Transmission between Archaic and Modern Human Ancestors during the Evolution of the ...

16 Pages·2016·0.67 MB·English

Transmission between Archaic and Modern Human Ancestors
during the Evolution of the Oncogenic Human Papillomavirus 16
Ville N. Pimenoff,*,1,2 Cristina Mendes de Oliveira,1,3 and Ignacio G. Bravo1,4
1InfectionsandCancerLaboratory,CancerEpidemiologyResearchProgramme,CatalanInstituteofOncology,Barcelona,Spain
2UnitofBiomarkersandSusceptibility,BellvitgeInstituteofBiomedicalResearch(IDIBELL),Barcelona,Spain
3VirologyLaboratory,InstituteofTropicalMedicine,UniversityofS~aoPaulo,S~aoPaulo,Brazil
4MIVEGEC(UMRCNRS5290,IRD224,UM),NationalCenterforScientificResearch(CNRS),Montpellier,France
*Correspondingauthor:E-mail:[email protected].
Associateeditor:BethShapiro
Abstract
D
Everyhumansuffersthroughlifeanumberofpapillomaviruses(PVs)infections,mostofthemasymptomatic.Anotable o
w
exception are persistent infections by Human papillomavirus 16 (HPV16), the most oncogenic infectious agent for nlo
a
humansandresponsibleformostinfection-drivenanogenitalcancers.Oncogenicpotentialisnothomogeneousamong d
e
HofPVth1e6HlinPeVa1g6ese,vaonldutgioenneatriychvaisrtioartyionwawsitshtiinllHwPaVn1ti6nge.xhWibeithsasovemaengaeloygzeradphexictasntrtuHctPuVre1.6Hdoiwveervseirt,yaannidn-cdoemptphaarendalythsies d from
evolutionary and phylogeographical patterns of humans and of HPV16. We show that codivergence with modern h
ttp
humans explains at most 30% of the present viral geographical distribution. The most explanatory scenario suggests s
thatancestralHPV16alreadyinfectedancestralhumanpopulationsandthatvirallineagesco-divergedwiththehostsin ://a
c
a
parallelwiththesplit betweenarchaicNeanderthal-Denisovansandancestralmodernhumanpopulations,generating d
e
m
the ancestral HPV16A and HPV16BCD viral lineages, respectively. We propose that after out-of-Africa migration of
ic
modern human ancestors, sexual transmission between human populations introduced HPV16A into modern human .o
u
p
ancestorpopulations.WehypothesizethatdifferentialcoevolutionofHPV16lineageswithdifferentbutcloselyrelated .c
o
ancestralhumanpopulationsandsubsequenthost-switcheventsinparallelwithintrogressionofarchaicallelesintothe m
/m
genomes of modern human ancestors may be largely responsible for the present-day differential prevalence and asso- b
e
ciationwithcancersforHPV16variants. /a
rtic
Keywords:divergence,evolutionarymedicine,Homininevolution,host-switch,humanpapillomavirus,infectionand le
cancer,sexuallytransmittedinfection,variant,virus-hostcoevolution. -ab
s
tra
c
t/3
4
Introduction /1
A /4/2
Virus lifestyle shapes viral population structure through es- HumanPVs(HPVs)infectdividingepithelia,andvirtuallyall 6
r 8
t sential virus life traits, such as infectivity, immunogenicity, humansarehoststoavariablenumberofHPVsinfectionsat 08
i 0
cle laantdendcuy,ratrtaionnsmoifsstihoenirnafteec,tmionut(aSthioanrpra2t0e,0v2i)r.ioTnhepriondteurcatcitviiotyn, csiutetasn(eMouase(tAanlt.o2n0s1so4)n. eTthael.v2i0ra0l3)inbfeucttioofntendoaelssonaottmkuilclotshael 0 by g
u
between the virus and the host’s immune system strongly targetcellandinmostcasesPVscancompletetheirlifecycle e
s
influences viral evolution: immune memory reduces the andbemaintainedasachronic,asymptomaticinfectionwith t o
n
numberofsusceptiblehosts,anddifferentialimmunerecog- viral genomes remaining episomally as plasmids in the in- 1
0
nition and response against different pathogen phenotypes fectedcell(Doorbaretal.2012).Insomecases,theycancause A
p
F mayfavourselectionofcertainvirallineages(Holmes2008). productive, wart-like lesions or even be involved in certain ril 2
a Finally,theevolutionaryhistoryofthehostconstrainsfurther cancers(Doorbaretal.2012).Thefinebalancebetweenviral 01
9
s the population structure of the virus. Thus, for viruses and replicationandhostimmunetolerancesuggestsalongcoex-
t
hostswithalongsharedevolutionaryhistory,theviruspop- istence between PVs and their hosts, and indeed ancestral
T
ulationisshapedbypopulation-levelprocessesofgeneticdrift PVsprobably infectedtheancestralamniotes(Garc(cid:2)ıa-Vallve´
r
a andnaturalselection,inboththevirusandthehostpopula- et al. 2005) and possibly all bony vertebrates (L(cid:2)opez-Bueno
c tions(Holmes2008). etal.2016).TheevolutionofPVsinmammalslikelystarted
k
Papillomaviruses(PVs)havealongcommonhistorywith with an initial adaptive radiation event that generated a
amniotes (Bravo and Fe´lez-S(cid:2)anchez 2015). PVs are double- handful of viral crown groups, linked to the evolution of
strandedDNAviruses,withacirculargenomeofabout8kb. mammalian fur and skin glands (Gottschling et al. 2011;
More than 300 PVs have been described and above 200 of Bravo and Fe´lez-S(cid:2)anchez 2015). This diversification was fol-
themhavebeenretrievedfromhumans(Bzhalavaetal.2015). lowedbylimitedhost-linkedevolutionandencompassedalso
(cid:2)TheAuthor2016.PublishedbyOxfordUniversityPressonbehalfoftheSocietyforMolecularBiologyandEvolution.
ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommonsAttributionNon-CommercialLicense
(http://creativecommons.org/licenses/by-nc/4.0/),whichpermitsnon-commercialre-use,distribution,andreproductioninany Open Access
medium,providedtheoriginalworkisproperlycited.Forcommercialre-use,[email protected]
4 Mol.Biol.Evol.34(1):4–19 doi:10.1093/molbev/msw214 AdvanceAccesspublicationOctober7,2016
MBE
Origin,Evolution,andDispersalofHPV16 . doi:10.1093/molbev/msw214
incomplete lineage sorting and host-switch events thecontinent.ThevirallineageHPV16CDgaveriseinallop-
(Gottschlingetal.2007;Gottschlingetal.2011).Atshallower atry to the HPV16C variant in Africa and to the HPV16D
evolutionarytimescale,ithasbeencommonlyassumedthat variant outside Africa. Later, the interbreeding events be-
HPV16 has co-diverged with modern human populations, tweenNeanderthalandDenisovanpopulationswithmodern
based on certain geographical structure of HPV16 variant human ancestor populations lead to a host-switch through
distribution (Bernard 1994; Cornet et al. 2012), but this hy- sexualtransmissionoftheHPV16Aviruslineagefromarchaic
pothesishasneverbeenrigorouslytested. populationsintothemodernhumanancestors.TheHPV16A
Infections by anogenital HPVs are very common: >80% lineage thus transmitted expanded rapidly in the new host
ofallsexuallyactiveadultsareinfectedbyoneoftheseHPVs populations and became dominant in Eurasia and in the
at least onceintheir lifetime(Einstein etal.2009; Chesson Americas.
etal.2014),andthetimepointprevalenceofcervicalHPVs
infectionsinsexuallyactivehealthywomenisestimatedto
Results
bearound12%(Brunietal.2010)orevenhigherinyounger
D
women (Molden et al. 2016). At least 12 evolutionarily re- HPV16Phylogeography o
w
lated HPVs are carcinogenic to humans (Bouvard et al. Weinferredthephylogeneticrelationshipamongallavailable, n
lo
2009),causingdifferentfractionsofanogenitalandoropha- non-recombinant HPV16 genomes (n¼118) under maxi- ad
e
ryngealcancers(Moscickietal.2012).HPV16isnotonlythe mum likelihood (ML) framework for both the full-genome d
most prevalent HPV in infection-associated cancers of the alignment (supplementary material S1, Supplementary fro
m
cervix,vulva,vagina,anus,penis,andoropharynx(Moscicki Materialonline)andforthecodingregionalignment(supple h
etal.2012)butalsothemostprevalentHPVinfectionofthe mentary material S2, see also supplementary table S1, ttps
genitaltractoccurringasymptomaticallyinhealthyindivid- Supplementary Material online). Phylogenetic inference re- ://a
c
a
uals(Brunietal.2010).WithintheHPV16lineage,distribu- covered all previously reported HPV16 variant lineages, and d
e
tion of genetic diversity presents certain geographic weretainedforsubsequentanalysisHPV16A1-3,A4,B,C,and m
ic
structure,withdifferentHPV16variantsshowingdifferential D lineages, all supported by >98% bootstrap values for the .o
u
prevalence in different geographical regions (Cornet et al. full-genome alignment (fig. 1A and supplementary fig. S1, p.c
o
2012). Furthermore, the oncogenic potential is not homo- Supplementary Material online). Pairwise distances under m
geneous for all HPV16 variants (Schiffman et al. 2010) and ML were significantly larger (2.28 times, 95% confidence in- /m
b
e
variesinassociationwithdifferenthumanpopulations(Villa terval [CI], 1.88–2.69; Wilcoxon–Mann–Whitney test P¼2. /a
etal.2000;Berumenetal.2001;Burketal.2003;Xietal.2006; 2e–16) for the full-genome than for the selection-filtered rtic
le
Zuna et al.2011; Cornet et al. 2013).Such differential con- alignment (supplementary fig. S2, Supplementary Material -a
b
nection between viral phylogeography and oncogenic po- online). s
tential might indicate that the evolution of HPV16 lineage To assess HPV16 phylogeography, we analyzed a total of trac
hasbeenatleastpartly shaped by the differential host im- 1,719HPV16isolatecases(alignmentsavailableassupplemen t/34
muneresponse. tary materials S3–S4, Supplementary Material online) by /1/4
Inthisstudy,wehaveanalyzedhumanandvirusgenomic complementing the 118 HPV16 full-genome sequences /26
8
datatoinfertheevolutionaryhistoryofHPV16.Thecommon with 1,601 partial HPV16 isolate sequences spanning the 0
8
0
understandingabouttheevolutionofHPVsisthatthemod- LCR, the E6 oncogene, and the L2 capsid gene. A total of 0
b
ern repertoire of diverse HPVs has coevolved with modern 1,680globalHPV16isolatesequenceswithknowngeograph- y
g
humansasahostpopulation,sothatthecurrentgeographic ical origin could be unambiguously assigned to a precise u
e
s
distribution of HPVs reflects modern human migration dis- HPV16 lineage using an evolutionary placement algorithm t o
n
persalpatterns(Hoetal.1993;Bernard1994).Here,weshow (supplementary table S2, Supplementary Material online). 1
0
forthefirsttimethatdifferentialcoevolutionofHPV16line- Phylogeography of the 1,680 isolate cases showed that the A
p
ageswithdifferentbutcloselyrelatedancestralhumanpop- HPV16A1-3lineagepredominatedinEurope,SouthAsia,and ril 2
ulations together with recent host-switch events may be Central/South America, and was also present in all other 0
1
largelyresponsibleforthepresent-daydifferentialprevalence continental subgroups, albeit with very low prevalence in 9
and association with cancers for HPV16 variants. The most sub-SaharanAfrica(fig.2).HPV16A4wasthemostprevalent
parsimonious interpretation of our results requires that the lineageinEastAsiaandwasalsopresentinNorthAmerica,
ancestorofHPV16alreadyinfectedtheancestralhumanpop- but was virtually absent elsewhere. Variants B and C were
ulations>500thousandsyearsago(kya).Thesplitbetween largely restricted to Africa and were especially prevalent in
Neanderthals/Denisovansandmodernhumanancestorpop- Sub-Saharan Africa, although they were also observed in
ulations was mirrored by a split in the viral populations, NorthAmerica.VariantDwaspresentinallcontinents,dis-
namely HPV16A, carried by ancestral human populations, playinglowprevalenceinSub-SaharanAfrica,andthehighest
and HPV16BCD, carried by the populations of modern hu- frequencyinCentral/SouthAmerica.
