Viruses in the kingdom Bamfordvirae comprise one of the most diverse groups in terms of their genome complexity, ecology and morphology. These dsDNA viruses include the largest viruses characterised to date (Legendre et al., 2014; Scheid, 2016), virophages which are virus parasites of other viruses (Fischer and Suttle, 2011; La Scola et al., 2008), endogenous viruses that colonise the genomes of eukaryotes (Kapitonov and Jurka, 2006; Pritham et al., 2007), and a diverse set of viruses that have been identified from metagenomic data (Bellas and Sommaruga, 2021; Moniruzzaman et al., 2020; Paez-Espino et al., 2019; Roux et al., 2017; Schulz et al., 2020; Yutin et al., 2015). More formally, these viruses are classified into the Nucleocytoplasmic Large DNA Viruses (NCLDVs) which comprise families in the phylum Nucleocytoviricota (Aylward et al., 2021), the virophage parasites of NCLDVs (family Lavidaviridae; Fischer, 2021), adenoviruses (family Adenoviridae) which infect vertebrates (Harrach et al., 2019), the Maverick/Polinton endogenous viruses that colonise the genomes of eukaryotes (Kapitonov and Jurka, 2006; Pritham et al., 2007), Polinton-like viruses (PLVs) which are abundant in aquatic metagenomes (Bellas and Sommaruga, 2021; Yutin et al., 2015), and capsidless elements such as transpovirons (Desnues et al., 2012), mitochondrial and cytoplasmic linear plasmids (Krupovic and Koonin, 2015; Meinhardt et al., 1997). The wide taxonomic distribution of NCLDV and Maverick hosts, which comprise all major eukaryotic lineages (Kapitonov and Jurka, 2006; Pritham et al., 2007; Schulz et al., 2020), seem to point to an ancient origin of these viral groups.

Despite their diversity, the elements share an ancestral gene module used for capsid morphogenesis, which is the feature that distinguishes viruses from other mobile genetic elements (Koonin et al., 2021). The ancestral module is formed by double and single jelly-roll capsid proteins, a family C5 (adenoviral-like) protease and a family FtsK/HerA DNA packaging ATPase (Krupovic et al., 2016c; Yutin et al., 2015). In fact, the jelly-roll capsid proteins and DNA packaging ATPase, also occur in phages from the families Turriviridae, Tectiviridae, Corticoviridae, and Autolykiviridae, which suggests a common viral ancestor for eukaryotic bamfordviruses and their prokaryotic virus relatives (Koonin et al., 2020; Woo et al., 2021). These observations are at odds with the suggestion that NCLDVs originated by reductive evolution, possibly from a fourth domain of cellular life (Colson et al., 2018; Legendre et al., 2012; Patil and Kondabagil, 2021).

Currently, two hypotheses have been proposed for the origin of the eukaryotic Bamfordvirae: the ‘nuclear-escape’ and ‘virophage-first’ scenarios (Figure 1). According to the nuclear-escape scenario, the elements in this lineage evolved from an endogenous virus in the nucleus of an early eukaryote, a Maverick-like ancestor (Koonin and Krupovic, 2017; Krupovic and Koonin, 2015; Krupovic and Koonin, 2016a). Adenoviruses, cytoplasmic linear plasmids and NCLDVs evolved after their ancestor escaped from the nucleus (Koonin et al., 2015a; Krupovic and Koonin, 2015). Therefore, the nuclear-escape hypothesis predicts that adenoviruses form a clade with NCLDVs and cytoplasmic linear plasmids, and that the proteins shared by cytoplasmic linear plasmids and NCLDVs have a single common origin (Koonin and Krupovic, 2017; Krupovic and Koonin, 2015). The nuclear-escape hypothesis is based on phylogenetic trees of the protein-primed DNA polymerase B, which show a paraphyletic group of Mavericks at the base of the other lineages (Koonin and Krupovic, 2017; Krupovic et al., 2016c; Krupovic and Koonin, 2015). However, the trees are missing NCLDVs which encode a non-homologous nucleotide-primed DNA polymerase, and could therefore not be included in the analyses, and only show the position for Mavirus-like virophages which encode the protein-primed DNA polymerase.

