Evaluating the evidence for virus / host co-evolution. Curr. Opin ...

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Evaluating the evidence for virus / host co-evolution. Curr. Opin ...

Evaluating the evidence for virus/host co-evolution Sharp and Simmonds 437Figure 1Figure 2A - 1972AncestorB - 1990C - 1981D - 1995E - 1985F - 1990Time1960 1970 1980 1990Current Opinion in VirologytCalibrating the molecular clock for rapidly evolving viruses. If virusesevolve at roughly constant rates, in an evolutionary tree with branchlengths drawn to scale viruses isolated at later time points have branchtips extending further from the root of the tree. Dates of isolation andbranch lengths can be used to estimate the rate of nucleotidesubstitution [1,2], and to estimate the dates of ancestral nodes in thetree; in this example, the ancestral virus at the root of the tree (red circle)would be placed around 1950.Polyomavirus JCJC virus (JCV) is human polyomavirus with a very highglobal prevalence, which causes persistent, largelyasymptomatic, infections. Strains of JCV fall into variousclades that are found predominantly within particulargeographical regions [7,8], suggesting that their divergenceoccurred with the divergence of human races andthe emergence of modern Homo sapiens from Africa, some50 000–100 000 years ago. This timescale implies a comparativelyslow rate of evolution around 4 10 7 substitutionsper site per year [9], as expected for a DNA virusthat is replicated by a cellular DNA polymerase with aproofreading function. However, two recent analysespropose a very different model of JCV evolution[10,11]. Firstly, it was concluded that there is no substantialmatch between the evolutionary relationships ofhuman populations and those of the JCV clades infectingthem [10]. Then, from a comparison of the sequences ofisolates collected at different time points, it was estimatedthat the rate of JCV evolution was almost 50 times higherthan the earlier estimate, implying that the commonancestry of all current strains dates back to only about1300 years ago [10].However, there are major problems with these conclusions.Firstly, the human population dendrogram used(a summary of overall similarity) is not expected to applyto any particular genetic marker, because the populationsdiverged recently relative to the time taken for lineagesorting to occur. For example, a tree for human mtDNA[12] does not match this and so there can be no expectationthat the JCV phylogeny should match it either.(a) (b) (c)Current Opinion in VirologyGene (or virus) trees may not match host species trees. Circles linked bylines represent alleles of a host gene (or polymorphic variants of a coevolvingvirus) during the divergence of species A, B and C. Thedescendants of two alleles (or viruses) present in the ancestor arehighlighted in red and blue. Polymorphism persisted during the period(time t) between (i) the initial split of species C and (ii) the later splitbetween A and B. After subsequent lineage sorting, the genes (viruses)present in species B happened to be more closely related to those inspecies C, so that a phylogeny for this gene (virus) differs from the truephylogeny for the three host species. The probability that a gene (orvirus) tree differs from the true tree for the host species is higher whenthe time t is shorter and when the effective population size of the host (orvirus) is larger [5].Secondly, nearly all of the sequences used were isolatedwithin a 15-year period. Over 15 years, at the proposedrate of 1.7 10 5 substitutions per site per year, onaverage only a single nucleotide change is expected toarise in a JCV genome of 5000 nucleotides, providinginsufficient signal to calibrate the molecular clock; thusthe rate estimate here must be doubtful.The clearest indication that these analyses have greatlyunderestimated the time depth of the JCV phylogenycomes from one particular genotype, 2A2. Nearly all theviruses within this clade were isolated from Native Americansfrom Canada, USA, Mexico, Guatemala, Peru andArgentina. From the molecular clock calculations, theancestor of this clade would be placed at around 300years ago [10], which is quite implausible epidemiologically.Of course, the predominance of a single, otherwiserare, clade of JCV among native peoples from North,Central and South America is exactly what would beexpected if the dispersion of the viruses reflected thewww.sciencedirect.com Current Opinion in Virology 2011, 1:436–441