manancestorsinAfrica.Afterthelastout-of-Africamigration To explain the evolution and diversity of HPV16 and to
event60–120kya,themodernhumanancestorpopulations inferitsorigins,weexploredthedifferentialfittothedataof
thatleftAfricacarriedareducedsampleoftheviraldiversity twoalternativescenarios:1)therecent-out-of-Africa(ROOA)
in the continent: the HPV16B lineage remained in African model of exclusive codivergence for HPV16 with modern
populations but was lost by lineage sorting in those leaving human populations and 2) the Hominin-host-switch (HHS)
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MBE
Pimenoffetal. . doi:10.1093/molbev/msw214
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FIG.1.Phylogenetictreeofthe118HPV16completegenomes.(A)UnrootedMLphylogenetictreeinferredusingthecompletecodingregionalignment m h
afterexcludingatotalof26positivelyselectedand115negativelyselectedcodons.Thefinalalignmentencompassed118sequences,6,093bpand316 ttp
sduisbtsinticttuatiloignnsmpeenrtnpuactleteortnids.eBsoitoet.s(tBra)pMsauxpimpourmtafctleard5e0c0reredpibliicliattyetsriesegiinvefenrrfeodrbforarnscehleecstiloeand-fiinltgetreodthHePAV11–63g,eAn4o,mB,eCc,oanddinDgrveagriioanntalliingenamgeesn.tScuanledebratrhine s://ac
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HHSscenario,9.6(cid:2)10(cid:3)9[5.5(cid:2)10(cid:3)9–13.6(cid:2)10(cid:3)9]subs/site/yrassubstitutionratepriorandenforcingtwotimepointcalibrations:archaicHominin d
e
divergenceat500kya(95%CI,400–600kya)andrecentmodernhumanmigrationout-of-Africaat90kya(95%CI,60–120kya).Scalebarinmillionsof m
ic
yearsago.Nodebarsindicatethe95%probabilityintervalsforthecorrespondingnodeage. .o
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FspIGe.c2ifi.cPHhyPlVog1e6ovgarraipanhticlidniesatrgiebu(steioenthoeftchoelo1r,6c8o0dHinPgVfo16rAse1q–u3e,nAc4e,sBe,nCc,oamndpaDssvianrgiatnhtesL).CTRh,eE6siazendofLt2hgeepnioemchealortcsi.isEapcrhopseoqrtuioenncaeltwoatshaessniugnmebdetrooaf pril 2
0
sequencesfromthecorrespondinggeographicregion(supplementarytableS3,supplementarymaterialonline). 19
model, including a viral transmission between archaic and To test the explanatory power of the ROOA model, we
ancestral modern human populations. On the one hand, analyzed the correlation between geography-based popula-
the ROOA scenario required exclusive codivergence of tionstructureofmodernhumansandofHPV16bycompar-
HPV16lineageswithmodernhumandispersals.Ontheother inggeneticdistancesbetweengeographicallydefinedhuman
hand,theHHSscenarioimpliedanancestralvirus-hostcodi- metapopulationswiththegeneticdistancesbetweenHPV16
vergenceepisodeduringthesplitbetweenHomosapiensand isolates.Weusedninepreviouslydescribedmetapopulation
H. neanderthalensis lineages,followedby morerecent trans- groups(supplementarytableS3,SupplementaryMaterialon-
missioneventsbetweenNeanderthals/Denisovansandmod- line),excludingNorthAmericaduetolackofhumangenome
ern human ancestors (fig. 3). Both scenarios are plausible data, and tested the correlation between the F distance
ST
giventhetopologyofthephylogeneticrelationshipsbetween matrices for humans and for HPV16 (supplementary fig.S3,
HPV16 lineages (fig. 1) and the impossibility to root the SupplementaryMaterialonline).Weobservedindeedcorre-
HPV16treeusingextantHPVssequences. lation between both matrices, but geographical structure
6
MBE
Origin,Evolution,andDispersalofHPV16 . doi:10.1093/molbev/msw214
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FIG.3.Timelineofdivergenceforarchaicandmodernhumanancestors,andforHPV16.(A)Datedandclassification-confirmedHomininfossil
taxa(lightgreenrepresentsuncertainclassification,asreviewedbyScallyandDurbin2012).(B)Phylogeneticrelationshipofmodernhuman,
NeanderthalandDenisovanpopulations.VerticalarrowsindicatetheproposedinterbreedingandsubsequentgeneflowfromtheNeanderthal
and Denisovan populations to the ancestors of present-day modern humans. The evolutionary relationships between Neanderthals and
Denisovansarestillunresolved(Sawyeretal.2015;StringerandBarnes2015).(C)Phylogeneticrelationshipsfor118selection-filteredHPV16
codinggenomesequencesusingmaximumcladecredibilitytreeundertheHomininhost-switchscenario.Bluebarsindicatethe95%probability
intervalsforthecorrespondingnodeage.Arrowsindicatethenodesusedforcalibration.
acrossdifferenthumangenomelociexplained<30% ofthe Notably,mostoftheEuropeanandsub-SaharanAfricanas-
worldwide HPV16 geographical structure (table 1, see also certainedautosomalhumangenomeloci variability showed
supplementary table S4, Supplementary Material online). significant but limited (<30%) correlation with the HPV16
7
MBE
Pimenoffetal. . doi:10.1093/molbev/msw214
Table1. Mantel’sPermutationTestforSimilarityofF DistanceMatricesbetweenHPV16andHumanGenomeSequenceDataSets.
