Why are viruses thought to have evolved from cells

Furthermore, multiple host-specific and metagenomic studies of marine RNA viruses most of them demonstrated or thought to infect diverse unicellular eukaryotes have recovered a large number of novel picorna-like viruses but only one tombus-like virus and no alpha-like viruses Culley et al. Notably, none of these viruses encode JRC and, consistently, do not form icosahedral virions. Instead, members of the Nidovirales have enveloped virions which vary from roughly spherical to rod-shaped, depending on the organization of the helical nucleocapsids Gorbalenya et al.

However, certain evolutionary affinity between RdRps of picornavirus-like viruses and nidoviruses, together with the presence of distantly related proteases responsible for polyprotein processing in both of these virus groups Gorbalenya et al. Thus, the extreme diversity of the picorna-like viruses, with respect to both the host range and the genome architecture, suggests that picornaviral ancestors have evolved concomitantly with or shortly after the emergence of eukaryotes, rapidly diversified and spawned the ancestors of the alphavirus-like and flavivirus-like superfamilies as well as the Nidovirales that are known to infect only vertebrates, insects and crustaceans , perhaps later in evolution Fig.

This question has been addressed through a focused search for potential prokaryotic roots of picorna-like viruses Koonin et al. In addition to validating the tight relationship between the three superfamilies of the eukaryotic positive-strand RNA viruses, in-depth sequence analysis of the RdRps of the picornavirus-like superfamily has revealed remarkably high similarity of picornavius-like RdRps to the reverse transcriptases RTs of the bacterial group II retroelements self-splicing introns , in contrast to the much lower similarity to the RdRps of RNA bacteriophages Koonin et al.

Considering the wide spread of the group II retroelements in bacteria Lambowitz and Zimmerly, , Lambowitz and Zimmerly, , in contrast to the scarcity of RNA bacteriophages, it appears plausible that the prokaryotic RTs were the ancestors of picornavirus-like RdRps.

Search for the closest homologs of the 3CPro confidently identified bacterial and mitochondrial proteases of the HtrA family Gorbalenya et al. These cellular jelly-roll proteins are considerably more compact than CPs of microviruses and thus might be more likely to have been the ancestors of JRC of RNA viruses. Consequently, bacterial origins for these genes are conceivable as well, leading to an evolutionary scenario in which the ancestral picorna-like virus was assembled from diverse building blocks derived from the proto-mitochondrial endosymbiont during eukaryogenesis Koonin et al.

Clearly, this scenario is most plausible within the framework of the symbiogenetic scenario for the origin of eukaryotes. Under the protoeukaryote scenario, the ancestral picorna-like virus could be construed as a direct descendant of the primordial RNA world that survived and thrived in the protoeukaryotic lineage Fig. In this case, the RdRp of the picorna-like viruses would be viewed as the primordial replicase, and S3H and JRC accordingly would be considered ancestral forms of the respective proteins.

Incidentally, the only reported putative RNA virus of archaea shows a similar genome architecture although it is premature to discuss its possible role in the evolution of the viruses of eukaryotes until the archaeal host range is validated Bolduc et al. The 3CPro, for which the bacterial origin appears undeniable, could be a later acquisition concurrent with the symbiogenesis. Searches for the most closely related homologs of the leviviral RdRps identified the RdRps of these two narrow groups, fungal Narnaviridae and plant Ourmiavirus , as the eukaryotic descendants of the leviviruses.

The narnaviruses hardly meet the narrow definition of viruses because they are neither infectious nor possess an extracellular encapsidated form Hillman and Cai, The entire replication cycle of the narnaviruses of the genus Mitovirus takes place within fungal mitochondria. Given the origin of the mitochondria from an alphaproteobacterial endosymbiont, it appears most likely that the ancestral narnavirus evolved from an RNA bacteriophage brought along by the protomitochondrion, by losing the capsid and thus switching to the status of a mitochondrial RNA plasmid.