438 Virus evolutioninitial migrations of humans to the Americas from Asia,around 15 000 years ago; 50 times the divergence timeestimated. In the case of JCV it seems clear that themolecular clock approach has foundered, and virus/hostco-evolution remains the likely explanation of theobserved distribution of genotypes.Primate lentivirusesSimian immunodeficiency viruses (SIVs) are retrovirusesin the genus Lentivirus, whose evolutionary history is ofparticular interest because the AIDS viruses, HIV-1 andHIV-2, originated by cross-species transmission of SIVs tohumans [13 ]. Some SIVs may have co-diverged with theirhosts [14]. For example, vervet, grivet, sabaeus and tantalusmonkeys are all species in the genus Chlorocebus (theAfrican green monkeys, AGM); each has been found toharbour its own form of SIV, and those four viral clades areeach others’ closest relatives [15]. Thus, the commonancestor of the four viral clades may have infected thecommon ancestor of the AGMs, around 3 Myr ago [16]. Onthe other hand, the rate of evolution of HIV-1 has consistentlybeen estimated at around 1–2 10 3 substitutionsper site per year [17], a very fast rate reflecting the errorprone nature of replication using reverse transcriptase andthe rapid rate of viral replication; there is no reason tobelieve that SIVs evolve at a substantially different rate.Using this clock, the time of the common ancestor of allSIVs would be put at only a few hundreds or thousands ofyears ago [18–20]. Thus, here, the co-evolution and molecularclock approaches lead to timescales which differ bythree or four orders of magnitude.The evidence for co-speciation of SIVs with the AGMshas been challenged, based on the lack of a matchbetween the relationships among the four monkeyspecies (from mtDNA) and among the four viral clades[16]. However, concordance of the two phylogenies couldonly be expected if sufficient time elapsed betweensuccessive host speciation events for lineage sorting tohave occurred (Figure 2). In the case of the AGMs, it isevident that this is not the case [16]; indeed, there couldhave been perfect co-speciation of SIV and the AGMs, yetneither the mtDNA nor the viruses may reveal their trueevolutionary history.Recent analysis of SIV strains in monkeys from the islandof Bioko, which became isolated from Africa at least10 000 years ago, has confirmed that molecular clocksunderestimate the timescale of SIV evolution [21 ].Indeed, other evidence has emerged that the lentivirusesoriginated millions of years ago. Endogenous lentiviruseshave been found in the genome sequences of a rabbit [22]and lemurs [23,24]. The rabbit virus is shared by specieswith a common ancestor around 12 Myr ago [25,26]. Thelemur virus is estimated to have entered the genomearound 3 Myr ago [23], and is especially pertinent becauseit is on the same lineage as the SIVs (Figure 3). SinceCurrent Opinion in Virology 2011, 1:436–441Figure 3pSIVSIVcolSIVsunSIVlhoSIVmndSIVtanSIVverSIVsykSIVmonSIVgsnSIVsmmCurrent Opinion in VirologyRelationships among representative primate lentiviruses (adapted fromRef. [23]). The lemur virus (pSIV) is thought to have become endogenousaround 3 Myr ago [23]; all other viruses (SIVs) are from monkey speciesand are exogenous. On biogeographical grounds, it has been suggestedthat the common ancestor (red circle) of the lemur and monkey virusesmay have existed around 14 Myr ago [23]; then, if long-term rates ofdivergence have been