ST
Selection-filtered Includingpositionsunderselection
Taxa Loci Region/SNPs n Correlation(%)a P-valueb FDRc Correlation(%)a P-valueb FDRc
mtDNA 1 16kbgenome 875 12.4 0.037 0.017 15.8 0.026 0.018
NRY 1 5,000kb 551 8.5 0.062 0.028 11.8 0.044 0.036
Europe chr1 6,353 773 8.8 0.062 0.029 12.7 0.033 0.026
Europe chr2 5,918 773 6.3 0.091 0.040 9.6 0.054 0.040
Europe chr3 5,325 773 8.8 0.063 0.032 12.7 0.037 0.030
Europe chr4 4,211 773 8.9 0.063 0.030 12.7 0.036 0.029
Europe chr5 4,743 773 5.6 0.104 0.047 8.7 0.061 0.047
Europe chr6 4,736 773 6.3 0.095 0.041 9.5 0.055 0.042
Europe chr7 4,162 773 5.2 0.112 0.048 8.1 0.062 0.048
Europe chr8 3,750 773 8.0 0.070 0.036 11.6 0.045 0.037
Europe chr9 3,222 773 8.8 0.064 0.033 12.7 0.038 0.033 D
o
Europe chr10 4,223 773 9.2 0.059 0.026 13.1 0.035 0.028 w
Europe chr11 3,850 773 5.9 0.099 0.046 9.2 0.058 0.046 nlo
Europe chr12 3,339 773 5.1 0.116 0.049 8.0 0.066 0.049 ad
e
Europe chr13 2,234 773 5.8 0.098 0.045 9.2 0.057 0.045 d
Europe chr14 2,307 773 5.9 0.097 0.043 9.3 0.056 0.043 fro
Europe chr15 2,346 773 6.2 0.096 0.042 9.3 0.054 0.041 m
h
Europe chr16 2,636 773 7.5 0.078 0.038 11.1 0.045 0.038 ttp
Europe chr17 2,109 773 6.8 0.084 0.039 10.1 0.045 0.039 s
Europe chr18 2,243 773 9.8 0.056 0.025 13.9 0.033 0.025 ://a
c
Europe chr19 1,175 773 3.9 0.139 0.050 6.5 0.085 0.050 ad
Europe chr20 2,067 773 9.9 0.055 0.023 13.8 0.031 0.021 em
Europe chr21 973 773 10.0 0.055 0.024 14.1 0.031 0.022 ic
.o
Europe chr22 1,141 773 7.7 0.073 0.037 11.6 0.042 0.034 u
p
.c
NOTE.—HPV16sequencedata(1,192bp)encompassingLCR(735bp)andE6(457bp)regionsfor1,101worldwideisolateswereusedinthecorrelations.mitochondrialDNA om
(mtDNA);nonrecombiningpartoftheYchosomosome(NRY);autosomalSNPdatastratifiedbychromosomeandascertainedusingaEuropean(Europe)ancestrydata /m
(autosomalSNPdataascertainedusingasub-SaharanancestrydataisprovidedinsupplementarytableS8,supplementarymaterialonline).Forbothdatasetsninegeographic b
e
metapopulationsweredefined:North/East/West/SouthernAfrica,SouthAsia,EastAsia,Europe,CentralandSouthAmerica(supplementarytableS2andS5.supplementary /a
amRa2toefritahleoncolinrree)l.ationcoefficient. rticle
bMantel-testafter10,000permutations. -a
b
cFalsediscoveryratecontrollingprocedure(q¼0.05). s
tra
c
LCR-E6variability.Veryinterestingly,afterexcludingthesites obtainedafterforcingourtwoalternativescenarios,namely, t/34
/1
under selection in the HPV16 E6 gene only the correlation theHHSandROOAmodels,differedby<0.01%,andneither /4
with the mitochondrial genome variability and most of the theShimodaira–HasegawatestnortheRobinson–Fouldssplit /26
8
sub-Saharan African but not of the European ascertained method showed significant differences between both topol- 0
8
0
autosomalgenomedataremainedsignificant,andaccounted ogies.WhenintroducingtimeintotheBayesian(BEAST)phy- 0
b
forbarely 15% oftheglobal distributionofHPV16 diversity. logenetic analyses without imposing any prior on tree y
g
Nevertheless,itisimportanttonotethataftercontrollingfor topology, the same (A,(B,(C,D))) topology (i.e., the HHS ue
s
falsediscoveryratenoneofthehumangenomeandofHPV16 model) was systematically the preferred one for both t o
n
correlationsshowedtobesignificant. HPV16completeandHPV16selection-filteredcodingregion 1
0
alignments (supplementary fig. S4, Supplementary Material A
p
TimeInferenceforHPV16Diversification online). The combined difference in topology and branch ril 2
ToestimatedivergencetimesforHPV16diversificationunder lengthbetweentreesobtainedwiththefull-lengthandwith 0
1
the two alternative evolutionary scenarios, we applied a the selection-filtered alignments was very small (as assessed 9
Bayesian Markov chain Monte Carlo (MCMC) inference. by a K-score<0.004) (supplementary table S5,
First, we tested whether we could accurately identify the SupplementaryMaterialonline).Weresortedthentodated
rootoftheHPV16genomediversitybyperformingphyloge- BayesianMCMCinferenceforidentifyingthemoreplausible
neticinferenceincorporatingthemostcloselyrelatedHPVs, between the two alternative evolutionary scenarios. For the
members of Alphapapillomaviruses species 9. The long evo- HHSscenario,weusedthearchaicHominindivergenceat500
lutionary distances between these viruses and HPV16 pre- kya (95% CI, 400–600 kya, see references in Materials and
vented unambiguous identification of the root of HPV16 Methods)tocalibratethetimeforthemostrecentcommon
lineages, with either ML (RAxML) or Bayesian (Phylobayes) ancestor (tmrca) of extant HPV16 lineages, as well as the
approaches (supplementary fig. S4, Supplementary Material recent modern human migration out-of-Africa at 90 kya
online). In all reconstructions, the preferred topology was (95% CI, 60–120 kya, see references in Materials and
(A,(B,(C,D))), which corresponded to the HHS scenario. Methods)tocalibratethetmrcaoflineagesHPV16CandD.
Nevertheless, the likelihood values for the HPV16 trees For the ROOA scenario, we used the recent migration
8
MBE
Origin,Evolution,andDispersalofHPV16 . doi:10.1093/molbev/msw214
out-of-Africawiththesame90-kyasettingsasabovebutinthis HPV16 isolates showed higher average number of pairwise
casetocalibratethetmrcaofallHPV16lineages.Bothstrictand differencescomparedwithsub-SaharanAfricanisolates,even
relaxed clock were tested for all MCMC calibrations and the after accounting for intralineage diversity. Furthermore, to
best log-likelihood value using Bayes Factor (2lnBF) was ob- estimatethegeographicaloriginoftheHPV16E6genehap-
tainedforrelaxedclock(2lnBF>38).Thedemographicmodels lotypediversity,weconstructedamedian-joininghaplotype
ofexponentialgrowthorofBayesianskylineforthepopulation network for the E6 gene sequences (table 5, see also supple
function of the coalescent tree prior yielded in both cases mentaryfig.S7,SupplementaryMaterialonline).Twoofthe
growthratesconsistentlyabovezero,excludingthusconstant most common HPV16A1-3 lineage E6 haplotypes were ob-