Because their RdRps are related to those of narnaviruses, whereas the intercellular movement and possibly capsid proteins are related to respective proteins of tombusviruses, it has been proposed that ourmiaviruses evolved via recombination between a narnavirus-like element from a plant-pathogenic fungus and a tombusvirus Rastgou et al.

However, the recent accelerated pace of discovery of new, diverse dsRNA viruses might soon challenge this perception Liu et al. The inclusion of two families of dsRNA viruses, Totiviridae and Partitiviridae , into the picornavirus-like superfamily is in full accord with this evolutionary scenario.

Notably, the divergence of birnaviruses from tetraviruses has apparently occurred following the acquisition of the JRC protein gene by their common ancestor from a nodavirus Wang et al. The family of capsid-less viruses Endornaviridae that is currently classified with dsRNA viruses clearly evolved from an alphavirus-like ancestor as indicated by the conservation of a signature set of core replication genes Koonin and Dolja, Evolutionary scenarios based on the phylogenetic analysis of viral replication proteins often deviate from those centered on the evolution of other functional modules, in particular those of viral capsid proteins Krupovic and Bamford, , Krupovic and Bamford, Thus, for comprehensive reconstruction of virus evolution, that would reflect the intrinsic modularity of this process, it is essential to complement phylogenetic and comparative genomic analyses with the analysis of structural data Koonin et al.

The emerging picture of the evolution of dsRNA viruses is among the best illustrations of this general principle. Based on comparisons of the virion and CP structures, it has been proposed that reoviruses are most closely related to cystoviruses whereas picobirnaviruses, partitiviruses, and totiviruses form another, distant branch of dsRNA viruses El Omari et al.

Thus, bacterial cystoviruses appear to have contributed the structural genes to most of the dsRNA viruses infecting eukaryotes. The reoviruses, the largest family of dsRNA viruses that infect diverse eukaryotic hosts Fig.

The global ecology of the dsRNA viruses appears rather peculiar. As a case in point, the family Reoviridae includes viruses that infect vertebrates, arthropods, mollusks, fungi, flowering plants and a unicellular green alga. Likewise, Partitiviridae infect fungi, flowering plants and an apicomplexan unicellular eukaryote, whereas host range of Totiviridae includes fungi and several unicellular eukaryotic parasites from the Excavate supergroup King et al. Such ecological patterns including two or three supergroups of eukaryotic hosts for each of the three largest families of the dsRNA viruses point to their ancient origins from the dsRNA bacteriophage and picornavirus-like ancestors as discussed above Fig.

The role of HVT in the evolution of the dsRNA viruses is most apparent for the family Endornaviridae where the plant and fungal virus branches in the phylogenetic trees of viral RdRps often intermingle within the same cluster Roossinck et al. A contribution of HVT appears likely also in the evolution of reoviruses many of which, both from vertebrates and from plants, are also capable of infecting their arthropod vectors Ng and Falk, , Quito-Avila et al.

Negative-strand RNA viruses of eukaryotes include the order Mononegavirales that consists of three related virus families with non-segmented genomes and 5 families of viruses with segmented genomes Supplementary Table S3. The protein sequences, as well as virion and genome architectures, are highly similar between animal and plant viruses in the families Rhabdoviridae and Bunyaviridae. Furthermore, arthropod parasites of animals and plants could have readily served as HVT vehicles because both plant and animal rhabdoviruses and bunyaviruses are transmitted by and replicate in their arthropod vectors Ammar el et al.

The discovery of four —RNA viruses that infect soybean cyst nematodes further expands the ecological reach of these viruses within animal lineage of evolution Bekal et al.

This reasoning is further buttressed by the recent identification of a nematode-infecting flavi-like virus Bekal et al. Whether this ancestral picorna-like virus was assembled from several distinct building blocks of bacterial origin during eukaryogenesis Fig. The answer critically depends on the choice of the scenario for the origin of eukaryotes that hopefully will be informed by the further advances of archaeal and bacterial genomics.