approximately clock-like, the common ancestor(yellow circle) of SIVtan and SIVver, from tantalus and vervet monkeys,respectively (two African green monkeys species) was around 3–4 Myrago.lemurs are restricted to Madagascar, unless a virus crossedthe sea in an insect, bat or bird, the common ancestor ofthe lemur virus and the SIVs must have existed at least 14Myr ago [23], consistent with the common ancestor of theSIVs in AGMs dating to around 3 Myr ago (Figure 3).PegivirusesPegiviruses are a newly designated genus within theFlaviviridae [27]. Human pegivirus (HPgV, formerlyGBV-C) is very widely distributed. The most closelyrelated viruses (SPgV) have been found in chimpanzees,and in a number of New World monkeys [28]. Varioushostvirus co-divergence events have been inferred, bothwithin and between species [29]. The different genotypesof HPgV are prevalent in different human populations,and like JCV may have diverged during the emergence ofhuman races [30], while strains of SPgVcpz infectingdifferent chimpanzee subspecies may have split withtheir hosts, up to one million years ago; HPgV andSPgVcpz may have diverged with the ancestors of theirhosts around 7 Myr ago. Finally, the SPgV types found indifferent New World monkey species may have divergedat various time points over the last 20 Myr. The concordancebetween SPgV and New World monkey speciesphylogenies has recently been tested and hostvirus codivergencewas rejected [31]. However, that analysisignored probable cage transmissions and used an apparentlyunreliable host phylogeny (Figure 4). The consensusview of the host relationships exactly matches thewww.sciencedirect.com


Evaluating the evidence for virus/host co-evolution Sharp and Simmonds 439Figure 4HostsVirusesATCJSNSOSMSLSPgV-ATSPgV-CJSPgV-SNaSPgV-SNbSPgV-SOSPgV-SMSPgV-SLaSPgV-SLbCurrent Opinion in VirologyConcordance of phylogenies for SPgV strains (right) and their New World monkey hosts (left). Abbreviations: AT, Aotus trivirgatus; CJ, Callithrixjacchus; SN, Saguinus nigricollis; SO, Saguinus oedious; SM, Saguinus mystax; SL, Saguinus labiatus. The trees are adapted from Ref. [30]. Two virustypes were found in SN and in SL; in each case one type (SNb and SLa) was common, while the other type was found only once — the latter viruses(SNa and SLb) likely reflect recent cross-species transmissions in captivity, and are ringed. Dark red lines connect the other viruses to their hosts.Previously, SO and SL were treated as closest relatives [31,45] yielding a mismatch between the host and virus trees. Here, the relationships amongSaguinus species in the host tree are corrected to the consensus view [46–48], indicating complete concordance between the two phylogenies.virus phylogeny and the evidence for co-divergenceseems quite compelling.Nevertheless, estimates of the rate of HPgV evolution inhumans are consistently high, within the typical range forRNA viruses [31,32]. These molecular clocks would yielddivergence times orders of magnitude more recent thanthe co-divergence scenarios. However, using these ratesto date the deeper divergences within the phylogeny ofHPgV or SPgV seems to yield implausible results. Thevarious human genotypes would be predicted to havearisen around 200 years ago, which makes little senseepidemiologically, requiring a rapid global epidemicspread to even extremely highly isolated human populationsfor which no means is known. Similarly, thecommon ancestor of all pegiviruses in humans and otherprimates would be placed within the last 1000 years,though no plausible transmission route linking all of thesespecies over that time scale is apparent.Concluding remarks and future directionsRecently, numerous additional examples of remnants ofviral genomes incorporated within mammalian genomeshave been described, indicating that several other viralfamilies are much older than had been realised [33–35,36 ,37–39]. Over this longer timescale, co-divergenceof viruses with their hosts may have