population size as a model. In addition, Bayesian skyline plot servedinEurasianisolatebackground,andonly1–3%ofthese
estimating changes in effective population size through time common haplotypes originated from sub-Saharan African
showedasignificantincreaseoftheHPV16populationinthe isolates.Incontrast,themostfrequentHPV16BandCvariant
last12kya(supplementaryfig.S5,SupplementaryMaterialon- E6haplotypeswereobservedin>92%ofAfricanisolateback-
line).Forfinalanalyses,weusedtheevolutionarymodelsand ground.ThemostcommonHPV16DE6haplotypedisplayed
D
priors showing the best performance, namely, relaxed log- the highest frequency (58%) in the American isolate back- o
w
normal molecular clock and a Bayesian skyline coalescent ground and the lowest (4–5%) in North and sub-Saharan n
lo
model(2lnBF>83).Comparisonofdivergencetimeestimates Africanisolates.ThesecondmostcommonHPV16DE6hap- ad
e
betweentheHHSandROOAscenariosforHPV16evolutionis lotypeshowedthehighestfrequency(58%)inNorthAfrican d
presented in table 2. For the analyses based on the positions isolates, intermediate frequencies in Eurasian and in fro
m
evolving neutrally, the log-marginal likelihoods showed the Americanisolates(18%and21%,respectively)andverysmall h
highest value and strongest support (2lnBF¼8.9) for the (3%)ofthesub-SaharanAfricanisolatebackground. ttps
HHS scenario with a substitution rate18.4 (cid:2) 10(cid:3)9 (95% CI, ://a
c
14.3 (cid:2)10(cid:3)9–22.1 (cid:2) 10(cid:3)9) subs/site/yr. For the analyses that ad
Discussion e
included the positions under selection, the HHS model was m
ic
againthepreferredmodelalbeitwithasubstitutionratetwo HPV16 is the most oncogenic virus for humans, and epide- .o
u
times higher. The log-marginal likelihood value for the HHS miological evidence suggests that its oncogenic potential is p.c
o
scenarioincludingthepositionsunderselectiondidnotsignif- associatedwithhighviralloadsandwithinfectionpersistence m
icantlydifferfromthatfortheROOAmodel(2lnBF¼1.2)al- (Doorbar et al. 2012; Moscicki et al. 2012). Viral genotypic /m
b
e
though the inferred evolutionary rate in the case of ROOA variation may underlie strong phenotypic variation so that /a
modelneededtobearoundfivetimeshigher.Maximumclade differentHPV16variantsmaydisplaydifferentialpersistence rtic
le
credibility tree inferred for selection-filtered HPV16 genome and viral load and therefore differential carcinogenicity. -a
b
codingregionalignmentundertheHHSscenarioandenforcing Several reports have communicated differential oncogenic s
thetwoHHSmodeltimepointcalibrationsispresentedinfig potential for different HPV16 variant lineages (Villa et al. trac
1B.Furthermore,toestimatewhetherourtimepointcalibra- 2000; Schiffman et al. 2010; Zuna et al. 2011; Freitas et al. t/34
tionshadanimpactonthedivergencetimeestimates,wealso 2014). However, the differential risks for different variants /1/4
performedMCMCanalysiseitherbyimposingtheHHSmodel seem to depend on the host population (Cornet et al. /26
8
topologyorwithoutimposinganypriorontreetopologyand 2013; Qmichou et al. 2013), and to vary with the specific 0
8
0
withoutusinganytimepointcalibrations(table3).Depending individual genetic background (Xi et al. 2006; Lopera et al. 0
b
onsubstitutionratepriors,divergencetimesofextantHPV16 2014). In the present study, we have addressed the origin, y
g
lineagesshowedtobebetween260kyaand4.8Ma.Inallcases, diversification, and dispersal of HPV16. We have used the u
e
s
thepreferredmodelwastheHHSscenario.AlthoughHPV16A largest available collection of HPV16 full-length genomes t o
n
was thus always the basal clade, divergence within HPV16A and partial sequences to generate estimates of the world- 1
0
showed to belower than within HPV16BCD (supplementary widephylogeographyanddivergencetimeofextantHPV16 A
p
fig.S6,SupplementaryMaterialonline). lineages. Our results support a scenario of codivergence of ril 2
HPV16withseparatebutcloselyrelatedancestralHominin 0
1
VariationwithintheHPV16E6Oncogene populations with subsequent host-switch events, likely 9
ToinvestigategeographicaldifferencesinHPV16geneticdi- through sexual transmission between archaic and modern
versity, we estimated summary statistics within each geo- human ancestral populations in the recent human evolu-
graphic HPV16 population using all 1,123 available HPV16 tionary history. We have further compared the genetic di-
nearly complete E6 sequences (table 4). Overall, HPV16 E6 versitypatternsofHPV16withthoseestimatedformodern
geneticdiversitywashighestoutsidesub-SaharanAfrica.Both humanpopulationsusinggenomedata.Altogether,ourre-
Tajima’sDandFu’s-Li’sDstatisticsaswellasthemorerobust sults suggest that virus-host coevolution and host switch
R2 index showed statistically large negative values for events have been fundamental factors that have shaped
European isolates, suggesting past selective sweeps and/or HPV16evolution.
population expansion, for HPV16 population in Europe Purifyingselectioncanmasktheancientoriginofrecently
only. HPV16 E6 haplotype diversity was similar in sub- sampledpathogens(WertheimandKosakovskyPond2011),
SaharanAfrica,Europe,andSouthAmericaandsignificantly andourresultspointinthesamedirection.Resultsbasedon
higher in North Africa and Central America than in sub- onlyHPV16genomepositionsevolvingneutrallyshowedsig-
Saharan Africa (table 4). East Asian and Central American nificantly better fit to the data for our HHS model while
9
MBE
Pimenoffetal. . doi:10.1093/molbev/msw214
nome kya) HPD) –129)–124)–144)–201)–128)–312)–115)–56)–148)–138)–173)–232)–132)–319)–115)–58)
Ge D( 5% (82(76100158(75(95(53(14106(95131189(80111(54(17
d C 9 (( ( 88 (
n-Filtere tmrca mean( 1051011221801011978534127116152(214(1052098436
o
plete(Full)orSelecti tmrcaBCD(kya) mean(95%HPD) 197(121–293)184(109–273)250(158–360)408(267–575)185(105–280)311(157–471)134(72–203)54(24–87)246(164–343)216(140–300)330(212–455)411(320–498)186(110–271)320(176–473)130(73–193)55(27–88)
m
HPV16Co A1–4(kya) (95%HPD) (48–133)(42–123)(80–190)(284–578)(40–128)(55–206)(23–91)(9–38)(101–200)(79–166)(167–324)(518–705)(53–142)(78–240)(31–100)(12–44) Download