Regardless of the impending solution to this key problem, a limited footprint of RNA bacteriophages on the evolution of eukaryotic RNA viruses is apparent in the origin of narnaviruses and ourmiaviruses from leviviruses, and most likely, reoviruses from cystoviruses. To recapitulate the key points on the eukaryotic RNA virome, the enormous diversity of RNA viruses is a hallmark of the eukaryotic part of the virus world. We are far from a full understanding of the underlying causes of this remarkable bloom of RNA viruses but it stands to reason that the eukaryotic cytosol, with its extensive endomembrane system provides a niche that is highly conducive to RNA replication.

There is sufficient evidence to derive the great majority of eukaryotic RNA viruses from a common, positive-strand ancestor that might have been assembled from several components with distinct roots in prokaryotes including a reverse transcriptase. The striking diversification of RNA viruses in eukaryotes, in part, depended on switches in genome replication-expression strategies from positive-strand to double-stranded and negative-stranded genomes and multiple exchanges of genes between far diverged groups of viruses.

An extremely common and abundant class of selfish elements in eukaryotes consists of reverse-transcribing elements or retroelements for short , including retroviruses. Similar to the case of RNA viruses, the single common denominator of these extremely diverse elements is the polymerase involved in their replication, in this case, the reverse transcriptase RT which defines the key feature of the reproduction cycle, namely reverse transcription of RNA into DNA Eickbush and Jamburuthugoda, , Finnegan, , Kazazian, , Xiong and Eickbush, Beyond this unifying step, retroelements show all conceivable reproduction strategies: some behave like mobile elements that jump around host genomes via reverse transcription and integration, and regularly degrade to become integral parts of the host genomes; others behave as DNA or RNA plasmids; yet others, the best-characterized ones, are bona fide viruses that pack in the virions either RNA or DNA, or even a DNA—RNA hybrid, and go through an essential or facultative stage of integration into the host genome during virus replication.

Although all retroelements are relatively small, their genomic complexity varies greatly, from solo RT to sophisticated build-ups of viral genomes with over 10 genes, for example in the case of HIV. Given that the RT is the only universal gene among the retroelements, a natural approach to the reconstruction of their evolution involves using a phylogenetic tree of the RT as a framework.

Phylogenetic analysis Gladyshev and Arkhipova, divides the RTs into four major branches that include: 1 retroelements from prokaryotes including Group II self-splicing introns and retrons, 2 LINE-like elements, 3 Penelope-like elements, 4 reverse-transcribing viruses and related retrotransposons that contain Long Terminal Repeats LTR Fig. Historically, all retroelements, with the exception of reverse-transcribing viruses and their relatives, are often called non-LTR retrotransposons.

The 4 main branches of RTs as well as several branches within each of them see below are well resolved but the position of the root is not known. Evolution of retroelements and reverse-transcribing viruses.

Genomic organizations of selected representatives of the major groups of retroelements overlay the phylogenetic tree of the reverse transcriptases.

The topology of the tree is from Gladyshev and Arkhipova, The archaeal and bacterial retroelements that comprise one of the 4 major clades in the RT tree Fig. The fourth group in this clade of RTs includes the so-called retroplasmids that replicate in fungal mitochondria, and given the endosymbiotic origin of the mitochondria, are likely to be of bacterial origin Griffiths, In addition, analysis of bacterial and archaeal genomes revealed many RTs of unclear provenance that are likely to constitute or derive from uncharacterized retroelements Simon and Zimmerly, In addition to bacteria and some archaea, Group II introns are commonly present in mitochondrial genomes of fungi, plants and some protists.

The large protein encoded in Group II introns, in addition to the RT, encompasses an endonuclease domain that is involved in transposition. This endonuclease domain belongs to the HNH family which is one of the nucleases frequently encoded also in Group I introns Stoddard, Thus, from the evolutionary standpoint, Group II introns are likely to have evolved from self-splicing, endonuclease-encoding introns similar in architecture to Group I introns but with a distinct ribozyme structure that acquired an RT gene resulting in a more autonomous reproduction strategy.

The RT of the retrons makes multiple copies of a branched RNA-DNA hybrid but accumulation of these unusual molecules does not result in any discernible phenotype in the bacteria.

