The Evolution of Endogenous Viral Elements
2011; Cell Press; Volume: 10; Issue: 4 Linguagem: Inglês
10.1016/j.chom.2011.09.002
ISSN1934-6069
Autores Tópico(s)Bacteriophages and microbial interactions
ResumoEndogenous retroviruses are a common component of the eukaryotic genome, and their evolution and potential function have attracted considerable interest. More surprising was the recent discovery that eukaryotic genomes contain sequences from RNA viruses that have no DNA stage in their life cycle. Similarly, several single-stranded DNA viruses have left integrated copies in their host genomes. This review explores some major evolutionary aspects arising from the discovery of these endogenous viral elements (EVEs). In particular, the reasons for the bias toward EVEs derived from negative-sense RNA viruses are considered, as well as what they tell us about the long-term "arms races" between hosts and viruses, characterized by episodes of selection and counter-selection. Most dramatically, the presence of orthologous EVEs in divergent hosts demonstrates that some viral families have ancestries dating back almost 100 million years, and hence are far older than expected from the phylogenetic analysis of their exogenous relatives. Endogenous retroviruses are a common component of the eukaryotic genome, and their evolution and potential function have attracted considerable interest. More surprising was the recent discovery that eukaryotic genomes contain sequences from RNA viruses that have no DNA stage in their life cycle. Similarly, several single-stranded DNA viruses have left integrated copies in their host genomes. This review explores some major evolutionary aspects arising from the discovery of these endogenous viral elements (EVEs). In particular, the reasons for the bias toward EVEs derived from negative-sense RNA viruses are considered, as well as what they tell us about the long-term "arms races" between hosts and viruses, characterized by episodes of selection and counter-selection. Most dramatically, the presence of orthologous EVEs in divergent hosts demonstrates that some viral families have ancestries dating back almost 100 million years, and hence are far older than expected from the phylogenetic analysis of their exogenous relatives. Although it has long been known that the eukaryote genome contains a myriad of complete and partial relatives of retroviruses called endogenous retroviruses that are now inherited passively with the host genetic component, it was surprising to discover that sequences of RNA viruses, which do not make a DNA intermediate and usually do not enter the host cell nucleus, were also present in eukaryotic genomes (Crochu et al., 2004Crochu S. Cook S. Attoui H. Charrel R.N. De Chesse R. Belhouchet M. Lemasson J.J. de Micco P. de Lamballerie X. Sequences of flavivirus-related RNA viruses persist in DNA form integrated in the genome of Aedes spp. mosquitoes.J. Gen. Virol. 2004; 85: 1971-1980Crossref PubMed Scopus (227) Google Scholar). Although integrated copies of single-strand DNA (ssDNA) viruses were found in the genomes of plant viruses some years ago (Bejarano et al., 1996Bejarano E.R. Khashoggi A. Witty M. Lichtenstein C. Integration of multiple repeats of geminiviral DNA into the nuclear genome of tobacco during evolution.Proc. Natl. Acad. Sci. USA. 1996; 93: 759-764Crossref PubMed Scopus (132) Google Scholar), a number of endogenized ssDNA viruses were recently described in a diverse set of animal genomes (Belyi et al., 2010aBelyi V.A. Levine A.J. Skalka A.M. Sequences from ancestral single-stranded DNA viruses in vertebrate genomes: the parvoviridae and circoviridae are more than 40 to 50 million years old.J. Virol. 