Evidence for Archaic Asian Ancestry on the Human X Chromosome

14 Pages·2004·0.19 MB·English

by  Dan Garrigan

LETTER
Evidence for Archaic Asian Ancestry on the Human X Chromosome
Daniel Garrigan,* Zahra Mobasher,* Tesa Severson,* Jason A. Wilder,* and
Michael F. Hammer*(cid:1)
*Division of Biotechnology, and(cid:1)Department ofEEB, University of Arizona, Tucson
ThehumanRRM2P4pseudogenehasapatternofnucleotidepolymorphismthatisunlikeanylocuspublishedtodate.A
gene tree constructed from a 2.4-kb fragment of the RRM2P4 locus sequenced in a sample of 41 worldwide humans
clearlyrootsinEastAsiaandhasamost-recentcommonancestorapproximately2Myrbeforepresent.Thepresenceof
thisbasallineageexclusivelyinAsiaresultsinhighernucleotidediversityamongnon-AfricansthanamongAfricans.A
global survey of a single-nucleotide polymorphism that is diagnostic for the basal, Asian lineage in 570 individuals
shows that itoccurs at frequencies upto 53% in south China, whereas only one of 177surveyed Africans carries this
archaic lineage. We suggest that this ancient lineage is a remnant of introgressive hybridization between expanding
anatomically modern humans emerging fromAfrica andarchaic populationsin Eurasia.
Introduction
Recently,Hammeretal.(2004)analyzedglobalhuman size,weestimatedtheparameter,h (¼3N l,whereN is
ml e e
nucleotidevariationat15X-linkedloci,oneofwhichstands theeffectivepopulationsizeandlisthemutationrate),by
out as unique in its pattern of polymorphism. In a global generatingasingle-likelihoodcurvecoveringawiderange
sample of 41 individuals, sequence variation at the ribo- of possible values. Based on this value of h , we then
ml
nucleotidereductaseM2subunitpseudogene4(RRM2P4)is estimatedtheN andTMRCA.TheG/Asingle-nucleotide
e
partitionedintotwodivergent,basallineages.Bothofthese polymorphismatposition2020wasgenotypedinasample
lineagesarefoundinAsia,whereasonlyoneisfoundinsub- of570Africans andnon-Africans with theTaqMangeno-
Saharan Africa (fig. 1B). The two lineages differ by five typing assay (Applied Biosystems, Foster City, Calif.),
fixedmutations,leadingtoanestimateforthetimetoamost- followingthemanufacturer’sprotocol.Thesampleincluded
recentcommonancestor(TMRCA)thatisapproximately2 22KhoisanfromNamibia,39DogonfromMali,47Bantu
Myrbeforepresent(B.P.).Suchlongbasalbranchesofthe from South Africa, 25 Bakola from Cameroon, 44 Dinka
globalRRM2P4genealogyarenotexpectedunderaneutral fromSudan,46Mongolians,40SriLankans,11Tibetans,
panmicticmodel(Wall1999,2000).Moreover,agenetree 48 Baining from New Britain, 26 Japanese, 28 Han from
that roots in Asia has not been previously observed in northernChina,30YaofromsouthernChina,28Altaians,
publishedhumannucleotidepolymorphismdatasets(e.g., 24PapuaNewGuineans,45ItaliansfromcentralItaly,39
Takahata,Lee,andSatta2001)andraisesintriguingques- Dutch,and27Iranians.Allsamplingprotocolswerecarried
tionsconcerningtheorigin andexpansion ofanatomically outwiththeapprovaloftheUniversityofArizonaHuman
modern humans. In this paper, we explore the possibility SubjectsCommittee.
thatpolymorphismatRRM2P4recoversahistoryofadmix-
ture between Homo sapiens and an archaic Asian form of
Results and Discussion
Homo before the latter went extinct in the late Middle
Pleistocene(Swisheretal.1996). Figure1Adepictsthe13polymorphicsitesweobserve
inatotalof2,385bpofRRM2P4sequence,andtable1lists
summarystatisticsforthelocus.Althoughlevelsofnucleo-
Methods
tide diversity are only slightly higher than the genomic
The methodology and samples used to assay nucleo- average (Yu et al. 2002), RRM2P4 is one of the few sur-
tide polymorphism at the RRM2P4 locus has been pre- veyed loci that exhibits more variation in non-Africans
viously reported by Hammer et al. (2004). Summary thaninAfricans.ItisworthnotingthatthisRRM2pseudo-
statistics were calculated with the computer application geneislocatedinaregionwithahighrateofcrossing-over
DnaSPversion3.99(Rozasetal.2003).TheTMRCAwas (;3.6cM/Mb)andalowgenedensityonXq27.3(Hammer
estimatedbydividingtheobservednetpairwisenucleotide et al. 2004). Despite its genomic context, our 2.4-kb frag-
differencesbetweenlineages(D [Nei1987])bytwicethe ment shows no direct evidence of historical recombina-
A
mutation rate. We also used a maximum-likelihood ap- tionbythefour-gametetestofHudsonandKaplan(1985).