The DGRs are unusual retroelements that are present in some bacteriophage and bacterial genomes and have been shown to employ the RT to modify specific target genes and accordingly their protein products in a specific fashion resulting in changes in phage receptor specificity, helping the phage to evade bacterial resistance Medhekar and Miller, Bacterial retroelements, primarily Group II introns, have reached substantial diversity, with several distinct groups revealed by phylogenetic analysis, and invaded most of the bacterial divisions Simon et al.

In contrast, in archaea, the spread of these elements is restricted to a few groups of mesophiles, such as Methanosarcina , that appear to have acquired numerous bacterial genes via HGT. The same route has been proposed for the retroelements Rest and Mindell, In a stark contrast to the prokaryotic retroelements that are rather sparsely represented among bacteria, are rare in archaea and do not reach high copy numbers, diverse eukaryotic genomes are replete with retroelements of different varieties.

Although usually not reaching such extravagant excesses, retroelements are abundant also in genomes of diverse unicellular eukaryotes Bhattacharya et al. The eukaryotic retroelements show limited diversity of the RT sequences compared to the prokaryotic retroelements which is in sharp contrast with the enormous diversity of genome organizations and reproduction strategies.

We discuss these elements in accord with their branching in the phylogenetic trees of the RTs Fig. This complete form of PLE so far has been identified only in animals. However, a shorter PLE variants that lack the endonuclease are integrated in subtelomeric regions of chromosomes in a broad variety of eukaryotes Gladyshev and Arkhipova, The recruitment of the PLE-related RT for the telomerase function clearly was an early, pivotal event during the evolution of the eukaryotic cell.

Remarkably, several groups of eukaryotes, in particular insects, have lost the TERT gene and instead use a distinct variety of non-LTR retrotransposons as telomeric repeats Pardue and DeBaryshe, Thus, it seems that retroelements provide for the replication of chromosome ends in all eukaryotes thanks to their intrinsic ability to generate sequence repeats.

These endonuclease domains are small and highly diverged, so establishing evolutionary relationships is difficult. Thus, the complete forms of PLE found in animals might have evolved by fusing a viral intron-encoded endonuclease domain to the ancestral RT.

The LINE elements Long Interspersed Nuclear Elements comprise another group of simple retroelements that appear to be both the most common retroelements in eukaryotes, being represented in the genomes of diverse organisms of all major eukaryotic groups, and the most abundant among the extant retroelements as they reach extremely high copy numbers in animal genomes de Koning et al. Most of these LINE elements are inactivated and decaying but a small fraction remains active and spawns new copies.

In addition, the active LINE RT mediate the retrotransposition of SINEs such as the Alu elements that are extremely abundant in primate genomes , small elements that lack any protein-coding genes but still follow the retrotransposon life style and propagate to extremely high numbers in animal genomes de Koning et al.

A typical, complete vertebrate LINE consists of two genes one of which encodes the RT and endonuclease domains whereas the second one encodes an RNA-binding domain that is required for transposition. Although some phylogenetic analyses suggest that RNase H is a late acquisition in the history of non-LTR retroelements Malik, , it does not appear possible to rule out that this is the ancestral architecture among the LINEs. Furthermore, comparative analysis of the LINEs in plants has shown that, in addition to the AP endonuclease, a group of these elements acquired a distinct RNase H domain, surprisingly, of apparent archaeal origin Smyshlyaev et al.

In the phylogenetic tree of the RT Fig. Members of the RVT group have been identified also in several bacterial genomes suggesting the possibility of horizontal gene transfer the direction of which remains uncertain Gladyshev and Arkhipova, Among the RT-elements, bona fide viruses, with genomes encased in virus particles, and typical infection cycles including an extracellular phase, are a minority Supplementary Table S4. Importantly, capsid-less retroelements are found in all major divisions of cellular organisms, and by inference, are ancestral to this entire class of genetic elements.