2010; 84: 12458-12462Crossref PubMed Scopus (103) Google Scholar, Katzourakis and Gifford, 2010Katzourakis A. Gifford R.J. Endogenous viral elements in animal genomes.PLoS Genet. 2010; 6: e1001191Crossref PubMed Scopus (450) Google Scholar). Such an array of virally derived genetic material raises a number of important evolutionary questions, which forms the basis of this review. Perhaps the most important theme is that more than expanding our basic knowledge of the composition of eukaryotic genomes, the presence of endogenous viruses has had a profound impact on our understanding of the time-scale of virus evolution, the consequences of which are yet to be fully understood. Although endogenous viruses have been classified in different ways, a useful collective term for them all that reflects their generally fragmentary nature is "endogenous viral elements" (EVEs) (Katzourakis and Gifford, 2010Katzourakis A. Gifford R.J. Endogenous viral elements in animal genomes.PLoS Genet. 2010; 6: e1001191Crossref PubMed Scopus (450) Google Scholar). From here on, the term EVE will be used to refer to all endogenous viruses, whether derived from retroviruses, DNA viruses, or RNA viruses, although this review will generally focus on the latter group. EVEs are generated when a double-stranded DNA (dsDNA) copy of the viral genome is integrated into the host germline (Figure 1). Although the production of dsDNA intermediates that integrate into host genomic DNA is an obligatory part of the retroviral life cycle, germline as opposed to somatic cell integration is expected to be a rare event. Despite this, endogenous retroviruses are surprisingly common; for example, approximately 5%–8% of the human genome is composed of endogenous retroviruses (Katzourakis and Tristem, 2005Katzourakis A. Tristem M. Phylogeny of human endogenous and exogenous retroviruses.in: Sverdlov E.D. Retroviruses and Primate Genome Evolution. Landes Bioscience, Austin, TX2005: 186-203Google Scholar). These comprise at least 31 distinct families, such that there have been at least 31 separate integration events, and likely many more. In some animal species, it has even proven possible to see retroviral endogenization in action (Tarlinton et al., 2006Tarlinton R.E. Meers J. Young P.R. Retroviral invasion of the koala genome.Nature. 2006; 442: 79-81Crossref PubMed Scopus (278) Google Scholar). Not surprisingly, those EVEs derived from nonretroviruses are far rarer and hence represent the consequence of sporadic evolutionary events. In addition, while effectively complete genomes of endogenous retroviruses are relatively commonplace, this is not the case for those EVEs generated by other types of virus, which are usually composed of partial genomic fragments. Although the presence of retroviral EVEs was described many years ago (Benveniste and Todaro, 1974Benveniste R.E. Todaro G.J. Evolution of C-type viral genes: inheritance of exogenously acquired viral genes.Nature. 1974; 252: 456-459Crossref PubMed Scopus (127) Google Scholar, Weiss et al., 1973Weiss R.A. Mason W.S. Vogt P.K. Genetic recombinants and heterozygotes derived from endogenous and exogenous avian RNA tumor viruses.Virology. 1973; 52: 535-552Crossref PubMed Scopus (140) Google Scholar), the first description of a gene sequence of an RNA virus (that replicate using an RNA-dependent RNA polymerase [RdRp]) integrated into the host genome did not occur until 2004. This example involved the insect flavivirus cell fusing agent (CFA), fragments of which were found to be integrated into the genomes of Aedes spp. mosquitoes (Crochu et al., 2004Crochu S. Cook S. Attoui H. Charrel R.N. De Chesse R. Belhouchet M. Lemasson J.J. de Micco P. de Lamballerie X. Sequences of flavivirus-related RNA viruses persist in DNA form integrated in the genome of Aedes spp. mosquitoes.J. Gen. Virol. 