proachtoestimatetheTMRCAwiththecomputerprogram This result is not unexpected, because complete linkage
GENETREE version 9.0 (Griffiths 2002). Using the null disequilibrium is known to extend beyond 2.4 kb in both
demographic model of panmixia and constant population African and non-African populations (Reich et al. 2001).
However, this lack of recombination does permit recon-
structionofasingle,nonreticulatinggenetree(fig.1B).The
Key words: hybridization, human origins, polymorphism, popula-
genomic context of RRM2P4 makes it less likely that the
tionsubdivision,pseudogene.
elongatedbasalbranchesaretheresultoflinkagetoafunc-
E-mail:[email protected].
tional site(s) subject to some form of balancing selection.
Mol.Biol.Evol.22(2):189–192.2005 Additionally, there are more restricted conditions for
doi:10.1093/molbev/msi013
AdvanceAccesspublicationOctober13,2004 a X-linked balanced polymorphism compared with the
Molecular Biology and Evolution vol. 22 no. 2 (cid:1) Society for Molecular Biology and Evolution 2005; all rights reserved.
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190 Garriganetal.
FIG.1.—(A)Sequencesand(B)genetreefortheeightRRM2P4haplotypes.Scalebardenotestimeinunitsofmillionsofyearsbeforepresent.
Mutationsarelabeledwithadotalongtheedgesofthegenealogyandareplacedaccordingtothemaximum-likelihoodestimateoftheirrespectiveages.
BelowthetipsofthegenetreearethemultiplicitiesofeachhaplotypeinboththeAfricanandthenon-Africansamples.
autosomes (Hedrick and Parker 1997). Indeed, the fre- givenabovewithanaverageof8.25nucleotidedifferences
quency spectrum of mutations at RRM2P4 does not reject observed between the two human RRM2P4 lineages, then
the null hypothesis of neutral mutation-drift equilibrium we can estimate that the two lineages diverged approx-
(Tajima’sDstatistic¼20.206,P¼0.489)(table1). imately 1.96 MYA. This estimate is in reasonable
Outgroup sequencing reveals that there are 18 nucle- agreement with a TMRCA of 2.44 Myr B.P. obtained
otide substitutions between human RRM2P4 sequences fromthecoalescent-basedmaximum-likelihoodmethodof
and one common chimpanzee (Pan troglodytes) sequence Griffiths(2002),whichassumesapanmicticpopulationof
and 62 substitutions between human sequences and one constantsize(fig.1B).Thisplacesthemost-recentcommon
orangutan (Pongo pygmaeus) sequence. The human- ancestor ofRRM2P4 in the late Pliocene,a time when the
chimpanzee comparison yields a neutral mutation rate of genus Homo first appears in the fossil record (Wood and
7.4310210 substitutions per site per year (assuming a 6 Collard 1999). The maximum-likelihood method also
Myr human-chimpanzee divergence time). This rate is estimates that the effective population size of RRM2P4 is
onlyslightlyslowerthanthemean15-locusratecalculated approximately 25,000. Two other surveyed X-linked loci
with the data of Hammer et al. (2004) of 8.4310210 per (DMD44 and PDHA1) yield comparably large TMRCAs
siteperyear.Utilizingsequencefromallthreespecies,the andeffectivepopulationsizes(Hammeretal.2004;Harris
relativeratetestofTajima(1993)doesnotrejectaconstant and Hey 1999) and may also provide evidence of ancient
rate of nucleotide substitution at the RRM2P4 locus (v2¼ population structure (Harding 1999).