By contrast, reverse-transcribing viruses are derived forms that apparently evolved at an early stage in the evolution of eukaryotes see below. The reproduction strategy of the retroviruses family Retroviridae partly resembles that of RNA viruses, combining aspects analogous to both positive-strand RNA viruses and negative-strand RNA viruses. The retroviruses are effectively RNA viruses that have evolved the capacity to convert to DNA, integrate into the host genome and then exploit the host replication and transcription machinery.

In addition to the typical infectious retroviruses, vertebrate genomes carry numerous endogenous retroviruses that are largely transmitted vertically and are often inactivated by mutation but, until that happens, have the potential to get activated and yield infectious virus Stoye, , Weiss, The two other families of reverse-transcribing viruses, Hepadnaviridae infecting animals and Caulimoviridae infecting plants collectively often denoted pararetroviruses , have ventured further into the DNA world: these viruses package the DNA form of the genome or sometimes a DNA—RNA, in the case of hepadnaviruses into the virions but retain the reverse transcription stage in the reproduction cycle Nassal, , Rothnie et al.

In contrast to the retroviruses, for viruses of these families, integration into the host genome is not an essential stage of the reproduction cycle although apparent spurious integration is common among caulimoviruses Harper et al. The remaining two families of reverse-transcribing viruses, Metaviridae and Pseudoviridae , include RT-encoding elements that are traditionally not even considered viruses but rather retrotransposons because they normally do not infect new cells, although it has been suggested that Gypsy elements of Drosophila are infectious Kim et al.

In any case, these elements, e. Among all retroelements, the reverse-transcribing viruses possess the most complex genomes Fig. All retroviruses share 3 major genes that are traditionally denoted pol , gag and env , and in many cases, also additional, variable genes. The retrovirus RT is a domain of the Pol polyprotein.

Two other domains, integrase and aspartic protease, are found only in a subset of pol polyproteins. However, superposition of the domain architectures of the pol polyproteins over the phylogenetic tree of the RTs strongly suggests that the common ancestor of the reverse-transcribing viruses encoded the complex form of Pol, most likely one with the PR-RT-RH-INT arrangement that is shared between retroviruses and metaviruses Fig.

The phylogenies of the RT, RH and INT domains of reverse-transcribing viruses appear to be concordant and cluster metaviruses with retroviruses to the exclusion of pseudoviruses Malik and Eickbush, , in agreement with the RT phylogeny in Fig. Under this scenario, caulimoviruses have lost the integrase domain whereas hepadnaviruses have lost both the integrase and the protease but acquired the terminal protein domain that is involved in the initiation of DNA synthesis.

The ultimate origin of the RH in retroelements is not easy to decipher because, for this short domain, the topology of the deep branches in the tree is unreliable. The presence of this derived shared character indicates that the retroelements have acquired a eukaryotic RNH I at an early stage of their evolution.

The aspartic protease of the LTR retroelements is homologous to the pan-eukaryotic protein DDI1, an essential, ubiquitin-dependent regulator of the cell cycle whereas DDI1 itself appears to have been derived from a distinct group of bacterial aspartyl proteases Krylov and Koonin, , Sirkis et al. Thus, strikingly, the ancestral Pol polyprotein of the LTR retroelements seems to have evolved through assembly from 4 distinct components only one of which, the RT, derives from a pre-existing retroelement.

Apart from the Pol polyprotein, the relationships between genes in different groups of reverse-transcribing viruses are convoluted. Although homologs of the Gag proteins in animals have been discovered and shown to be important in development, the respective genes apparently have been transferred from retroviruses to the host genomes Kaneko-Ishino and Ishino, The origin of the env genes of the vertebrate retroviruses that appear not to be homologous to any of the above env genes remains obscure.

Thus, despite the lack of a readily traceable ancestral relationship, it is thus conceivable that vertebrate retroviruses assembled their env proteins from preexisting protein domains of other eukaryotic viruses. Thus, at least one domain of the ancestral nucleocapsid protein of reverse-transcribing viruses survives in caulimoviruses.