2004; 85: 1971-1980Crossref PubMed Scopus (227) Google Scholar), and which has also been observed in some other insect flaviviruses (Roiz et al., 2009Roiz D. Vázquez A. Seco M.P. Tenorio A. Rizzoli A. Detection of novel insect flavivirus sequences integrated in Aedes albopictus (Diptera: Culicidae) in Northern Italy.Virol. J. 2009; 6: 93Crossref PubMed Scopus (71) Google Scholar). Shortly afterward, integrated sequences of the RNA virus Potato virus Y (PVY, a potyvirus) were found in the genomes of some grapevine varieties (Tanne and Sela, 2005Tanne E. Sela I. Occurrence of a DNA sequence of a non-retro RNA virus in a host plant genome and its expression: evidence for recombination between viral and host RNAs.Virology. 2005; 332: 614-622Crossref PubMed Scopus (61) Google Scholar). Since this time, a number of other endogenous RNA viruses have been discovered, comprising bornaviruses (also referred to as endogenous Borna-like N elements [EBLN]; Figure 2) (Belyi et al., 2010bBelyi V.A. Levine A.J. Skalka A.M. Unexpected inheritance: multiple integrations of ancient bornavirus and ebolavirus/marburgvirus sequences in vertebrate genomes.PLoS Pathog. 2010; 6: e1001030Crossref PubMed Scopus (221) Google Scholar, Horie et al., 2010Horie M. Honda T. Suzuki Y. Kobayashi Y. Daito T. Oshida T. Ikuta K. Jern P. Gojobori T. Coffin J.M. Tomonaga K. Endogenous non-retroviral RNA virus elements in mammalian genomes.Nature. 2010; 463: 84-87Crossref PubMed Scopus (351) Google Scholar), bunyaviruses (Katzourakis and Gifford, 2010Katzourakis A. Gifford R.J. Endogenous viral elements in animal genomes.PLoS Genet. 2010; 6: e1001191Crossref PubMed Scopus (450) Google Scholar), filoviruses (Belyi et al., 2010bBelyi V.A. Levine A.J. Skalka A.M. Unexpected inheritance: multiple integrations of ancient bornavirus and ebolavirus/marburgvirus sequences in vertebrate genomes.PLoS Pathog. 2010; 6: e1001030Crossref PubMed Scopus (221) Google Scholar, Taylor et al., 2010Taylor D.J. Leach R.W. Bruenn J. Filoviruses are ancient and integrated into mammalian genomes.BMC Evol. Biol. 2010; 10: 193Crossref PubMed Scopus (136) Google Scholar), orthomyxoviruses (Katzourakis and Gifford, 2010Katzourakis A. Gifford R.J. Endogenous viral elements in animal genomes.PLoS Genet. 2010; 6: e1001191Crossref PubMed Scopus (450) Google Scholar), reoviruses (Katzourakis and Gifford, 2010Katzourakis A. Gifford R.J. Endogenous viral elements in animal genomes.PLoS Genet. 2010; 6: e1001191Crossref PubMed Scopus (450) Google Scholar), and rhabdoviruses (Katzourakis and Gifford, 2010Katzourakis A. Gifford R.J. Endogenous viral elements in animal genomes.PLoS Genet. 2010; 6: e1001191Crossref PubMed Scopus (450) Google Scholar), although usually at very low copy numbers (i.e., less than 100 elements per genome). A list of animal EVEs is provided in Table 1, with bornaviruses being the only endogenous RNA viruses found in the human genome. Similarly, endogenous viruses have been observed in various fungal (Frank and Wolfe, 2009Frank A.C. Wolfe K.H. Evolutionary capture of viral and plasmid DNA by yeast nuclear chromosomes.Eukaryot. Cell. 2009; 8: 1521-1531Crossref PubMed Scopus (50) Google Scholar, Taylor and Bruenn, 2009Taylor D.J. Bruenn J. The evolution of novel fungal genes from non-retroviral RNA viruses.BMC Biol. 2009; 7: 88Crossref PubMed Scopus (85) Google Scholar) and bacterial (Salanoubat et al., 2002Salanoubat M. Genin S. Artiguenave F. Gouzy J. Mangenot S. Arlat M. Billault A. Brottier P. Camus J.C. Cattolico L. et al.Genome sequence of the plant pathogen Ralstonia solanacearum.Nature. 