erredfor tmrca mean 8778130423791255422147120240616951566327 ed from h
Ago(kya)Inf ABCD(kya) (95%HPD) (365–561)(358–553)(396–580)(488–655)(357–5559)(389–587)(92–346)(54–115)(387–568)(364–551)(431–607)(571–727)(346–544)(390–586)(99–322)(54–115) ttps://academ
ofYears tmrca mean 4614564845714574902108547645951965044649019984 parison. ic.oup.c
usands 2lnBF Ref6.815.9180.510.510.912.58.94.7Ref44.9383.15.81.111.2 BF)com om/mb
dDivergenceTimeEstimateswithHighestProbabilityDensity(HPD)inThoeHHSortheROOAScenarios,andConsideringDifferentPriors. 9(cid:3)RateuniformpriorData10(subs/site/yr)Log(cid:2)marginal 9(cid:3)m10(subs/site/yr)(95%HPD)likelihood(cid:2) a(cid:2)Neutral18.4(14.5–22.1)12476.94PVsestımate[13.2–24.7](cid:3)bNeutral20.3(16–25.1)12480.34HumanmtDNA[17.6–32.3](cid:3)cPVsestimate[5.5–13.6]Neutral12.8(11.1–14.3)12484.91(cid:3)dNeutral3.6(3.1–4.1)12567.19Mammalgenome[2.0–2.4](cid:3)4.5-4.5E–11Neutral20.2(14.0–26.8)12482.18(cid:3)4.5-4.5E–11Neutral13.6(8.1–20.3)12482.41(cid:3)4.5-4.5E–11Neutral32.1(17.0–49.6)12483.21(cid:3)4.5-4.5E–11Neutral80.5(40.3–128)12481.41(cid:3)a(cid:2)PVsestımate[13.2–24.7]Full22.9(20.3–25.3)19313.69(cid:3)bHumanmtDNA[17.6–32.3]Full27.5(23.5–31.0)19311.33(cid:3)cFull14.4(13.1–15.8)19333.81PVsestimate[5.5–13.6](cid:3)dFull4.6(4.0–5.2)19502.91Mammalgenome[2.0–2.4](cid:3)4.5-4.5E–11Full33.9(24.4–43.4)19314.23(cid:3)4.5-4.5E–11Full22.0(13.2–31.2)19311.87(cid:3)4.5-4.5E–11Full55.0(31.8–82.9)19311.82(cid:3)4.5-4.5E–11Full130.6(71.8–206.0)19311.94(cid:3) thebest-supportedmodels,takenasreference(Ref)forthepathsamplingBayesfactor(2ln e/article-abstract/34/1/4/2680800 by guest on 10 April 2019
Table2.SubstitutionRateanAlignment(Neutral),underth ModelCalibration HHSHHS2calibHHSHHS2calibHHSHHS2calibHHSHHS2calibHHSHHS2calibHHSHHS1calib500kyaHHSHHS1calib90kyaROOA90kyaHHSHHS2calibHHSHHS2calibHHSHHS2calibHHSHHS2calibHHSHHS2calibHHSHHS1calib500kyaHHSHHS1calib90kyaROOA90kya N.—LikelihoodvaluesinboldareOTEaRectoretal.(2007).bFuetal.(2014).cShahetal.(2010).dKumarandSubramanian(2002).
10
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Origin,Evolution,andDispersalofHPV16 . doi:10.1093/molbev/msw214
Table3.SubstitutionRateandDivergenceTimeEstimateswithHighestProbabilityDensity(HPD)inThousandsofYearsAgo(kya)InferredforHPV16Complete(Full)orSelection-FilteredGenomeAlignment(Neutral)EitherundertheHHSScenarioorwithoutImposingAnyPrioronTreeTopology,andwithoutUsingAnyTimePointCalibrations,andUsingInsteadOnlySubstitutionRatePriors. 9(cid:3)DataModelCalibrationUniformprior10(subs/site/yr)tmrcaABCD(kya)tmrcaA1-4(kya)tmrcaBCD(kya)tmrcaCD(kya)(cid:2) 9(cid:3)m10(95%HPD)Mean(95%HPD)Mean(95%HPD)Mean(95%HPD)Mean(95%HPD)(cid:2)(subs/site/yr) 18.0(12.5–23.8)581(298–911)188(109–278)391(221–589)261(146–392)FullNotopologyNocalibPVsestimateaNeutralNotopologyNocalib18.2(12.4–24.4)340(168–573)90(46–141)231(121–355)156(83–247)[13.2–24.7]NeutralHHSNocalib18.2(12.4–24.2)361(178–592)92(50–147)228(123–353)145(81–222)23.6(16.4–31.1)440(223–693)142(85–214)296(167–442)198(112–296)FullNotopologyNocalibHumanmtDNAbNeutralNotopologyNocalib24.0(16.4–31.7)258(124–420)68(37–107)175(94–269)118(61–186)[17.6–32.3]NeutralHHSNocalib23.9(16.4–31.6)273(136–444)70(37–108)173(95–271)110(60–167)9.0(5.2–12.8)1181(532–2037)384(201–627)803(400–1330)536(267–870)FullNotopologyNocalibPVsestimatecNeutralNotopologyNocalib9.1(5.2–13.2)698(296–1228)185(85–313)185(86–312)317(145–539)[5.5–13.6]NeutralHHSNocalib9.1(5.2–13.1)742(324–1297)189(90–320)469(220–791)298(141–493)2.1(1.8–2.4)4819(2914–7086)1564(1077–2133)3249(2108–4458)2177(1466–3015)FullNotopologyNocalibMammalgenomedNeutralNotopologyNocalib2.1(1.8–2.5)2863(1576–4415)755(457–1086)1919(1206–2741)1301(784–1916)[2.0–2.4]NeutralHHSNocalib2.1(1.8–2.4)3010(1686–4582)767(475–1123)1900(1187–2738)1208(761–1691) aRectoretal.(2007).bFuetal.(2014).cShahetal.(2010).dKumarandSubramanian(2002). Table4.SummaryStatisticsoftheHPV16GeneSequences(1,123)withGeographicOriginoftheSample.E6n¼ ababcbbbbbbMetapopulationbpShHd(95%CI)(95%CI)MPD(95%CI)(95%CI)WIMPTajima’sD-value(95%CI)-valueFu’s-Li’sD*(95%CI)-valueR2(95%CI)-valuenPPPP >21345634320.754(0.712(0.4393.049(2.739(0.8151.459–1.4270.1(–1.6420.047–3.459(–2.1780.0030.044(0.0330.100sub-SaharanAfrica–0.796)–0.892)–3.359)–7.389)to2.053)to1.523)–0.148)>(0.6534.985(4.52(1.5430.969–0.1960.1(–1.5980.519–3.288(–1.9590.4660.081(0.0350.533NorthAfrica22145630260.861(0.839–0.883)–0.918)–5.45)–12.592)to2.097)to1.311)–0.14)<Europe16145631250.734(0.688(0.161.62(1.401(0.1941.187–2.0430.05(–1.620.001–3.825(–1.9580.0020.026(0.0280.017–0.78)–0.838)–1.839)–4.219)to2.05)to1.447)–0.164)>SouthAsia139456860.523(0.455(0.0560.998(0.831(0.0430.464–0.7240.1(–1.5090.253–0.454(–2.3020.2810.062(0.0260.302–0.591)–0.797)–1.165)–2.744)to2.026)to1.297)–0.193)>(0.4953.425(3.079(0.8531.7121.2110.1(–1.5930.091–2.848(–2.4150.0140.054(0.0320.180EastAsia20745631370.643(0.567–0.719)–0.894)–3.771)–8.014)to2.11)to1.606)–0.146)>5045621140.889(0.851(0.5894.551(3.641(1.1971.803–0.2370.1(–1.683Central0.475–1.027(–2.5680.1670.103(0.0520.503America–0.927)–0.925)–5.461)–10.979)to2.033)to1.511)–0.177)>13240218170.78(0.744(0.4863.184(2.774(0.7720.947–0.0960.1(–1.6130.526–0.850(–2.3710.1850.087(0.0350.542SouthAmerica–0.816)–0.893)–3.594)–7.859)to1.896)to1.543)–0.156) N.—Numberofsamples(),basepair(bp),Segregatingsites(S),haplotypes(h),haplotypediversity(Hd),meanpairwisedifference(MPD),weightedintralineagemeanpairwisedifference(WIMP)(Hurlesetal.2002),Tajima’sD,Fu’sandLi’sD*nOTEandR2statisticswerecalculatedusingDnaSP(LibradoandRozas2009).aCalculcatedfromempiricaldistribution.bCalculatedfromacoalescentsimulationwith1,000replicationsandnorecombination.cCalculatedassumingbetadistribution. Downloaded from https://academic.oup.com/mbe/article-abstract/34/1/4/2680800 by guest on 10 April 2019
11
MBE
Pimenoffetal. . doi:10.1093/molbev/msw214
Table5. HPV16E6GeneMajorHaplotypeFrequencieswithinEachLineageandGeographicalBackground.