In contrast, the core protein of hepadnaviruses shows no significant sequence similarity to capsid proteins of retroviruses or caulimoviruses, and might be a displacement of uncertain provenance. However, based on similar dimerization principles and sequence conservation patterns, it has been suggested that the capsid protein of hepadnaviruses and the C-terminal domain of retroviral CA actually are distant homologs Steven et al.

The origins of the family-specific genes of reverse-transcribing viruses remain uncertain, with the notable exception of the movement protein MP of caulimoviruses.

Clearly, the MP gene horizontally spread among diverse viruses driven by selection for the ability to cross plasmodesmata and hence cause systemic infection in plants Koonin et al. A much better known, textbook case of viral genes with a clear provenance are the oncogenes of numerous animal retroviruses e.

Most likely, retroelements have been an integral part of biological systems since the stage of the primordial replicators when they gave rise to the first DNA genomes Koonin, Indeed, under the RNA World scenario, the transition to DNA genomes would necessarily require reverse transcription, with the implication that some varieties of retroelements already existed at that stage of evolution.

However, in prokaryotes, retroelements maintain a low profile and never attain complex genomic architectures. In eukaryotes, the fortunes of retroelements have turned around: they proliferated dramatically, have become a defining factor of genome evolution and spawned several families of reverse-transcribing viruses.

The wide spread of each of the major groups of retroelements across the diversity of eukaryotes indicates that the principal events in the evolution of retroelements occurred before the radiation of the eukaryotic supergroups. A much more complex series of events led to the emergence of the LTR retroelements in particular, reverse-transcribing viruses including highly derived forms such as caulimoviruses and hepadnaviruses. The parsimonious version of the scenario for the origin of the eukaryotic retroelements depends on the scenario for the origin of eukaryotes.

The symbiogenetic scenario would root the entire diversity of the eukaryotic retroelements in prokaryotic ones, most likely, Group II introns. This origin of the eukaryotic retroelements appears compatible with the ancestral relationship between Group II introns and the eukaryotic spliceosomal introns that have lost both protein-coding genes and the self-splicing capacity as well as the snoRNAs, the catalytic components of the spliceosome Chalamcharla et al.

Remarkably, the essential, highly conserved yet functionally poorly characterized pan-eukaryotic protein subunit of the spliceosome, Prp8, also is an inactivated RT derivative that most likely evolved from the Group II intron RT Dlakic and Mushegian, Thus, under the symbiogenetic scenario, prokaryotic retroelements provide intermediates between the primordial genetic pool and the diversity of the eukaryotic retroelements.

In contrast, the protoeukaryote scenario implies that both prokaryotic and eukaryotic retroelements are direct descendants of primordial genetic entities that adopted distinct routes of evolution in prokaryotes and eukaryotes. The sequence variability of the prokaryotic RTs is extremely high, with only the essential motifs of the RT domain conserved throughout, by far exceeding the variation among the eukaryotic retroelements Simon and Zimmerly, This greater sequence diversity of the RTs in prokaryotes, despite their relatively low abundance, seems to be compatible with the origin of all eukaryotic retroelements from a distinct branch of prokaryotic retroelements, such as Group II introns.

Furthermore, given the apparent origin of the eukaryotic splicing from Group II introns, the symbiogenetic scenario seems to offer a simpler evolutionary narrative than the protoeukaryotic scenario. Regardless, the remarkable diversification of the retroelements in eukaryotes could have been triggered by the typically weaker purifying selection compared to prokaryotes which allowed for the massive proliferation of integrated retroelements and provided the playground for their further evolution Lynch, , Lynch and Conery, To summarize, the retroelements enjoyed no less success in eukaryotes than RNA viruses with which they could share the ultimate common origin from prokaryotic Group II elements self-splicing introns.

However, bona fide reverse-transcribing viruses are derived forms and show limited diversity. Notably, although all these viruses share a common origin, they seem to have acquired the envelope proteins from different sources and on independent occasions.