2002; 415: 497-502Crossref PubMed Scopus (762) Google Scholar) genomes.Table 1Distribution and Age of Endogenous Viral Elements Derived from RNA and DNA Viruses Found in Animal GenomesViral Family and TypeHost RangeNumber of ElementsEstimated Minimum AgeReferenceBornaviridae (ssRNA−)aMononegavirales.MammalsbIncludes humans.6793 MYABelyi et al., 2010bBelyi V.A. Levine A.J. Skalka A.M. Unexpected inheritance: multiple integrations of ancient bornavirus and ebolavirus/marburgvirus sequences in vertebrate genomes.PLoS Pathog. 2010; 6: e1001030Crossref PubMed Scopus (221) Google Scholar, Horie et al., 2010Horie M. Honda T. Suzuki Y. Kobayashi Y. Daito T. Oshida T. Ikuta K. Jern P. Gojobori T. Coffin J.M. Tomonaga K. Endogenous non-retroviral RNA virus elements in mammalian genomes.Nature. 2010; 463: 84-87Crossref PubMed Scopus (351) Google Scholar, Katzourakis and Gifford, 2010Katzourakis A. Gifford R.J. Endogenous viral elements in animal genomes.PLoS Genet. 2010; 6: e1001191Crossref PubMed Scopus (450) Google ScholarFiloviridae (ssRNA−)aMononegavirales.Mammals2530 MYAcWill vary according to the date used for the divergence of rat and mouse.Belyi et al., 2010bBelyi V.A. Levine A.J. Skalka A.M. Unexpected inheritance: multiple integrations of ancient bornavirus and ebolavirus/marburgvirus sequences in vertebrate genomes.PLoS Pathog. 2010; 6: e1001030Crossref PubMed Scopus (221) Google Scholar, Katzourakis and Gifford, 2010Katzourakis A. Gifford R.J. Endogenous viral elements in animal genomes.PLoS Genet. 2010; 6: e1001191Crossref PubMed Scopus (450) Google Scholar, Taylor et al., 2010Taylor D.J. Leach R.W. Bruenn J. Filoviruses are ancient and integrated into mammalian genomes.BMC Evol. Biol. 2010; 10: 193Crossref PubMed Scopus (136) Google ScholarBunyaviridae (ssRNA−)aMononegavirales.Insects40UnknownKatzourakis and Gifford, 2010Katzourakis A. Gifford R.J. Endogenous viral elements in animal genomes.PLoS Genet. 2010; 6: e1001191Crossref PubMed Scopus (450) Google ScholarRhabdoviridae (ssRNA−)aMononegavirales.Insects143UnknownKatzourakis and Gifford, 2010Katzourakis A. Gifford R.J. Endogenous viral elements in animal genomes.PLoS Genet. 2010; 6: e1001191Crossref PubMed Scopus (450) Google ScholarOrthomyxoviridae (ssRNA−)Insects1UnknownKatzourakis and Gifford, 2010Katzourakis A. Gifford R.J. Endogenous viral elements in animal genomes.PLoS Genet. 2010; 6: e1001191Crossref PubMed Scopus (450) Google ScholarReoviridae (dsRNA)Insects1UnknownKatzourakis and Gifford, 2010Katzourakis A. Gifford R.J. Endogenous viral elements in animal genomes.PLoS Genet. 2010; 6: e1001191Crossref PubMed Scopus (450) Google ScholarFlaviviridae (ssRNA+)Insects5UnknownCrochu et al., 2004Crochu S. Cook S. Attoui H. Charrel R.N. De Chesse R. Belhouchet M. Lemasson J.J. de Micco P. de Lamballerie X. Sequences of flavivirus-related RNA viruses persist in DNA form integrated in the genome of Aedes spp. mosquitoes.J. Gen. Virol. 2004; 85: 1971-1980Crossref PubMed Scopus (227) Google Scholar, Katzourakis and Gifford, 2010Katzourakis A. Gifford R.J. Endogenous viral elements in animal genomes.PLoS Genet. 2010; 6: e1001191Crossref PubMed Scopus (450) Google ScholarParvoviridae (ssDNA)Mammals9930 MYAcWill vary according to the date used for the divergence of rat and mouse.Belyi et al., 2010aBelyi V.A. Levine A.J. Skalka A.M. Sequences from ancestral single-stranded DNA viruses in vertebrate genomes: the parvoviridae and circoviridae are more than 40 to 50 million years old.J. Virol. 2010; 84: 12458-12462Crossref PubMed Scopus (103) Google Scholar, Katzourakis and Gifford, 2010Katzourakis A. Gifford R.J. Endogenous viral elements in animal genomes.PLoS Genet. 2010; 6: e1001191Crossref PubMed Scopus (450) Google ScholarCircoviridae (ssDNA)Mammals568 MYABelyi et al., 2010aBelyi V.A. Levine A.J. Skalka A.M. Sequences from ancestral single-stranded DNA viruses in vertebrate genomes: the parvoviridae and circoviridae are more than 40 to 50 million years old.J. Virol. 