CCD CD CD CD CD CD CDTe Myt oEve: Molecular ________0Bioogyand uman Origins = H *30

Francisco J. Ayala HsI P0039

It has been proposed that modern humans descended from a single woman, the "mi- chimpanzeepa'so(Pt)tDNseuences. THe)segmetsotochondrial Eve" who lived in Africa 100,000 to 200,000 years ago. The human immune coimparzedae 270

DNnuceoties.Thamke upgmexntsystem DRBl genes are extremely polymorphic, with gene lineages that coalesce into an 2 of the DRB1I gene. The differences hetweenancestor who lived around 60 million years ago, a time before the divergence of the apes sequences are represented hy vertical hars.from the Old World monkeys. The theory of gene coalescence suggests that, throughoutthe last 60 million years, human ancestral populations had an effective size of 100,000 other two( gecnes, Hs"0302 and Pt*0302, areindividuals or greater. Molecular evolution data favor the African origin of modern humans, also miore similar to o)ne another than tobut the weight of the evidence is against a population bottleneck before their emergence. I1sIIs 103 or Pt*0309, and they are alsoThe mitochondrial Eve hypothesis emanates from a confusion between gene genealogies pa,ired In Fig. 21. Thei two) douiblets are theni-and individual genealogies. IInked to Indicate that all fouir tienes deriveC

fromi ai commiioti ancestral genie. Branchlen-gthis calm be made proportional to rhe11number itf nuc leot ide Changes that o)ccurred

Thei DNA of trganisms embo)(dies v,irttially ancestor. Othier mi-ntatiOns are- favo)red_ by in each b-ranch, as in-ferred fromi- Table I.unrlimited Ino rmation aboUt thieir eVoLu- natural setecthinm becauISe theyC~ benefit the One m)otew( irthy property Of theISe fouirtionary history. The informnation is ecoded(I(- organilsm. Somie o)f these muLtations Spread geneIs is) thalt the two) humian sequtences areInI thelinea111C-Sequence o)f the fouLr nueLCICo - amon(g the 1individtiLalS and aICCUmuIlate In mo1re different fromi o)ne another thanride comiponencits o)t DNA (adenine, Cy- thei Specie, aInd th-is process is AlSo rime-i- eaich is from on(e chimpne ee Hence,tosine, guanline, and thymiine) in thei samei dependent. The reguLIlarity of thei pirocess b)y the lineage(is o)f thei two( htniman genes cdi-falshion as semantic information is ecoI(ded which nulotICAide Substitutions o)ccur maiikes Verged fromi each o)ther miore than 6 mil-in the SequenceIC oletrofaEnistx. it possible to recconstruiCt thec historical reLa lion yeCars ago (Ma), thec approximate timeiMOleCuLaLr evolution invecstigatio)ns o)f DNA tionts amIOng Species and also to aissign dlares wheni the lineages of htimans and chiml-SequencIAes ha~ve been largely directed to- to reClevant events. That is, theire is a miolec- panze--es diverged. Thei ancient o)riginl Ofward reconstruLCting thei phylogeny (evo()lu- ULar- clo)ck o)feVolUtion, which is not a miet- these aind o)ther DR?B1 genei lineages is aitiona.ry hiistory) oft Species relations. Btit roniomiic clock like o)rdinary timiepieces thait proper-ty that makes themii particularlynmany o)ther ISSueCS Can be explo)red. I have meaC"Sure- rimeI interval.1S preCCISely, buit ratherai suitaIble for- ascertaining, the history o)f an-uISed genecs oft a particular k-ind, tho(se in1- stochamstic chi)ck- that is dependent, like ra- C ient huL11man popul11ations.vol1ved in thei '11immune response, to investi- dioactive deca,y, o)n events that o)ccur withg~ate theC SiZe of human1-11 INpopulations from the Constant probhabilities. Genealogy of DRB1 Genesrlime o)f thei origiln o)f out species aind earlier Tevouionary inforatio en-Codein o)rder to ascertain whether the existence In the DNA has the n-otoriouis aittribute of DRB3 IS one of 100 genes th-at ma-cke uipof the mythical Eve hias been confirmed by being, effectively inexhauiStible. The nucde- the hUnman Ileukocyte antigen (1HLA) comi-science, as somei reports Claim (1) Otide SequLence of a singl gnorsal plex, which extends ovxer a DNA segmien-t 4