Retroelements including retro-transcribing viruses evolve in a much closer integration with the eukaryotic hosts than RNA viruses and sequences from these elements have been extensively recruited by eukaryotes for a variety of cellular functions at all stages of evolution.

Viruses with ssDNA genomes are increasingly appreciated as a rapidly expanding, highly diverse class of economically, medically and ecologically important pathogens. They infect hosts from all three domains of cellular life and are present in all conceivable environments, from near-surface atmosphere Whon et al. Bacterial and archaeal ssDNA viruses are grouped into four families, whereas the eukaryotic ssDNA viruses are classified into 6 families, Anelloviridae , Bidnaviridae , Circoviridae , Geminiviridae , Nanoviridae and Parvoviridae , and one unassigned genus Bacilladnavirus Supplementary Table S5.

Anelloviruses appear to be restricted to various mammals Okamoto, ; circoviruses are known to infect different avian species and pigs Delwart and Li, ; nanoviruses and geminiviruses infect plants Grigoras et al. Thus, ssDNA viruses prey on a wide range of eukaryotic hosts; however, numerous metagenomic and paleovirological studies suggest that the host range of eukaryotic ssDNA viruses might be even considerably broader Labonte and Suttle, , Rosario et al.

All eukaryotic ssDNA viruses, except for the members of the family Bidnaviridae see below , replicate their genomes using a rolling-circle or rolling-hairpin mechanism which involves nicking of the viral genome by a virus-encoded rolling-circle replication initiation endonuclease, RC-Rep.

The same replication mechanism is also used by most prokaryotic ssDNA viruses, many plasmids and some transposons Chandler et al. By contrast, none of the known prokaryotic ssDNA viruses encodes a S3H domain, whereas the endonuclease domains are not significantly similar to those of eukaryotic viruses, except for the short regions encompassing the three diagnostic sequence motifs that are common to all endonucleases of the HUH superfamily Chandler et al.

Thus, it appears extremely unlikely that ssDNA viruses of eukaryotes are direct descendants of their prokaryotic counterparts; the distantly related endonuclease domains involved in the mechanistically similar replication initiation processes probably were acquired independently and from different sources. A The catalytic motifs of the nicking endonuclease and superfamily 3 helicase S3H domains. Note the absence of the S3H domain in the prokaryotic ssDNA viruses and the inactivation of the endonuclease domain in the dsDNA-containing papillomaviruses and polyomaviruses.

B Homologous structures of the endonuclease domains. In contrast, the eukaryotic ssDNA viruses share the endonuclease-helicase domain architecture with the RC-Reps of various bacterial plasmids Fig.

Furthermore, RC-Reps from different families of eukaryotic ssDNA viruses are typically more similar to homologs form different groups of bacterial plasmids than they are to each other, suggesting a close evolutionary relationship between bacterial plasmids and eukaryotic ssDNA viruses Koonin and Ilyina, In particular, RC-Reps of geminiviruses and fungal gemycircularviruses cluster in phylogenetic trees with the homologous proteins encoded by plasmids of phytoplasmas parasitic wall-less bacteria replicating in plant and insect cells rather than the RC-Reps of other plant or animal ssDNA viruses, such as nanoviruses and circoviruses Krupovic et al.

Accordingly, it has been hypothesized that geminiviruses have evolved from bacterial replicons Koonin and Ilyina, , and specifically, from phytoplasmal plasmids Krupovic et al.

In contrast, RC-Reps of circoviruses show closer similarity to proteins from a different group of bacterial plasmids, represented by the plasmid p4M of Bifidobacterium pseudocatenulatum Gibbs et al.

A striking, independent finding that is compatible with an evolutionary relationship between bacterial RC replicons and eukaryotic ssDNA viruses is that genomes of certain plant geminiviruses retain functional bacterial promoters and can replicate in different bacterial cells in an RC-Rep-dependent manner Rigden et al. Although it is usually difficult to pinpoint the exact origin of viral RC-Reps, the above examples strongly suggest that RC-Reps of eukaryotic ssDNA viruses are polyphyletic and their roots are in different groups of bacterial plasmids.