2010; 84: 12458-12462Crossref PubMed Scopus (103) Google Scholar, Katzourakis and Gifford, 2010Katzourakis A. Gifford R.J. Endogenous viral elements in animal genomes.PLoS Genet. 2010; 6: e1001191Crossref PubMed Scopus (450) Google ScholarHepadnaviridae (dsDNA)Birds8>19 MYAGilbert and Feschotte, 2010Gilbert C. Feschotte C. Genomic fossils calibrate the long-term evolution of hepadnaviruses.PLoS Biol. 2010; 8: e1000495Crossref PubMed Scopus (116) Google Scholar, Katzourakis and Gifford, 2010Katzourakis A. Gifford R.J. Endogenous viral elements in animal genomes.PLoS Genet. 2010; 6: e1001191Crossref PubMed Scopus (450) Google ScholarMYA, million years ago.a Mononegavirales.b Includes humans.c Will vary according to the date used for the divergence of rat and mouse. Open table in a new tab MYA, million years ago. As well as the expanded catalog of endogenous RNA viruses, the sequences of a number of small DNA viruses are also integrated into host genomes, namely the circovirus (Belyi et al., 2010aBelyi V.A. Levine A.J. Skalka A.M. Sequences from ancestral single-stranded DNA viruses in vertebrate genomes: the parvoviridae and circoviridae are more than 40 to 50 million years old.J. Virol. 2010; 84: 12458-12462Crossref PubMed Scopus (103) Google Scholar), geminivirus (Bejarano et al., 1996Bejarano E.R. Khashoggi A. Witty M. Lichtenstein C. Integration of multiple repeats of geminiviral DNA into the nuclear genome of tobacco during evolution.Proc. Natl. Acad. Sci. USA. 1996; 93: 759-764Crossref PubMed Scopus (132) Google Scholar), and parvovirus (Belyi et al., 2010aBelyi V.A. Levine A.J. Skalka A.M. Sequences from ancestral single-stranded DNA viruses in vertebrate genomes: the parvoviridae and circoviridae are more than 40 to 50 million years old.J. Virol. 2010; 84: 12458-12462Crossref PubMed Scopus (103) Google Scholar, Kapoor et al., 2010Kapoor A. Simmonds P. Lipkin W.I. Discovery and characterization of mammalian endogenous parvoviruses.J. Virol. 2010; 84: 12628-12635Crossref PubMed Scopus (57) Google Scholar) families of ssDNA viruses, as well as the hepadnaviruses (dsDNA) (Gilbert and Feschotte, 2010Gilbert C. Feschotte C. Genomic fossils calibrate the long-term evolution of hepadnaviruses.PLoS Biol. 2010; 8: e1000495Crossref PubMed Scopus (116) Google Scholar). For example, endogenous fragments of the Parvoviridae are found in mammalian hosts as diverse as cats, elephants, platypus, and wallabies. With the continual increase in the number of eukaryotic genome sequences, it is certain that more EVEs will be described. In addition, it is likely that the phylogenetic signal for the integration of some very ancient EVEs, particularly those that occurred early in eukaryote evolution and that evolve without functional constraints, has been lost through the accumulation of multiple nucleotide substitutions. Of those EVEs recently discovered, perhaps the most surprising were the endogenous filoviruses (Figure 3). Although novel exogenous filoviruses have recently been discovered (Barrette et al., 2011Barrette R.W. Xu L. Rowland J.M. McIntosh M.T. Current perspectives on the phylogeny of Filoviridae.Infect. Genet. Evol. 2011; (in press. Published online June 30, 2011)PubMed Google Scholar), they generally infect a small number of mammalian species—particularly primate and bat species from equatorial Africa—with occasional high-profile spillovers into human populations. Indeed, there has been a long running debate as to the natural reservoir of filoviruses, with various species of fruit bat being perhaps the most likely candidate (Leroy et al., 2005Leroy E.M. Kumulungui B. Pourrut X. Rouquet P. Hassanin A. Yaba P. Délicat A. Paweska J.T. Gonzalez J.P. Swanepoel R. Fruit bats as reservoirs of Ebola virus.Nature. 