes) were analyzed (denoted Loki_contigs in the figures). In the process of reconstructing the genomic bins of the Asgard archaea superphylum, 232.3 Gbp of sequence data from a deep sea sediment sample near Loki’s Castle was assembled using different assembly programs and parameters . The DJR MCP proteins identified as described above were used to create a HMM profile with HMMER 3 , and these profiles were used to search Loki’s Castle assemblies. The assembly that was chosen to extract the sequences was assembled using Ray Meta , with a k-mer size of 45 which was identified as optimal for yielding the longest contigs matching the MCP query .
Sequence analysis of MCP-encoding contigs
Protein coding sequences in contigs obtained as described above were predicted using GeneMark hmm prokaryotic and translated (version 3.25) ., The resulting proteins sequences were used as queries to search the nr database using PSI-BLAST, the Conserved Domain Database (CDD) using RPS-BLAST  and the PDB, CDD and Pfam databases using HHPred . For poorly characterized proteins, multiple alignments were constructed using MUSCLE, profiles were constructed from the resulted multiple alignments. Additional searches of the same database were performed using these profiles as queries for PSI-BLAST and HHpred, in an attempt to identify homologs with low sequence similarity to the query proteins. This procedure was terminated when such homologs were confidently identified, but in cases where none were found, was iterated until convergence. The MCP sequences were clustered by similarity (BLOSUM62 matrix, E = 10− 03) using the CLANS program which generates a network representation of pairwise sequence similarities between proteins using a version of the Fruchterman-Reingold graph layout algorithm .
Protein sequences were aligned using MUSCLE, and poorly aligned (low information content) positions were removed . Phylogenetic trees were constructed using the FastTree program, with default parameters .
Search of genomic and metagenomic sequence databases for prokaryotic viruses encoding DJR MCP
Five of the identified groups of (putative) viruses encoding DJR MCP include prototype genomes of previously characterized viruses, whereas the Odin group is new. Many of the contigs were flanked by inverted or direct repeats and appear to represent complete, extrachromosomal viral genomes. Below, we present detailed genomic analysis of each of the 6 groups.
A striking feature of the Odin group is the absence of a detectable packaging ATPase that otherwise appears to be an integral component of the DJR MCP structural module. It seems highly unlikely that a packaging ATPase was missed in our searches because P-loop ATPases are readily identified through the presence of the Walker A and B motifs, even if more precise classification of these ATPases is challenging in many cases [33, 48, 49]. In all these contigs, the DJR MCP gene is preceded by a conserved gene encoding a small protein without detectable sequence or structural similarity to any known proteins (see Additional file 1). Given the conspicuous absence of the packaging ATPase and the typical juxtaposition of the MCP and ATPase genes in other viral genomes ( and see below), it seems likely that this protein is essential for DNA packaging into the Odin group virions. However, inspection of the multiple alignment of this small protein shows no conserved polar residues which, together with the small size of the protein, strongly suggests that it has no enzymatic activity. The only other DJR MCP-containing virus lacking a putative genome packaging ATPase is the recently discovered Flavobacterium-infecting bacteriophage FLiP  (see below), which has a circular ssDNA rather than a dsDNA genome, as is the case for all other known viruses of this class. Thus, these viruses with small genomes apparently employ a distinct mechanism of DNA encapsidation that does not require a virus-encoded ATPase. In this respect, they resemble ssDNA viruses and polyoma/papillomaviruses that all lack a dedicated packaging ATPase.
Other proteins that are conserved in this group but not in the other groups of DJR MCP viruses described here are nucleases of the ParB and PD-(D/E)XK families and 3 uncharacterized proteins, one of which is predicted to adopt a single jelly-roll fold (Fig. 4 and see Additional file 1) and thus might be a minor capsid protein. Some of the typical viral proteins are only sporadically present in viruses of the Odin group including family B DNA polymerase, glycosyl transferase, lysozyme, M15 family peptidase, predicted transcription regulators containing a helix-turn-helix (HTH) domain, and integrase.
This is the largest group that includes about 60% of the detected putative genomes encoding DJR MCP (see Additional files 3, 4). Most of the contigs in this group contain the MCP and other virus genes embedded within a typical bacterial genomic context, mostly, characteristic of Proteobacteria, i. e. represent prophages. Indeed, numerous bacterial PM2-like prophages have been described previously . Several contigs are flanked by long repeats and are likely to represent complete viral genomes. The only characterized virus in this group is Pseudoalteromonas virus PM2, the sole current member of the family Corticoviridae .
The MCP tree for the PM2 group consists of two major branches one of which includes prophages, whereas the other one represents virus-like contigs (Additional file 3). Because genomes of PM2-like prophages have been analyzed in detail previously , we examined in detail only the genomes from the second branch (Additional file 3).