The key step in the transformation of a plasmid into a virus is the acquisition of the genetic determinants allowing genome encapsidation and inter-cellular transfer. Indeed, some cryptic bacterial RC plasmids encode a single protein, the RC-Rep, and thus the only qualitative difference between such plasmids and the simplest eukaryotic ssDNA viruses, such as circoviruses, is the presence of a capsid protein CP gene in the latter Krupovic and Bamford, Were viruses an evolutionary stepping stone to more complex cellular life?

Or did they spring up later? The question is thorny. And without a fossil record to study, it has been almost impossible to untangle their lineage. To try to unpick the question of virus evolution, Caetano-Anolles developed a new way to reconstruct the microbial family tree, and retrace bacteria and viruses back to their origins.

But this technique only lets you rewind a million years or so. Caetano-Anolles wanted to go back to the beginnings of life on Earth — around 3. Proteins are high-precision molecular machines — if you change their shape, you disrupt their function. While life can tolerate a continual gentle drift in the genetic code, protein shape is critical and therefore evolves much more slowly. The researchers developed algorithms to compare the protein shapes of 3, viruses and 1, cells. They found that protein folds were shared between cells and viruses, but 66 folds were unique to viruses.

Wherever possible, the team used fossil evidence to put an approximate date on the budding of specific branches. In a new study, researchers apply big-data analysis to reveal the full extent of viruses' impact on the evolution of humans and other mammals.

Their findings suggest an astonishing 30 percent of all protein adaptations since humans' divergence with chimpanzees have been driven by viruses. We knew that, but what really surprised us is the strength and clarity of the pattern we found," said David Enard, Ph.

The study was recently published in the journal eLife and will be presented at The Allied Genetics Conference, a meeting hosted by the Genetics Society of America, on July Proteins perform a vast array of functions that keep our cells ticking. By revealing how small tweaks in protein shape and composition have helped humans and other mammals respond to viruses, the study could help researchers find new therapeutic leads against today's viral threats. Previous research on the interactions between viruses and proteins has focused almost exclusively on individual proteins that are directly involved in the immune response -- the most logical place you would expect to find adaptations driven by viruses.

This is the first study to take a global look at all types of proteins. It turns out that there is at least as much adaptation outside of the immune response as within it.

SARS-CoV-2 probably passed through a similar tenuous phase before it acquired the key adaptations that allowed it to flourish, perhaps the mutation to the polybasic cleavage site, perhaps others not yet identified.

Many viruses that spill over to humans never do. About to viruses are known to infect people, but only about half are transmissible — many only weakly — from one person to another, says Jemma Geoghegan, an evolutionary virologist at the University of Otago, New Zealand. The rest are dead-end infections. Half is a generous estimate, she adds, since many other spillover events probably fizzle out before they can even be counted. The big question now is: What happens next? One popular theory, endorsed by some experts, is that viruses often start off harming their hosts, but evolve toward a more benign coexistence.

After all, many of the viruses we know of that trigger severe problems in a new host species cause mild or no disease in the host they originally came from. Any pathogen that kills the host too fast will not give itself enough time to reproduce.

This kind of evolutionary gentling may be exactly what happened more than a century ago to one of the other human coronaviruses, known as OC43, Fielding suggests. Today, OC43 is one of four coronaviruses that account for up to a third of cases of the common cold and perhaps occasionally more severe illness. For one thing, people who were infected in the pandemic apparently experienced nervous-system symptoms we now see as more typical of coronaviruses than of influenza. They speculated that it may have caused the pandemic and then settled down to a less nasty coexistence as an ordinary cold virus.

Other evolutionary biologists disagree. Evolution always favors increased transmissibility, because viruses that spread more easily are evolutionarily fitter — that is, they leave more descendants. Some germs do just fine even if they make you very sick.

The bacteria that cause cholera spread through diarrhea, so severe disease is good for them. Respiratory viruses, like influenza and the human coronaviruses, need hosts that move around enough to breathe on one another, so extremely high virulence might be detrimental in some cases.