Figure 1

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The virophage-first scenario is based on the close similarity in gene content between the Mavirus virophage and Mavericks, and the ability of Mavirus to integrate into eukaryotic genomes (Fischer and Hackl, 2016; Fischer and Suttle, 2011). Integrated Mavirus virophages reactivate upon giant virus infection and confer protection against Cafeteria roenbergensis virus in the flagellate Cafeteria burkhardae (Fischer and Hackl, 2016). The virophage-first scenario therefore suggests that an ancestral virophage evolved shortly after the origin of NCLDVs, and was able to parasitise NCLDVs by virtue of their shared promoter and poly-A sequences (Campbell et al., 2017; Fischer and Suttle, 2011). One of these lineages of ancestral virophages would have gained an integrase and endogenised into eukaryotic hosts providing an immune defence system, which gave rise to Mavericks and other elements (Fischer and Suttle, 2011; Katzourakis and Aswad, 2014). A nuclear-escape would have still occurred for adenoviruses and cytoplasmic linear plasmids, but not NCLDVs, which would belong to a different clade suggesting the immediate ancestor of NCLDVs was an exogenous virus.

Phylogenetics can be used to test competing evolutionary models of virus origins in a rigorous statistical framework. Each tree represents an evolutionary hypothesis which is inferred from matrices of aligned homologous characters with different states (the data). In molecular phylogenetics, nucleotide or amino acid alignments are used as the data to obtain the topology of a tree (and also rates or branch lengths). In statistical terms, the data matrices are used to calculate the tree likelihood (probability of the data given the parameters) in both maximum-likelihood and Bayesian frameworks (Schmidt and von Haeseler, 2009; Nascimento et al., 2017). In maximum likelihood, the preferred tree is the one with the parameter values that maximise the tree likelihood (Schmidt and von Haeseler, 2009). In Bayesian inference, a posterior probability distribution for the parameters is estimated from their prior distributions and the tree likelihood (probability of the parameters given the data) (Nascimento et al., 2017). Together, these approaches can be used to assess the plausibility of competing evolutionary models that make different predictions about tree topologies and the position of the root.

Understanding the diversification of these viruses remains a major open question in virus evolution. To address this problem, we have analysed a data set of virus representatives sampled across the diversity of the eukaryotic bamfordvirus lineage and focused on the 4 core virion proteins: major and minor capsid proteins, protease and ATPase. We use explicit hypothesis-testing methods and estimate the position of the root in our phylogenies, which allowed us to infer the direction of evolution followed by the proteins in the morphogenetic module. Our results suggest a new model for the evolutionary origins of these viruses, which is consistent with an exogenous, non-virophage ancestor.

The rooted Bayesian and maximum-likelihood trees estimated from the concatenated data had the best overall support and shared important topological similarities (Figures 2 and 3). In the Bayesian tree, adenoviruses were placed in a clade with Mavericks and most PLVs with a high posterior probability (0.94, Figure 2), and to the exclusion of NCLDVs. This arrangement was also observed in the maximum likelihood tree topology shown in Figure 3, although with a low bootstrap support (34%). The virophages (family Lavidaviridae) emerged as a strongly supported monophyletic group on both trees (posterior probability = 1 in the Bayesian analysis, 95% bootstrap support in the maximum-likelihood analysis), while Polinton-like viruses were clearly polyphyletic.

Figure 2 with 6 supplements see all

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Figure 3 with 1 supplement see all

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The position of the root inferred both through the Bayesian relaxed-clock analysis and by outgroup rooting with the Enterobacteria phage PRD1 (Tectiviridae), was between virophages and all the other viral lineages. In the Bayesian analysis, the root was placed on this position in 54% of trees (Figure 2), while in the maximum-likelihood analysis the clade of (Adenoviruses + Mavericks + PLVs+NCLDVs), that is to the exclusion of virophages, received a bootstrap support of 73% (Figure 3). We also examined alternative placements of the root sampled during the Bayesian Markov-chain Monte Carlo (MCMC) to assess the frequency of other hypotheses (Supplementary file 2). Rooting on the clade formed by NCLDVs + PLV BS_539 (ERX2821583_NODE_576) was observed in 27.4% of trees. The root positions at the next highest frequencies were on the branch of PLV BS_539 (5.6%), NCLDVs (5.3%) and PLV BS_539 + NCLDVs + virophages (5%). Roots on other branches were observed at frequencies lower than 1% (Supplementary file 2).