0.39, P¼0.532). If we combine the neutral mutation rate The Asian RRM2P4 lineage is found exclusively in
three of 31 sampled non-Africans (a Japanese, a Chinese,
Table 1 and a Melanesian individual), whereas the other, more
Estimates ofPopulation Genetic Parameters forthe diverse, lineage constitutes the entirety of African and the
RRM2P4 Locus majority of non-African variation. To obtain a better
estimate thefrequency ofthe Asian lineage andto test for
Population n S h (%) p(%) D
W
itspresenceinAfrica,wegenotypedtheSNPoccurringat
Global 41 13 0.127 0.119 20.206
position2020(fig.1A;alsoseeMethods)inatotalsample
Africans 10 6 0.089 0.090 0.068
Non-Africans 31 11 0.115 0.124 0.224 of 570 African and non-African individuals representing
17populations.Figure2showstheobservedgeographical
NOTE.—n is the number of individuals sampled; S is the number of distribution of the Asian lineage. There appears to be a
polymorphicsites;hWisWatterson’s(1975)estimateof3Nmpernucleotidesite decreasingfrequencygradientcenteredonsouthernChina,
(N is the effective population size and m is the neutral mutation rate); p is the
averagenucleotideheterozygosity;D–Tajima’s(1989)neutralitystatistic. wheretheAsianlineagereachesamaximumof53%inthe
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AncientHumanSubdivision 191
FIG. 2.—Geographical distribution of the archaic RRM2P4lineage in 17 populationsamples.Frequencydata canbe foundin Supplementary
Materialonline.
Yao of southern China and 29% in the Han Chinese. The lineageisfoundatlessthan1%inAfricanpopulations.The
Asian lineage is present in only one of 177 sampled distributionoftheAsianlineagestronglysuggestsanAsian
Africans (0.6%). This geographical pattern is consistent originbutshouldnotbetakenasdefinitiveproofthatitdid
with a Southeast Asian origin of this 2-Myr-old lineage. notoriginate inAfrica. The Asian lineageappears tohave
If we accept that the mutations occurring at the diverged from the globally distributed portion of the
RRM2P4 locus are selectively neutral (and, therefore, genealogy approximately 2MYA. It is interesting to note
influenced only by demographic history), then there are that this estimated divergence time is concordant with the
two alternative explanations for its unusual pattern of age of the oldest Homo erectus fossils found outside of
polymorphism. The first alternative is that the long basal Africa (Gabunia et al. 2000). Following further lines of
branches are simply the chance result of genetic drift in a investigation, if panmixia at the RRM2P4 locus can be
large,panmicticancestralpopulation.Itispossiblethatthe rejected,itwouldhaveimportantimplicationsforourview
divergent, basal lineage was carried out of Africa and ofHomosapiensasaspecies.Anydegreeofdualancestryin
subsequently lost in Africa and/or increased in frequency the modern human genome would either demonstrate that
in Asia by genetic drift. Second, it may be the result of thetransitiontoananatomicallymodernformdidnotoccur
recent admixture between two divergent populations; that inanisolated,panmicticpopulation(Cann,Stoneking,and
is, the expanding anatomically modern human population Wilson 1987) or that replacement of preexisting hominid
and Homo erectus. Distinguishing between these two populations was incomplete (e.g., Brauer 1989; Smith,
alternatives provesdifficult, giventhelowpowerafforded Falsetti,andDonnelly1989).
by any single locus (Nordborg 2000; Wall 2000). To
achieve greater single-locus power, it is preferable to
examinepatternsofpolymorphismoverphysicaldistances Acknowledgments
approximately 20 to 30 kb in length (Wall 2000).
WethankJ.WallforhisfruitfulcollaborationandR.
Sprissler for assistance with SNP genotyping. We also
thank Tanya Karafet, Dashtseveg Tumen, Giovanni
Conclusion
Destro-Bisol, Himla Soodyall, Andrea Novelleto, Peter
Polymorphism occurring at the RRM2P4 locus is de Knijff, Beverly Strassmann, William Wang, Jonathan
unique in that it clearly roots in East Asia, has an ancient Friedlaender, and Du Ruofu for providing DNA samples.
TMRCA,and also yields higher non-African than African Publicationofthisworkwasmade possible bygrant GM-
nucleotidediversity.OurSNPassayestimatesthattheAsian 53566 from the National Institute of General Medical
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192 Garriganetal.
Sciences (to M.F.H.). Its contents are solely the respon- Nordborg, M. 2000. On detecting ancient admixture. Genes,
sibility of the authors and do not necessarily reflect the fossils, and behaviour: an integrated approach to human
official views of the National Institutes of Health. evolution. IOSPress, Amsterdam.
Reich,D.E.,M.Cargill,S.Bolketal.(11co-authors).2001.Linkage
disequilibriuminthehumangenome.Nature411:199–204.
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