2005; 438: 575-576Crossref PubMed Scopus (1145) Google Scholar). In contrast, endogenous filoviruses have been detected in the genomes of diverse mammalian taxa, including both placental and marsupial mammals (Belyi et al., 2010bBelyi V.A. Levine A.J. Skalka A.M. Unexpected inheritance: multiple integrations of ancient bornavirus and ebolavirus/marburgvirus sequences in vertebrate genomes.PLoS Pathog. 2010; 6: e1001030Crossref PubMed Scopus (221) Google Scholar, Taylor et al., 2010Taylor D.J. Leach R.W. Bruenn J. Filoviruses are ancient and integrated into mammalian genomes.BMC Evol. Biol. 2010; 10: 193Crossref PubMed Scopus (136) Google Scholar). While much of the evolution of these endogenous filoviruses can be measured on time scales of millions of years—especially as EVEs from rat and mouse are inserted at homologous loci, strongly suggesting that they have codiverged with these species—it is evident that a number of independent insertion events have occurred (Taylor et al., 2010Taylor D.J. Leach R.W. Bruenn J. Filoviruses are ancient and integrated into mammalian genomes.BMC Evol. Biol. 2010; 10: 193Crossref PubMed Scopus (136) Google Scholar). Most notably, those filovirus EVEs infecting placental and marsupial mammals are not sister taxa, as expected given ancient virus-host codivergence, with the EVEs from marsupials more closely related to the exogenous filoviruses. This is a remarkable observation, given the geographic separation of these two groups; most known exogenous filoviruses are of African origin, whereas the marsupial endogenous filoviruses are largely from Australian species, with a single representative found in an American opossum that constitutes the closest relative of the exogenous filoviruses (Taylor et al., 2010Taylor D.J. Leach R.W. Bruenn J. Filoviruses are ancient and integrated into mammalian genomes.BMC Evol. Biol. 2010; 10: 193Crossref PubMed Scopus (136) Google Scholar). Such a disjunct distribution is highly suggestive of the presence of further, currently uncharacterized, exogenous filoviruses. Despite the evident under- and biased sampling of EVEs, there is a striking imbalance in the taxonomic origins of those EVEs derived from RNA viruses described to date; at the time of writing, only eight families of RNA viruses have been shown to possess endogenous relatives, five of which represent viruses with negative-sense genomes (ssRNA− viruses), and three of these falling into the Mononegavirales—a higher-order grouping of multiple families of ssRNA− viruses with unsegmented genomes (Table 1). In addition, those EVEs derived from positive-sense RNA viruses (ssRNA+ viruses) are at extremely low copy number; one genomic copy in the case of the Reoviridae, five in the case of the Flaviviridae, and probably a small number in PVY. Such a bias toward ssRNA− viruses merits explanation. In the case of the bornavirus EVEs, at least part of the explanation must relate to their nuclear replication cycle, increasing the chances of endogenization (see below). Similarly, there will be an elevated chance of endogenization for those viruses that cause persistent as opposed to acute host infections. However, as ssRNA+ viruses are as likely to generate persistent infections as ssRNA− viruses, this cannot explain the extreme distribution bias. It is also possible that some EVEs are better able to achieve germline integration than others (Horie et al., 2010Horie M. Honda T. Suzuki Y. Kobayashi Y. Daito T. Oshida T. Ikuta K. Jern P. Gojobori T. Coffin J.M. Tomonaga K. Endogenous non-retroviral RNA virus elements in mammalian genomes.Nature. 2010; 463: 84-87Crossref PubMed Scopus (351) Google Scholar, Johnson, 2010Johnson W.E. Endless forms most viral.PLoS Genet. 