Origin A1–3a A1–3b A4 B C D
n % n % n % n % n % n % n %
America 50 19.5 40 19.0 2 1.5 1 1.2 4 2.6 45 57.7 8 21.1
Eurasia 177 68.9 118 56.2 127 98.5 1 1.2 7 5.0 26 33.3 7 18.4
NorthAfrica 27 10.5 46 21.9 — — 4 4.7 53 37.6 4 5.0 22 57.9
Sub-SaharanAfrica 3 1.2 6 2.9 — — 79 92.9 77 54.6 3 3.8 1 2.6
aMajorhaplotypeincludingHPV16E6350Gallele.
bMajorhaplotypeincludingHPV16E6350Tallele.
analysesincludingpositionsunderselectionstillpreferredthe limitationsoftheavailabledatatocomparethehumange-
HHS model but could not differentiate the two alternative nome and of HPV16 genetic diversity restrained us from D
o
scenarios, namely, the ROOA and the HHS model, tested in further estimations of local adaptation between virus and w
n
thisstudy(table2).Moreimportantly,ourMCMCinference hostgenomes.Nevertheless,undertheROOAscenario,one loa
d
showedthatirrespectiveoftheevolutionaryratepriorused, would have expected a consistently high correlation be- e
d
divergence times for extant HPV16 lineages largely predate tween human and viral phylogeography. Instead, several fro
m
theestimatedrecentout-of-Africamigrationofmodernhu- lines of evidence argue further against this ROOA scenario h
manancestors60–120kya.Furthermore,althoughHPV16Ais forHPV16.First,theHHSscenarioispreferredoverROOAin ttp
s
theoldestlineage,thetmrcafortheHPV16BCDvariants(197 terms of HPV16 lineage phylogeny (supplementary fig. S6, ://a
kya,95% HPD121–291kya)wasolderthanthetmrcaforthe Supplementary Material online). Second, the hypothesis of ca
d
HPV16A lineage (88 kya, 95% HPD 50–134 kya), and the exclusivecodivergenceofallHPV16lineageswiththeances- em
HPV16Alineageencompasseslessgeneticdiversitythanthe tral dispersals of modern humans does not explain the ic
.o
sister HPV16BCD lineages. Taken together, the lower diver- largelypredominantroleofHVP16A(fig.2),themostbasal up
.c
gencewithinHPV16A,thegoodmatchforthetmrcaofthis HPV16lineage,inallcontinentsandinallindigenouspop- o
m
lineagewiththeout-of-Africamigrationofmodernhumans ulations, except in sub-Saharan Africa (Picconi et al., 2003; /m
b
and the delayed expansion of HPV16A reinforce the HHS Cornetetal.2012;Mendozaetal.2013;Qmichouetal.2013; e
/a
scenario: the exceptional interbreeding events between ar- Tanetal.2013;Loperaetal.2014).Moreover,forindigenous rtic
chaic and modern human populations resulted in a strong populations in South America, for instance, the increased le
-a
bottleneck for the transmission of HPV16A, so that only a presenceofHPV16Alineagevariantshasbeenproposedto b
s
small fraction of the HPV16A diversity available in the reflecttheinfluenceofrecentEuropeanoccupation(Picconi tra
c
Neandertal/Denisovan populations underwent effectively a et al. 2003). However, such a rapid selective sweep of the t/3
4
horizontal transfer toward populations of ancestral modern putative pre-Columbian HPV16A genetic diversity would /1
/4
humans. require strong selection forces for the viral dynamics in /2
6
Mountingevidencesuggeststhatvirus-hostcodivergence very short time scale, which are not compatible with our 8
0
8
is not the only essential driving force for PV evolution. At current understanding of PV evolution (Bravo and Fe´lez- 0
0
highertaxonomiclevelsvirus-hostco-phylogenyeventsex- S(cid:2)anchez 2015). Third, the geographical dichotomy for the b
y
plainonlyaround30%ofthePVevolutionaryhistory,while HPV16 E6 gene haplotype backgrounds consistently sup- g
u
e
additionaleventsoflineagesorting,lineageduplicationand ported our HHS model over ROOA: most common s
t o
hostswitchhaveplayedmajorrolesduringtheevolutionof HPV16A lineage haplotypes were observed mostly in n
1
PVs(Gottschlingetal.2011).Inthepresentstudy,wehave EurasianpopulationswhilemostcommonHPV16B,C,and 0
A
quantified for the first time that codivergence between DlineagehaplotypeswereobservedmainlyinAfricanpop- p
modernhumansandHPV16explains<30%ofthecurrent ulations(table5).Andfourth,whilehumangeneticdiversity ril 2
0
geographicaldistributionoftheviralextantdiversity,largely is highest in sub-Saharan Africa (1000 Genomes Project 19
basedonthevirtualabsenceofHPV16BandHPV16Cline- Consortiumetal.2015),ourresultsofHPV16E6variability
agesoutsideAfricaandontheenrichmentofHPV16Aand showedconsistentlyhighergeneticdiversityestimatesout-
HPV16D outside Africa (fig. 2). The contribution of virus- sidesub-SaharanAfrica(table4).