been much morefrequent than the recent literature would suggest. Theexamples described above indicate that molecular clockapproaches can underestimate, often by orders of magnitude,the ages of ancestral viruses. In the case of JCV itseems likely that the short-term rate of evolution hassimply been overestimated. For SIV and the pegiviruses,short-term rates of evolution are unarguably fast, but therates at which divergence accumulates over the longer termappear orders of magnitude slower — the question is why?Slightly deleterious [40,41 ] or transiently advantageous[42] mutations may contribute to faster short-term rates,but seem unlikely to explain the orders of magnitudedifference from longer-term rates. Another possibility isthat the extent of heterogeneity of rates across differentsites in the viral genome is far more extreme than hasbeen realised; underestimating this heterogeneity canlead to substantial underestimation of the true extentof divergence among more distantly related viruses [19].For example, in at least some positive-strand RNAviruses, genomic RNA forms extensive secondary structurethroughout the genome [43]. Maintenance of thisinternal base pairing provides a selective constraint onsequence changes over and above that due to encodingproteins and dramatically reduces the number of neutralsites. Short-term evolution could involve rapid accumulationof mutations at a very limited number of genomicsites which quickly become saturated with changes, whilelong-term evolution at constrained sites would occur at amuch slower rate. Intriguingly, there seems to be greaterpotential for extensive secondary structure formation inwww.sciencedirect.com Current Opinion in Virology 2011, 1:436–441


440 Virus evolutionRNA viruses that cause persistent infections, includingHPgV [44]. As yet, it is unclear how widespread thisconstraint on viral genomes is, or what fraction of therate disparities it can explain.Irrespective of the underlying mechanisms, however, it isclear that short-term rates of evolution cannot be usedreliably to infer deeper divergence events within viralphylogenies, and longer-term rates must be calibratedseparately.References and recommended readingPapers of particular interest, published within the period of review,have been highlighted as: of special interest of outstanding interest1. Rambaut A: Estimating the rate of molecular evolution:incorporating non-contemporaneous sequences into maximumlikelihood phylogenies. Bioinformatics 2000, 16:395-399.2. Drummond AJ, Ho SYW, Phillips MJ, Rambaut A: Relaxed phylogenetics and dating with confidence. PLoS Biol 2006, 4:e88.A description of the use of Bayesian inference methods to reconstructand date phylogenies while allowing substitution rates to vary amongbranches. These methods have subsequently been used to estimated ofevolutionary timescales for a wide range of viruses.3. Holmes EC: Molecular clocks and the puzzle of RNA virusorigins. J Virol 2003, 77:3893-3897.4.Switzer WM, Salemi M, Shanmugam V, Gao F, Cong ME, Kuiken C,Bhullar V, Beer BE, Vallet D, Gautier-Hion A et al.: Ancient cospeciationof simian foamy viruses and primates. Nature 2005,434:376-380.This was one of the first clear indications that viruses often similar tocurrently circulating strains circulated tens of millions of years ago. Thisdoes not fit the current idea for rapid, sustained diversification of virusesand the use of the molecular clock to date phylogenetic trees.5. Pamilo P, Nei M: Relationships between gene trees and speciestrees. Mol Biol Evol 1988, 5:568-583.6. Nieberding CM, Olivieri I: Parasites: proxies for host genealogy.Trends Ecol Evol 2007, 22:156-165.7. Sugimoto C, Kitamura T, Guo J, Al-Ahdal MN, Shchelkunov SN,Otova B, Ondrejka P, Chollet J-Y, El-Safi S, Ettayebi M et al.:Typing of urinary JC virus DNA offers a novel means of tracinghuman migrations. Proc Natl Acad Sci U S A 1997, 94:9191-9196.8. Agostini HT, Yanagihara R, Davis V, Ryschkewitsch, Stoner