The monophyly of virophages and the root on this branch were also observed in the single-protein trees. The major and minor capsid single-protein trees recovered a monophyletic Lavidaviridae (0.97 and 0.52 posterior probability), and also inferred the root to be placed between virophages and the other viruses (29% and 28%, Figure 2—figure supplement 1, Figure 2—figure supplement 2). Although the root was observed at a different position for the ATPase and protease trees; these analyses also failed to recover a monophyletic family of virophages (Figure 2—figure supplement 3, Figure 2—figure supplement 4). However, when virophages were constrained to be monophyletic the root was placed again between virophages and the other lineages, and thus in agreement with our findings using the concatenated data, major and minor capsid proteins (Figure 2—figure supplement 5, Figure 2—figure supplement 6).

The Bayesian and maximum-likelihood tests of topology were also consistent with each other. We used the Akaike information criterion (AIC) to compare the plausibility of the maximum-likelihood topologies consistent with the nuclear-escape and alternative scenarios. All the comparisons preferred a non-sister grouping of adenoviruses and NCLDVs (Table 1). Indeed, the Akaike weights, which can be interpreted as the normalised relative likelihood of the models given the data (Posada and Buckley, 2004), strongly favoured the alternative scenario over the nuclear-escape hypothesis (Concatenated data = 99.7%, Protease = 99.7%, Major capsid protein = 72%, Minor capsid protein = 94.3%). The approach using the posterior model odds, calculated following the method of Bergsten et al., 2013, also favoured the alternative scenarios in all of the data sets: concatenated and single-protein (Table 2). This was strongest for the concatenated data (posterior model odds, H₀/H₁=0.000536), but the same pattern held for the single-protein analyses (posterior model odds = {Protease: 0.00166, Major capsid: 0.11485, Minor capsid: 0.000639}). The Bayesian stepping-stone analysis on the concatenated data also strongly supported the alternative scenario (NCLDVs and adenoviruses are not sister groups), over the nuclear-escape hypothesis (NCLDVs and adenoviruses are sister groups; Table 3).

As an independent test of the predictions made by the nuclear-escape hypothesis, we analysed the origin of the transcriptional proteins shared between NCLDVs and cytoplasmic linear plasmids. According to the nuclear-escape hypothesis, these genes were acquired by the most recent common ancestor of cytoplasmic linear plasmids and NCLDVs, and should thus have a single origin. However, our analyses indicate that these proteins were acquired independently by cytoplasmic linear plasmids and NCLDVs. The maximum-likelihood trees for the Rbp2 subunit of the DNA-directed RNA polymerase, helicase and mRNA-capping proteins all suggest they have independent origins in NCLDVs and cytoplasmic linear plasmids (Figure 3—figure supplement 1). The homologues specific to cytoplasmic linear plasmids clustered with those of eukaryotes and their distribution agrees with a monophyletic origin in this group. Interestingly, the phylogenetic patterns for NCLDVs were consistent with a single-capture (monophyletic origin) for the mRNA-capping enzyme and the helicase, while the distribution of the Rpb2 was consistent with multiple-captures/exchanges (polyphyletic origin).

To gain a better understanding of the evolutionary history of the bamfordviruses of eukaryotes, we analysed a set of four core virion morphogenesis proteins (major and minor capsids, DNA-packaging ATPase and protease) sampled across the diversity of the lineage and using an explicit hypothesis-testing framework. In addition, we analysed the origins of three proteins shared by cytoplasmic linear plasmids and NCLDVs. We found strong evidence against the nuclear-escape hypothesis. We also found support for a position of the root between virophages (family Lavidaviridae) and the other viral lineages. This position of the root suggests a new evolutionary model for the origin of these viral lineages. However, we recognise that some alternative root positions were also observed at lower frequencies in the Bayesian analyses, which could be interpreted as ‘virophage-first’-like scenarios.

We have shown that adenoviruses and NCLDVs are not sister groups as proposed by the nuclear-escape hypothesis (Koonin and Krupovic, 2017; Krupovic and Koonin, 2015). Instead, adenoviruses belong to a clade with Mavericks, to the exclusion of NCLDVs. The phylogenies of the proteins shared by cytoplasmic linear plasmids and NCLDVs also disagree with a nuclear escape. Indeed, phylogenies of the protein-primed DNA polymerase place cytoplasmic linear plasmids as the sister-group to adenoviruses (Krupovic et al., 2016c), implying that adenoviruses, cytoplasmic linear plasmids and NCLDVs form a clade. If a single nuclear-escape had occurred we would expect the Rbp2, helicase and mRNA capping enzymes shared by cytoplasmic linear plasmids and NCLDVs to have a monophyletic origin (since they descend from the same ‘escaped’ ancestor). However, their distribution agrees with a more recent origin in cytoplasmic linear plasmids. These observations agree with the more restricted taxonomic distribution of cytoplasmic linear plasmids, which are known only to infect fungi in the Order Saccharomycetales (Division Ascomycota; Meinhardt et al., 1997), in contrast to the taxonomically diverse eukaryotic hosts of NCLDVs.