hostcodivergencetoHPV16evolution,regardlessofexclud- AfterrejectingtheROOAmodelasexplanatoryframework
ingtheviralcodingregionsitesunderselection,showedto for HPV16 evolution, we have explored the HHS model as
beconsistentonlyformitochondrialgenomevariabilityand alternative scenario, implying a host switch of an ancestral
lessconsistentusingEuropeanascertainedautosomalsingle HPV16lineagebetweenarchaicandmodernhumanancestral
nucleotide polymorphisms (SNPs) compared with sub- populations(fig.4).Indeed,recentgenomicstudieshavecon-
SaharanAfricanascertainedautosomalSNPs.Itistempting firmed the admixture of modern human ancestors with
to speculate that this difference in consistency might be Neanderthals and Denisovans through repeated interbreed-
partly due to the SNPs introgressed from archaic popula- ing after migration to Europe and Asia, respectively (Reich
tions into the genomes of non-African modern humans. et al. 2010; Lazaridis et al. 2014; Qin and Stoneking 2015;
However, the underlying biological complexities and Vernot and Akey 2015). Such interbreeding events lead to
12
MBE
Origin,Evolution,andDispersalofHPV16 . doi:10.1093/molbev/msw214
ancestral Hominin populations remaining in Africa, instead,
would have lead to HPV16B and CD lineages (fig 4). The
virtualabsenceofHPV16BoutsideSub-SaharanAfricaispar-
simoniously explained if in the last out-of-Africa expansion,
the modern human ancestors that left Africa probably lost
the ancestral HPV16B lineage by a lineage sorting event
(Johnsonetal.2003).Similarpatternofvirusextinctionafter
hostpopulationbottleneckhasbeenobservedinnon-human
primates(Kapusinszkyetal.2015).Afterthemodernhuman
dispersal, the HPV16CD ancestor generated in allopatry the
HPV16ClineageinthepopulationsremaininginAfrica,and
theHPV16DlineageinthepopulationsoutsideAfrica(fig.4).
DuringtheirexpansioninEuropeandinAsia,modernhuman
D
ancestors experienced limited admixture with Neanderthal o
w
and Denisovan populations and were exposed to the n
lo
HPV16A lineage, most likely through sexual contact. After ad
e
the adaptive introgression of Neanderthal-Denisovan alleles, d
anatomicallymodernhumansofnon-Africanancestrycarry fro
m
nowadaysinaveragebetween2%and4%oftheirgenomesof h
archaic human origin (Meyer et al. 2012; Pru¨fer et al. 2014). ttps
Remarkably, the horizontal transfer of genetic loci upon in- ://a
c
a
terbreeding ofNeanderthal/Denisovanancestryintothege- d
e
nomeofmodernhumanancestorsdidnotoccuratrandom m
ic
(Vernot and Akey 2014; Kuhlwilm et al. 2016; Vernot et al. .o
u
2016).Instead,genesinvolvedinkeratinocytedifferentiation p.c
o
and innate immunity, which are loci directly involved in m
host–PVinteraction,areparticularlyenrichedinintrogressed /m
b
e
genomic loci, displaying >60% of Neanderthal/Denisovan /a
ancestry in present day Eurasians (table 6) (Abi-Rached rtic
le
et al. 2011; Sankararaman et al. 2014; Vernot and Akey -a
b
2014; Vernot et al. 2016). Such genetic changes possibly al- s
tered the HPV16-human interplay, as this virus exclusively trac
FIG. 4. Cartoon timeline depicting interbreeding and subsequent infectskeratinocytesinparticularepitheliaandrequiresker- t/34
gmlineonedaeegflrenotwohuotmhfeaarnacsnhcaaeincsdtaoltrlheseleospfrfmroopomodseeNrdneashneuxdumearatlhntarpalsnoaspmnudliasDstiiooennnissooifnvHaEnPusVrai1ns6tiAao. avtiriinooncyptreoddiuffcetrieonnti(aDtiooonrbtoaraectcoaml.2p0li1sh2)t.hHeevnicrue,swlifeescpyeccleualantde /1/4/26
8
thattheadaptiveintrogressioninmodernhumansofarchaic 0
VirallineagesHPV16A,B,C,andDarelabeledatthebottom. 8
0
allelesinvolvedinkeratinocytedifferentiationandinnateim- 0
b
adaptive introgression of genetic material from our closest munitymayhaveelicitedchangesintheecologicalnicheof y
g
evolutionaryrelativesintothegenomeofasubsetofmodern HPV16 that significantly enhanced the adaptive value of u
e
s
human ancestors. We propose here that in parallel to the HPV16Aandleadtoincreasedprevalenceofthisvirallineage t o
n
introgressionofgeneticmaterial,sexualintercoursebetween inmodernhumanpopulationswithEurasianorigin(figs.2,3B 1
0
Neanderthals/Denisovansandmodernhumanancestorsalso andC,and4). A
p
promptedsexualtransmissionofPVs,chieflyoftheHPV16A Takentogether,ourHHSevolutionarymodelprovidesex- ril 2
lineage(fig.4).OurresultsonHPV16phylogeography,genetic planatorypotentialforthethreecentralflawsofthealterna- 0
1
diversity, and tmrca of the different HPV16 lineages sustain tive ROOA scenario for the evolution of HPV16, namely, 1) 9
thisHHSscenario,inwhichthedivergenceofextantHPV16 the distant phylogenetic relationship between HPV16A and
lineages (ca. 460 kya, table 2) predates the recent out-of- HPV16BCD clades (fig. 1A and B), which predates the most
Africa migration of modern human ancestors (fig. 3), and recent out-of-Africa migration of modern human ancestors
thus, ancestral HPV16 lineages probably already infected (table3);2)theglobalincreasedprevalenceofHPV16Aout-
theancestral,closelyrelatedHominingroups.Thehostsplit sideAfrica(fig.2),and3)theincreasedviralgeneticdiversity
betweentheancestralarchaic(Neanderthal/Denisovan)and outsidesub-SaharanAfrica (table4). In agreement with our
themodernhumanancestorpopulationswasprobablymir- HHS model, recent studies of parasites evolution have con-
roredbyaviralsplitresultingintheancestralHPV16Alineage cludedthatthedivergenceofatleastfivepresentdayhuman
andoftheancestralHPV16BCDlineage,respectively(fig.3B parasites(lice,tapeworm,folliclemites,aprotozoan,andbed-
and C). Among the recurrent out-of-Africa expansions of bug)predatesmodernhumanorigin.Themostlikelyexpla-
ancestral Hominin groups, which may have occurred some nationforthepresenceofthesecloselyrelatedancientpairs
460 kya, Neanderthals/Denisovans may have carried essen- ofparasitetaxainvolveshostswitchfromanarchaictomod-
tiallytheancestralHPV16A.EvolutionofHPV16genomesin ern human ancestors (Ashford 2000; Reed et al. 2004).
13