2010; 6: e1001210Crossref PubMed Scopus (21) Google Scholar), although the determinants of this process are currently unclear, nor is why it might occur more frequently with ssRNA− viruses. One possibility is that the messenger RNAs (mRNAs) of ssRNA− viruses are more favorable templates for L1-mediated reverse transcription than those of other viruses (Horie et al., 2010Horie M. Honda T. Suzuki Y. Kobayashi Y. Daito T. Oshida T. Ikuta K. Jern P. Gojobori T. Coffin J.M. Tomonaga K. Endogenous non-retroviral RNA virus elements in mammalian genomes.Nature. 2010; 463: 84-87Crossref PubMed Scopus (351) Google Scholar), although why is again unclear. One clue to the preponderance of ssRNA− viruses comes from the strong bias toward the integration of nucleoprotein (NP) genes (Figure 2, Figure 3). The Mononegavirales share a common genome organization, in which the NP gene has the most 3′ location and the L gene, which encodes the RdRp, the most 5′. In all Mononegavirales except the filoviruses genes are transcribed in a sequential manner from 3′ to 5′ and with stepwise attenuation. This results in discrete mRNAs for each gene and means that the most 3′ gene (NP) is the most abundant RNA, and the most 5′ (L) gene the least abundant, and hence that whole genomes of Mononegavirales are not expected to be endogenized. That most EVEs represent NP genes also suggests that endogenization is at least in part a function of relative mRNA abundance. Indeed, many ssRNA+ viruses produce a single large polyprotein, and it may be that L1-mediated reverse transcription occurs more efficiently on the shorter mRNAs produced by ssRNA− viruses. Similarly, it is possible that the life cycle of ssRNA+ viruses, in which translation occurs before transcription, also influences mRNA abundance and hence the probability of endogenization. As noted above, one reason why the existence of endogenous RNA viruses came as a surprise to researchers is that they require two unusual steps in the viral life cycle: first, the viral genetic material needs to enter the cell nucleus, when the fact that RNA viruses carry their own RdRp means that they usually (with a few exceptions) only inhabit the cytoplasm, and second, ssRNA needs to be converted into dsDNA (Figure 1). There are currently little meaningful data to determine how the first process occurs, although it is striking that endogenous bornaviruses are particularly commonplace and these are one of the few families of RNA viruses that replicate within the cell nucleus (Horie et al., 2010Horie M. Honda T. Suzuki Y. Kobayashi Y. Daito T. Oshida T. Ikuta K. Jern P. Gojobori T. Coffin J.M. Tomonaga K. Endogenous non-retroviral RNA virus elements in mammalian genomes.Nature. 2010; 463: 84-87Crossref PubMed Scopus (351) Google Scholar). There are, however, a number of plausible ways in which the conversion from ssRNA to dsDNA can occur. Perhaps the most likely involves a reverse transcription step using the reverse transcriptase (RT) present in the cellular retroelements that are abundant in eukaryotic genomes. For example, long interspersed nucleotide elements (LINES) are a common component of vertebrate genomes, particularly members of the L1 family, and therefore are a potentially rich source of RT. In fact, the flanking sequences of some EBLNs possess signatures suggestive of L1-mediated reverse transcription, such as the presence of 3′ poly-A tails and target site duplications (Belyi et al., 2010bBelyi V.A. Levine A.J. Skalka A.M. Unexpected inheritance: multiple integrations of ancient bornavirus and ebolavirus/marburgvirus sequences in vertebrate genomes.PLoS Pathog. 