EvALOluio is a rlime-dlependen-t gradua(LI DNA frtagiiieuelt IS Often SuffiCien tosove a mlillion nuCleti0tdeS 1(rng located o)n ch-ro-process. Ar the generic level, evolutiOn- oc- partiCuLtar eVOILuItionary question, but )organ mo1SOmeI 6. The HLA genecs specify mi-ole-CLirs by alCCumu-l1ated Sub-)Stitult(IonS of o)ne nu- ismis hiave ma.~ny genes ( 100,000 in pri- CUIes wNithl a Critical role in t'ISSue ConIpati-cleotide b-y ainothecr in thei DNA of the o)r- mlates and o)ther mamimals). The evlto- bilityvn in defense against parhl-ogenis andgYan ism. NuICIeotide mu1-tatiOns arise withl ar\s informa,tion obtained by investigating( prsts. These genies are arranged in two)COnstaint pr(obabilities, but miost are lo)st by One glene Can be Su1ppIlemented wvith the distinct groulps, clalss I and class II, separatedChance shortly after thecir origin. The fare of inve\stiga]tionI oft additional genecs unitil thei vs severall doe ,enes that have funi-ctionsthe rest depends o)n theicr effects o)n thei inlforimation becomes suifficient to settle ai nio(stly' UnrelCated to theC immuiiLne responiseirganisni. Many mu1Ltaltions are inljuLriouIS and particular- issuec. Thei practical limiits are rc- (FigI. 3).irereadily ehlmina~ted_ by~ natUral selectiOn, Souirces, financiall costs, aind timie. Thei I ILA comiplex IS hom(rl010og(rS to theI

Other mutaMtions are adaptivelIy neuLtral o)r majoir histi c0mpatib-i1ity gyene comiplexnearly so; that is, the replacem-rent 4i one-I The Reconstruction of Genealogy (MHCC) o)f mammials and- o)ther vertebratesnuicleot(ide by another is o)f little o)r n-o Con-_ (3). MHC IolecleCLIS On the surfaces o)f cer-SeqeCeLCIC to the orgaismls welfare. Th-ese Thec methodolo)gy uised to reconstruict evo(- rain cells bind proteini fragments (antigen-s)

IiUi~itOiisoccsionllyspred ad beome lutionaryT gene_Ialo)gieS Can- be) illustrated wNith an presenit theIcn to lymphocytes calledTfixed_ Inl thei species at rates that aIre constant, a simIple exaiple (2). Figure 1 show)XNs aso) that thei numbl-er o)f differences btweenvcr schemal"tic comiparison among fouir DR13 1 Tbe1 uhr fncetd ifrne

timesine thir iverencfro a ommo frm chmpazees eah of270nucloies; andetwo frombcipnees (Pnulet). ifeene

Sciencesat)Itheil derersty atCiYitex,rv,rnia, ni-ne-,arid ,, -1 -chaithehuma gene H-i4-110. n theAhIm-

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Hs*0302 relative to those from other species. For population would be heterozygotes (that is,

Pt*0302 example, the nine human genes at the top carrying two different genes), each for twoof Fig. 4 are closely related to one another, genes different from all others. The theory

Hs{1103 but they are more distantly related to other of gene coalescence and other mathemati-Pt*0309 human genes in the genealogy than they are cal theories formulated in the last decade

Fig. 2. Genealogical tree of the four DRB1 genes to the six genes immediately below them, provide models and analytical tools for ex-in Fig. 1, representing their patterns of evolution- including one drill gene and four macaque tracting information about human popula-ary divergence. Branch lengths are proportional to genes. The evolutionary divergence of the tions from the DRB 1 genealogy.the nucleotide differences between the genes (Ta- hominoids (humans and apes) from the cer- The coalescence theory examines theble 1). copithecoids (Old World monkeys) oc- genealogical relations between genes (11).

curred around 35 Ma, at the boundary be- According to this theory, all genes (alleles)cells. When antigen-presenting cells contact tween the Eocene and Oligocene epochs. present in an extant population must haveT cells that bear receptors matching a par- The relations shown in Fig. 4 demonstrate descended from a single gene, to which theyticular combination of protein fragment and that several human gene lineages already coalesce. The theory was first formulatedMHC molecule, the T cells are stimulated to existed at that time. for neutral or nearly neutral genes that doproliferate and to initiate the specific arm of The age of the human DRB1 lineages can not modify the welfare of the organism. In athe immune response, including the secre- be appraised by calibrating the DRBI molec- random mating population at equilibrium,tion of specific antibodies. ular clock, which yields a rate of 1.06 X 10-9 the mean coalescence time of neutral genes