Virophages emerged as a highly supported monophyletic group in our analyses. This supports the validity of the family Lavidaviridae which has been based on shared gene contents of virophages and their parasitic (or commensal) lifestyles (Fischer, 2021; Krupovic et al., 2016b). By using two independent rooting methods, relaxed-molecular clocks and outgroup rooting, we found that the root was placed most confidently between virophages and the other lineages; making them the most basal lineage of eukaryotic bamfordviruses. The basal position of virophages has also been found in an independent work that looked at phylogenies based on the ATPase and a concatenation of the ATPase and the major capsid protein (Woo et al., 2021). This basal position of virophages and their divergence prior to the origin of NCLDVs, suggests that the protovirophages were not parasites of other viruses. Instead, they would have become parasites of other viruses at a later point once the most recent common ancestor of NCLDVs had evolved (see Ideas and speculation).

The tree topologies that we estimated (Figure 2 and Figure 3), also suggest that the most recent common ancestor of Mavericks, adenoviruses and PLVs was not a virophage, which is at odds with a virophage-first scenario. Indeed, the basal position of virophages is inconsistent with the virophage-first hypothesis which proposes that protovirophages coevolved with NCLDVs, acquired an integrase and then gave rise to Mavericks and other elements in the lineage (Campbell et al., 2017; Fischer and Suttle, 2011). However, we found that the second-highest frequency root sampled in the Bayesian MCMC was on the branch of PLV BS_539 + NCLDVs (frequency = 27.4%). Rooting on this branch would be consistent with a ‘virophage-first’-like scenario, where the lineage of NCLDVs and associated viruses evolved early and in parallel with protovirophages. Therefore, we cannot definitely rule out a ‘virophage-first’-like scenario. In contrast, root placements on the branch leading to Mavericks and consistent with nuclear-escape were observed in 0% of the trees, which seems to rule out this possibility (Supplementary file 2).

The relative timing of events suggests that the most recent common ancestor of eukaryotic bamfordviruses existed more than a billion years ago. There is general agreement based on paleontological and molecular evidence that the Last Eukaryotic Common Ancestor (LECA) existed at least 1 billion years ago (Porter, 2020). Analyses of genetic exchanges between the DNA-dependent RNA polymerases of NCLDVs and eukaryotes have determined that the two super-clades of NCLDVs (PAM and MAPI) already existed before the origin of LECA (Guglielmini et al., 2019). Moreover, discovery and phylogenetic analysis of actin and actin-related proteins encoded in NCLDVs, also suggest that early gene transfers occurred between these viruses and proto-eukaryotes before the emergence of LECA (Da Cunha et al., 2022). The basal placement that we observed for virophages, or alternatively, their early origin after the divergence of the NCLDV lineage (‘virophage-first’-like scenario), suggest that virophages evolved after the origin of the first NCLDVs during the diversification of the early eukaryotes. These observations, together with the existence of various phage relatives that infect bacteria and archaea, point to a very early origin of the kingdom Bamfordvirae, perhaps extending to the initial stages of cellular life. Studies that consider the time-dependent rate phenomenon in reconstructing viral evolution may be able to shed light on these issues (Aiewsakun and Katzourakis, 2016; Ghafari et al., 2021).

Ideas and speculation

Our analyses favour a new model for the evolution of the major lineages of eukaryotic bamfordviruses; we call this model the ‘exogenous, non-virophage scenario’. The model is presented in Figure 4, where we have mapped shared character states onto a diagram of the concatenated Bayesian phylogeny (which has the best overall support). According to this idea, the most recent common ancestor of the eukaryotic bamfordviruses was a small exogenous dsDNA virus with a linear genome, flanked by inverted repeats. The virus had an autonomous (i.e. non-virophage) lifestyle. It used a protein-primed DNA polymerase B for replication and its morphogenetic module was formed by the major and minor jelly-roll capsid proteins, an adenoviral-like protease and the FtsK/HerA family DNA-packaging ATPase. The gain of the adenoviral-like protease differentiated this eukaryotic lineage from their phage relatives (Krupovic and Koonin, 2015). The first divergence from this ancestor led to the emergence of the protovirophages, and another lineage that would give rise to Mavericks, adenoviruses, PLVs, and NCLDVs (Figure 4).