GL:Asian genotypes of JC virus in Native Americans and in a Pacificisland population: markers of viral evolution and humanmigration. Proc Natl Acad Sci U S A 1997, 94:14542-14546.9. Hatwell JN, Sharp PM: Evolution of human polyomavirus JC. JGen Virol 2000, 81:1191-1200.10. Shackelton LA, Rambaut A, Pybus OG, Holmes EC: JC virusevolution and its association with human populations. J Virol2006, 80:9928-9933.11. Kitchen A, Miyamoto MM, Mulligan CJ: Utility of DNA viruses forstudying human host history: case study of JC virus. MolPhylogenet Evol 2008, 46:673-682.12. Cann RL, Stoneking M, Wilson AC: Mitochondrial DNA andhuman evolution. Nature 1987, 325:31-36.13. Sharp PM, Hahn BH: Origins of HIV and the AIDS pandemic. Cold Spring Harbor Perspect Med 2011, 1:a006841.This review provides the most detailed account yet for the origin of a virus(HIV-1) and the events in the following century that lead to its globalspread and the current worldwide pandemic.14. Bailes E, Chaudhuri RR, Santiago ML, Bibollet-Ruche F, Hahn BH,Sharp PM: The evolution of primate lentiviruses and the originsCurrent Opinion in Virology 2011, 1:436–441of AIDS.In The Molecular Epidemiology of Human Viruses. Editedby Leitner T. Boston: Kluwer Academic Publishers; 2002:65-96.15. Jin MJ, Hui H, Robertson DL, Muller MC, Barre-Sinoussi F,Hirsch VM, Allan JS, Shaw GM, Sharp PM, Hahn BH: Mosaicgenome structure of simian immunodeficiency virus fromwest African green monkeys. EMBO J 1994, 13:2935-2947.16. Wertheim JO, Worobey M: A challenge to the ancient origin ofSIVagm based on African green monkey mitochondrialgenomes. PLoS Pathog 2007, 3:e95.17. Korber B, Muldoon M, Theiler J, Gao F, Gupta R, Lapedes A,Hahn BH, Wolinsky S, Bhattacharya T: Timing the ancestor of theHIV-1 pandemic strains. Science 2000, 288:1789-1796.18. Sharp PM, Li W-H: Understanding the origins of AIDS viruses.Nature 1988, 336:315.19. Sharp PM, Bailes E, Gao F, Beer BE, Hirsch VM, Hahn BH: Originsand evolution of AIDS viruses: estimating the time-scale.Biochem Soc Trans 2000, 28:275-282.20. Wertheim JO, Worobey M: Dating the age of the SIV lineagesthat gave rise to HIV-1 and HIV-2. PLoS Comp Biol 2009,5:e1000377.21.Worobey M, Telfer P, Souquiere S, Hunter M, Coleman CA,Metzger MJ, Reed P, Makuwa M, Hearn G, Honarvar S et al.:Island biogeography reveals the deep history of SIV. Science2010, 329:1487.This and the previous paper highlight the uncertainty over dating times ofvirus divergence; resolution of their conflicting conclusions is central tothe issues discussed in the current review.22. Katzourakis A, Tristem M, Pybus OG, Gifford RJ: Discovery andanalysis of the first endogenous lentivirus. Proc Natl Acad Sci USA2007, 104:6261-6265.23. Gifford RJ, Katzourakis A, Tristem M, Pybus OG, Winters M,Schafer RW: A transitional endogenous lentivirus from thegenome of a basal primate and implications for lentivirusevolution. Proc Natl Acad Sci U S A 2008, 105:20362-20367.24. Gilbert C, Maxfield DG, Goodman SM, Feschotte C: Parallelgermline infiltration of a lentivirus in two Malagasy lemurs.PLoS Genet 2009, 5:e1000425.25. van der Loo W, Abrantes J, Esteves PJ: Sharing of endogenouslentiviral gene fragments among leporid lineages separatedfor more than 12 million years. J Virol 2009, 83:2386-2388.26. Keckesova Z, Ylinen LMJ, Towers GJ, Gifford RJ, Katzourakis A:Identification of a RELIK orthologue in the European hare(Lepus europaeis) reveals a minimum age of 12 million yearsfor the lagomorph lentiviruses. Virology 2009, 384:7-11.27. Stapleton JT, Foung S, Muerhoff AS, Bukh J, Simmonds P: The GBviruses: a review and proposed classification of GBV-A, GBV-C (HGV), and GBV-D in genus Pegivirus within the familyFlaviviridae. J Gen Virol 2011, 92:233-246.28. Bukh J, Apgar CL: Five new or recently discovered (GBV-A)virus species are indigenous to New World monkeys and mayconstitute a separate genus of the Flaviviridae. Virology 1997,229:429-436.29. Simmonds P: The origin and evolution of