This group includes virus-like contigs encoding MCPs with highly diverged sequences such that a single reliable phylogenetic tree could not be constructed. The previously described members of this group (family Turriviridae) include two Sulfolobus turreted icosahedral viruses (STIV1 and STIV2), two euryarchaeal proviruses, TKV4 and MVV , as well as integrative Thermococcus nautili plasmid pTN3  and an extra-chromosomal element of Pyrobaculum oguniense . No bacteria-associated members of this group have been reported.
All genomes in this group encode the packaging ATPase highly similar to that of STIV, which has been functionally and structurally characterized , although the juxtaposition of the MCP and ATPase genes is not conserved (Fig. 7, Additional file 6). Apart from the MCP and ATPase, no other genes are shared by all members of this group. Many genomes, including STIV, encode integrases of the tyrosine recombinase superfamily that obviously are implicated in provirus integration as well as various nucleases, such as Holliday junction resolvase (TK1364), HNH and PIN-domain endonucleases (Additional file 1). Notably, the integrase of STIV has not been recognized during the original genome annotation . However, HHpred and CD-search analyses indicated that STIV protein A510 (YP_024993) encodes a bona fide member of the tyrosine recombinase superfamily that is homologous to the extensively studied integrases of lambdoid phages (HHpred probability of 99.9 to the integrase of phage lambda). As described previously, TKV4 and MVV possess distinct replication gene modules, with a RCRE gene in MVV and an MCM helicase gene in TKV4 . Among the newly detected members of the STIV group, we identified several with TKV4-like replication genes, several with a distinct variant of MVV-like Rep, and some unique ones including three that encode a DNAP (Fig. 7).
The Toil group is named after the recently isolated Rhodococcus phage Toil, a divergent member of the family Tectiviridae . These phages and prophages share genes for MCP, ATPase, and lytic enzymes; some also encode DNAPs, including highly divergent, miniaturized variants, and/or predicted transcription regulators (Fig. 9, Additional file 7). Of special interest are two closely related Toil-like proviruses of Streptomyces noursei (CP011533) encoding homologs of Cas1, the integrase that is involved in the adaptation (spacer acquisition) by the CRISPR-Cas adaptive immunity systems in archaea and bacteria [66, 67]. Apart from the widespread CRIPSR-Cas systems, Cas1 homologs have been identified in casposons, a distinct family of archaeal and bacterial self-synthesizing transposons in which Cas1 functions as an integrase [68, 69]. The predicted Toil-like prophages in Streptomyces noursei and Streptomyces albulus have been previously described as Casposons of family 3 because their highly divergent MCP was not recognized at the time . The identification of the MCP makes these elements the first and so far the only viruses encoding Cas1 homologs. In the DNAP phylogeny, the Cas1-encoding elements are embedded among numerous Toil-like viruses and proviruses (Additional file 5), whereas in the Cas1 phylogeny, these elements are nested among capsid-less bacterial casposons . Given the apparent rarity of the Cas1-encoding viruses, it seems likely that these are chimeric elements that evolved via recombination between a casposon and a Toil-like prophage. Presumably, the acquisition of the cas1-like genes from casposons enabled the integration into the cellular chromosomes and, accordingly, stable vertical inheritance of the Streptomyces prophages in the population. By contrast, the majority of Bam35- and Toil-like prophages lack genes for recombinases and appear to reside in the respective hosts as extrachromosomal linear prophages.
FLiP phage-related group of rolling circle-replicating ssDNA viruses
The results of this work are not unexpected in the sense that they are fully compatible with the notion of accelerating expansion of the virosphere thanks to genome and metagenome mining efforts . It seems that, with the advances of metagenomics, an exhaustive search for distant relatives of any known group of viruses or for completely new groups is bound to reveal previously unsuspected diversity. Here we expanded the previously limited diversity and host range of small dsDNA (and in the case of the FLiP group, ssDNA) viruses of prokaryotes with icosahedral virions composed of DJR MCP. These findings restore the balance between viruses of prokaryotes and eukaryotes in the DJR MCP supergroup by demonstrating the wide spread of these viruses in prokaryotes. Although these viruses appear to be less abundant than the HK97 supergroup, their diversity, association with various hosts and presence in many environments revealed by the present analysis suggest that they comprise a substantial component of the prokaryotic virosphere and might be important ecological agents. While this manuscript was in review, a study describing a new family of tailless bacteriophages encoding a DJR MCP and denoted “Autolykiviridae” has been published . The autolykiviruses have been identified as the principal killers of the Vibrionaceae bacteria in the ocean, indicating a much greater ecological impact of tailless bacteriophages than previously suspected. Notably, all members of this putative new family belong to the PM2 group, one of the 6 groups of DJR MCP viruses of prokaryotes described here. In the phylogenetic tree of the MCP for the PM2 group, the autolykiviruses form one tight clade among several (Additional file 3), emphasizing the diversity of the prokaryotic DJR MCP viruses of which the new family is but a small part. Taken together, these findings reveal an unexpectedly wide spread of the DJR MCP class of viruses in the biosphere the full extent of which remains to be assessed.