2010; 6: e1001030Crossref PubMed Scopus (221) Google Scholar, Horie et al., 2010Horie M. Honda T. Suzuki Y. Kobayashi Y. Daito T. Oshida T. Ikuta K. Jern P. Gojobori T. Coffin J.M. Tomonaga K. Endogenous non-retroviral RNA virus elements in mammalian genomes.Nature. 2010; 463: 84-87Crossref PubMed Scopus (351) Google Scholar), while the endogenous PVY elements in plants possess direct repeats and lie within a sequence itself flanked by inverted repeats (Tanne and Sela, 2005Tanne E. Sela I. Occurrence of a DNA sequence of a non-retro RNA virus in a host plant genome and its expression: evidence for recombination between viral and host RNAs.Virology. 2005; 332: 614-622Crossref PubMed Scopus (61) Google Scholar), compatible with transposable element-mediated integration. More directly, nonhomologous recombination between an exogenous RNA virus and an intracisternal A-type particle (IAP) retrotransposon has been observed to result in the reverse transcription and cellular integration of viral RNAs (Geuking et al., 2009Geuking M.B. Weber J. Dewannieux M. Gorelik E. Heidmann T. Hengartner H. Zinkernagel R.M. Hangartner L. Recombination of retrotransposon and exogenous RNA virus results in nonretroviral cDNA integration.Science. 2009; 323: 393-396Crossref PubMed Scopus (112) Google Scholar). Alternatively, it is possible that the RT is provided by an exogenous retrovirus that is infecting the host at the same time, and particularly where this exogenous infection is associated with a high viral copy number and abundant RT. The situation is rather different for the endogenized DNA viruses. As small ssDNA viruses such as parvoviruses utilize host DNA polymerases for their replication, and therefore enter the cell nucleus, their endogenization should not come as a surprise. A similar story can be told for the endogenous hepadnaviruses, the first of which was discovered in the zebra finch and designated eZHBV (Gilbert and Feschotte, 2010Gilbert C. Feschotte C. Genomic fossils calibrate the long-term evolution of hepadnaviruses.PLoS Biol. 2010; 8: e1000495Crossref PubMed Scopus (116) Google Scholar) (Figure 4). Importantly, hepadnaviruses possess dsDNA genomes, utilize RT, replicate in the nucleus, and integrated copies are seen with the human form of the virus where they are associated with liver cancer (Bonilla Guerrero and Roberts, 2005Bonilla Guerrero R. Roberts L.R. The role of hepatitis B virus integrations in the pathogenesis of human hepatocellular carcinoma.J. Hepatol. 2005; 42: 760-777Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar). Although the precise mechanisms of genomic integration are unknown (Gilbert and Feschotte, 2010Gilbert C. Feschotte C. Genomic fossils calibrate the long-term evolution of hepadnaviruses.PLoS Biol. 2010; 8: e1000495Crossref PubMed Scopus (116) Google Scholar), hepadnaviruses clearly possess a number of the necessary attributes for endogenization. In this context, it is interesting that endogenous copies of another important agent of human cancer—the papillomaviruses—have yet to be discovered, even though they possess dsDNA genomes, enter the cell nucleus, and are commonplace in vertebrates (Bernard et al., 1994Bernard H.-U. Chan S.-Y. Delius H. Evolution of papillomaviruses.Curr. Top. Microbiol. Immunol. 1994; 186: 33-54Crossref PubMed Scopus (62) Google Scholar). While there is mounting evidence for the presence of virus genetic material in host genomes, there are few examples of host genetic material integrated into the genomes of RNA and small DNA viruses, such that lateral gene transfer is largely one-way traffic. This is most likely a reflection of the extreme size constraints faced by RNA and small DNA viruses, which rarely have genomes >20,000 nt and are characterized by a lac
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