hepatitis viruses inhumans. J Gen Virol 2001, 82:693-712.30. Tanaka Y, Mizokami M, Orito E, Ohba K-I, Nakano T, Kato T,Kondo Y, Ding X, Ueda R, Sonoda S et al.: GB virus C/hepatitis Gvirus infection among Colombian native Indians. Am J TropMed Hyg 1998, 59:267-462.31. Romano CM, de Zanotto PM, Holmes EC: Bayesian coalescentanalysis reveals a high rate of molecular evolution in GB virusC. J Mol Evol 2008, 66:292-297.32. Nakao H, Okamoto H, Fukuda M, Tsuda F, Mitsui T, Masuko K,Iizuka H, Miyakawa Y, Mayumi M: Mutation rate of GB virus C/hepatitis G virus over the entire genome and in subgenomicregions. Virology 1997, 233:43-50.33. Gilbert C, Feschotte C: Genomic fossils calibrate the long-termevolution of hepadnaviruses. PLoS Biol 2010, 8:e1000495.www.sciencedirect.com


Evaluating the evidence for virus/host co-evolution Sharp and Simmonds 44134. Belyi VA, Levine AJ, Skalka AM: Unexpected inheritance:multiple integrations of ancient bornavirus and ebolavirus/marburgvirus sequences in vertebrate genomes. PLoS Pathol2010, 6:e1001030.35. Taylor DJ, Leach RW, Bruenn J: Filoviruses are ancient andintegrated into mammalian genomes. BMC Evol Biol 2010,10:193.36. Katzourakis A, Gifford RJ: Endogenous viral elements in animal genomes. PLoS Genet 2010, 6:e1001191.A systematic and comprehensive analysis of a wide range of RNA andsmall DNA viruses integrated into mammalian genomes and the implicationsthese findings have for our understanding of the true evolutionaryages of variants within several virus families.37. Horie M, Honda T, Suzuki Y, Kobayashi Y, Daito T, Oshida T,Ikuta K, Jern P, Gojobori T, Coffin JM, Tomonaga K: Endogenousnonretroviral RNA virus elements in mammalian genomes.Nature 2010, 463:84-87.38. Kapoor A, Simmonds P, Lipkin WI: Discovery andcharacterization of mammalian endogenous parvoviruses. JVirol 2010, 84:12628-12635.39. Johnson WE: Endless forms most viral. PLoS Genet 2010,6:e1001210.40. Sharp PM, Bailes E, Chaudhuri RR, Rodenburg CM, Santiago MO,Hahn BH: The origins of acquired immune deficiency viruses:where and when? Philos Trans R Soc Lond B 2001, 356:867-876.41.Pybus OG, Rambaut A, Belshaw R, Freckleton RP, Drummond AJ,Holmes EC: Phylogenetic evidence for deleterious mutationload in RNA viruses and its contribution to viral evolution. MolBiol Evol 2007, 24:845-852.A useful attempt to resolve discrepancies in short- and long-term rates ofsequence change through the hypothesis that much of the rapid diversificationof viruses (and high measured substitution rates) reflects theappearance of transient deleterious mutations that are later purged bypurifying selection.42. Davenport MP, Loh L, Petravic J, Kent SJ: Rates of HIV immuneescape and reversion: implications for vaccination. TrendsMicrobiol 2008, 16:561-566.43. Simmonds P, Tuplin A, Evans DJ: Detection of genome-scaleordered RNA structure (GORS) in genomes of positivestrandedRNA viruses: implications of rvirus evolution andhost persistence. RNA 2004, 10:1337-1351.44. Davis M, Sagan SM, Pezacki JP, Evans DJ, Simmonds P:Bioinformatic and physical characterization of genome-scaleordered RNA structure in mammalian RNA viruses. J Virol2008, 82:11824-11836.45. Jacobs SC, Larson A, Cheverud JM: Phylogenetic relationshipsand orthogenetic evolution of coat color among tamarins(genus Saguinus). Syst Biol 1995, 44:515-532.46. Cropp SJ, Larson A, Cheverud JM: Historical biogeography oftamarins, genus Saguinus: the molecular phylogeneticevidence. Am J Phys Anthropol 1999, 108:65-89.47. Araripe J, Tagliaro CH, Rego PS, Sampaio I, Ferrari SF,Schneider H: Molecular phylogenetics of large-bodiedtamarins, Saguinus spp. (Primates, Platyrrhini). Zool Scr 2008,37:461-467.48. Surridge AK, Mundy NI: Trans-specific evolution of opsin allelesand the maintenance of triochromatic colour vision inCallitrichine primates. Mol Ecol 2002, 11:2157-2169.www.sciencedirect.com Current Opinion in Virology 2011, 1:436–441

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