The search for new viruses described here was performed using a straightforward approach, namely, searching the genomic and metagenomics databases for MCP homologs. It should be emphasized, however, that using the most sensitive and specific of the available database search approaches is critical for the success of such efforts. The majority of the putative viruses and proviruses that we describe here could be identified only when a manually curated alignment of MCP was used as the query for database search. Furthermore, many other proteins of the identified viruses are also highly diverged, making manual curation a must for robust genome analysis.
The putative viruses identified here with the single MCP probe show consistency in terms of genome size: all have some of the smallest genomes among dsDNA viruses, roughly, between 7 and 18 kb. These elements also encode varying assortments of proteins from a characteristic virus gene pool, the most prominent being the packaging ATPase of the FtsK-HerA superfamily. This consistency of genomic features suggests that the prokaryotic DJR MCP-encoding viruses occupy a distinct part of the virosphere. However, the other side of the coin is the extreme plasticity of the gene repertoires of these viruses. Not a single gene other than MCP that is present by design of our search protocol is shared by all genomes. Instead, within each of the defined virus groups, proteins from the replication, integration and lysis modules are recurrently replaced with functionally equivalent counterparts. Even the packaging ATPase that is one of the most stable functional partners of the DJR MCP is missing in the putative viruses of the Odin and FLiP groups, suggesting a distinct packaging mechanism. The viruses of the newly discovered Odin group have the smallest genomes in the DJR MCP supergroup, comparable in size to the genomes of the smallest dsDNA viruses of eukaryotes (polyoma/papillomaviruses) and ssDNA viruses with single jelly roll MCPs that lack a dedicated virus-encoded packaging ATPase. Many of these viruses appear to assemble the capsid around the viral genome [78, 79] instead of packaging the DNA into a preformed, empty capsid in an ATP-dependent fashion as dsDNA viruses with larger genomes do . A similar mechanism might be operative in the viruses of the Odin group as well as the FLiP group. More generally, the present findings emphasize the enormous evolutionary plasticity of viruses that can completely change the gene repertoire while retaining the same capsid structure and similar genome size. Parallel findings have been reported previously as a result of a search for eukaryotic DJR MCP viruses resembling the polinton class transposons [72, 81], suggesting that such plasticity is a general, still under-appreciated trend in the evolution of the virus world. It is our hope that the present analysis stimulates experimental characterization of some of the viruses identified here which will shed light on virus biology.
The findings reported here continue the general trend of metagenomic discovery whereby searches of sequence databases for new viruses employing powerful computational methods expand the diversity of (putative) viruses far beyond that established by traditional methods for virus isolation. It is not uncommon that groups of viruses that appeared relatively rare and minor, possibly, due to biases caused by difficulty of host cultivation, become comparable, in diversity and abundance, to previously identified major groups. Here, such a dramatic expansion is reported for the prokaryotic viruses encoding DJR MCP. The results suggest that these viruses that are the apparent ancestors of the most common dsDNA viruses of eukaryotes [21, 30] are important players in the prokaryotic virosphere as well. Furthermore, these small viruses show striking evolutionary plasticity such that not a single gene except for that encoding the MCP is shared by all of them.
We acknowledge the help from chief scientist R. B. Pedersen, the scientific party and the entire crew on board the Norwegian research vessel G.O. Sars for providing marine sediment samples from the Loki’s Castle hydrothermal vent area during the summer 2010 expedition.
NY and EVK are supported by intramural funds of the US Department of Health and Human Services (to the National Library of Medicine). TJGE is supported by grants of the European Research Council (ERC Starting Grant 310039-PUZZLE_CELL), the Swedish Foundation for Strategic Research (SSF-FFL5) and the Swedish Research Council (VR grant 2015–04959). MK is supported by l’Agence Nationale de la Recherche (France) project ENVIRA.
Availability of data and materials
Supporting data are available at ftp://ftp.ncbi.nih.gov/pub/yutinn/DJR_MCP_2017/.
EVK conceived of the project; NY performed research; NY, DB, TE, MK and EVK analyzed the results; NY and EVK wrote the manuscript that was edited and approved by all authors.
Natalya Yutin and Eugene V. Koonin are at the National Center for Biotechnology Information, National Library of Medicine. National Institutes of Health, Bethesda, MD 20894, USA; Disa Backstrom and Thijs J. Ettema are at the Department of Cell and Molecular Biology, Biomedical Centre Uppsala University, Box 596, SE-75123 Uppsala, Sweden; Mart Krupovic is at the Department of Microbiology, Institut Pasteur, 25 rue du Dr. Roux, Paris 75,015, Paris, France; Eugene V. Koonin is at the National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA.
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