Figure 4

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The second divergence would have given rise to the lineage from which NCLDVs evolved. The most recent common ancestor of NCLDVs is believed to have already had a complex genome (~40 genes), which involved the gain of numerous genes from their eukaryotic hosts, other viruses and bacteria (Iyer et al., 2006; Koonin and Yutin, 2010; Yutin and Koonin, 2012). Once this virus evolved the capacity to exploit significant cell resources, there would have been a window of opportunity for protovirophages to evolve into specialised parasites of NCLDVs, occupying this new ecological niche. The close match between virophage and NCLDV regulatory sequences, which underlie the capacity of virophages to parasitise NCLDVs, may have evolved by parallel evolutionary changes on the sequences of their shared virus ancestor. It is plausible that functional regulatory sequences in virophages could evolve de novo by a few changes in the ancestral promoters/terminators. For example, functional lac operon promoters have been evolved successfully even from random sequences in the presence of lactose in E. coli (Yona et al., 2018). A deletion mutant in the ORF 8 gene of the Guarani virophage expanded its host range to previously non-permissive giant viruses, so the acquisition and mutation of proteins involved in virus-virophage interactions may also be critical for virophage adaptation (Mougari et al., 2020). Interestingly, the exchange of the protein-primed DNA polymerase B by a nucleotide-primed DNA polymerase B (Mönttinen et al., 2021; Yutin and Koonin, 2012), may have been an early counter-measure of NCLDVs to decrease the parasitic burden imposed by virophages. The acquisition of this new polymerase, may be in part responsible for the considerable increases in genome size that we see in NCLDVs relative to other eukaryotic bamfordviruses. Therefore, we can hypothesise that the large genomes of NCLDVs, which is one of their most distinctive features, could have evolved as a result of their ancient interaction with virophages.

The distribution of the rve-integrase on the phylogeny suggests it was acquired independently on two separate occasions. Indeed, the rve-integrase is a universal feature of Mavericks + PLV BS_13, while it does not seem to be present in any of their closest relatives. Therefore, the rve-integrase seems to be a unique derived feature of the clade of Mavericks + PLV BS_13. Mavirus also encodes a rve-integrase but it appears to be the only virophage with this gene (no other hits found in a blastp search of the nr database using the labels ‘Lavidaviridae’ + ‘unclassified Lavidaviridae’). Since Mavirus is firmly nested within the phylogenies for the morphogenetic module, it seems likely that this is a unique derived feature of Mavirus. The most parsimonious explanation for these observations is that the integrase gene was acquired on two separate occasions and that the common ancestor of Mavirus and Mavericks was an exogenous virus without an integrase (# character state changes = 2 gains). This is in line with a previous proposal that Mavirus evolved by recombination of an ancestral virophage with a Maverick (Yutin et al., 2013).

We used maximum-likelihood and Bayesian hypothesis-testing methods to compare the plausibility of the nuclear-escape versus alternative evolutionary scenarios. We focused on the 4 core virion proteins shared by viruses in this lineage: major and minor capsid proteins, ATPase and protease. Rooted phylogenies were inferred from the data using a relaxed molecular-clock or an outgroup rooting method. We then assessed whether adenoviruses and NCLDVs formed a monophyletic group as predicted by the nuclear-escape scenario. Finally, we studied the origin of the proteins shared by cytoplasmic linear plasmids and NCLDVs. A more detailed description of methods is presented below.

The Hidden Markov Models used to find homologues of the four core proteins (n = 38), and concatenated and single-protein alignments used for phylogenetic inference have been deposited in Figshare. The scripts used for sequence concatenation and for the AIC analyses are available on GitHub (copy archived at Barreat, 2023).

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Author details

1. Jose Gabriel Nino Barreat

   Department of Biology, University of Oxford, Oxford, United Kingdom

   Contribution

   Conceptualization, Data curation, Software, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-4589-9473

2. Aris Katzourakis

   Department of Biology, University of Oxford, Oxford, United Kingdom

   Contribution

   Conceptualization, Supervision, Methodology, Project administration, Writing – review and editing

   For correspondence

   aris.katzourakis@biology.ox.ac.uk

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-3328-6204

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