The recognition of protein fragments is nucleotide substitutions per site per year is given by T = 4N[1 - (1/i)] generations,mediated by a specialized groove on the sur- (10). Figure 5 displays a genealogy of the 59 where T is the number of generations toface of the MHC molecule, called the pep- human DRB I genes, constructed by a meth- coalescence, N is the effective size of thetide-binding region, that consists of some 50 od that uses the average rate of evolution to population, i is the number of sampledamino acids (4). The composition of these determine the length of branches. The time genes, and the variance is large (12). Foramino acids varies from one MHC molecule scale at the bottom highlights three points any two genes (i = 2), the mean coales-to another, and this variation is responsible that approximately correspond to important cence time reduces to T = 2N generations;for the tremendous polymorphism character- events in human evolution: the divergence for a large number of genes, the mean co-istic of the MHC molecules and their encod- of the orangutan lineage at 15 Ma, the di- alescence time is T 4N. Thus, in a pop-ing genes. In people, as well as in other vergence of humans and African apes (chim- ulation with N = 1 million individuals,mammals, scores of gene variants (alleles) panzees and gorillas) at 6 Ma, and the emer- genes are expected to converge to their onemay exist at any one of several MHC loci, gence of Homo erectus at 1.7 Ma. ancestor 4 million generations earlier.and some of the allelic pairs may differ at These points of reference are useful for The coalescence equation can be used in>100 nucleotide sites (5). The MHC poly- determining the number of gene lineages in the opposite direction, so that we can esti-morphisms are ancient, with gene lineages existence at a given time, which is done by mate population size if the coalescence timethat can be traced back for millions of years, counting the number of lineages intersected is known. The human DRB I genes coalescein primates (6-8) as well as in rodents (9). by a vertical line drawn from the time to their last common ancestor at -60 Ma

Figure 4 represents the genealogy of 119 point. For example, 32 human lineages were (Fig. 5), in the middle Paleocene, 10 to 20DRBI genes, of which 59 are from humans, already in existence around 6 Ma, which million years (My) before the divergence of40 are from apes, and 20 are from Old implies, correspondingly, that the other 27 the New World and Old World monkeys. IfWorld monkeys (Table 2). In this genealo- lineages arose after the hominid lineage we assume that the average generation timegy, the length of each branch is proportion- diverged from the African apes. The gene- over this long span is 15 years (which isal to the number of nucleotide substitutions alogy of all human genes coalesces at -60 surely too high), the coalescence occurs 4that have occurred in that lineage. Thus, Ma, which is to say that the human DRBI million generations before the present. Ifwe see at the bottom of the figure that of genes started diverging that long ago.the two macaque genes, Mm*0301 andMm*0302, the first one has changed more Human Ancestral Populations Table 2. Species and number of DRB1 genes.than the second.

If 32 DRBI gene lineages have persisted Sym- Scientific name GenesAge of the Human since 6 Ma, it follows that no fewer than 16 bol (common name)DRB1 Lineages individuals could have lived at any given Apes

time over that long span. The minimum Hs Homo sapiens (human) 59The DRB 1 human gene lineages are very number of individuals must have been pp Pan paniscus (bonobo 4ancient, as is apparent from the distant much larger, because the probability is ef- or pygmyassociations between some human genes fectively zero that all 16 individuals in a chimpanzee)

Pt Pan troglodytes 24(chimpanzee)

Class 11 reaion Class.1 region Gg Gorilla gorilla (gorilla)10Or Pongo pygmaeus 2

DPB1 DPA1 DOB1 DOAl DRB1 DRB3 B C A (orangutan)

A-, | / Old World monkeysMm Macaca mulatta (rhesus 16

38 8 19 14 59 4 60 18 41 mcqe

r~~~~~~~~~}~~A , iL ,J/I'I'I}I,A---r.' /A---I Mn Macaca nemestrina 1o 300 400 700 800 900 2000 2100 2200 3400 3500 3800 (pigtail macaque)

Ml Mandrillus leucophaeus 2Fig. 3. Location of some polymorphic genes within the HLA complex in human chromosome 6. There are (drill)two sets of genes, class and class 11, separated by a region with unrelated genes. The number of variant Ph Paplo hamadryas1genes (alleles) known at a locus appears under the box that indicates the location of the gene. The scale (hamadryas baboon)below gives the number of nucleotides (xl1000) along the segment.

SCIENCE * VOL. 270 * 22 DECEMBER 1995 1931

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thei DRBI1polymicrphismn were neuCLtrail, thei mate of thei mecan of the popUlatio ovr ie, wth- theC Va_Lue of 4N = 60 My obtained byco,alescence date wotild requilre a long-term thei estimate refers to the harmionic miean, reconstrUCting the g'enealogy.poptUlation of I miilli'on tindiv,idt_ials. wvhich has thle important property of beingWe need to qualifly thils concIlusion with affected disproportionately miore bV smaller Experimental Simulated

two observations. First, airhori_gh N is an esti- than by tlarger numiibers. The estnimate of N isPopulationsthecrefore conisistent with population Si-es

muiLch g,reaiter tha-n miillion for many gener- Thei coalescence theory draws inferencesA20~~~~~~0A a~~~~tions, buit itt is not com1-pa,tible With muILCh about past ev,ents on the basis of observa-

04 0 7 ~~~smnaller population si:zes for verv many 1tener- tion_S ab)Otit Current polymiorphisms. TheiseL a~tions. Secorkid, becauLSe Of theC large variance

Hs-0402 ~~~of the coalescence equLation, thei estimIate of N

H-01P~~~~~~~~~~~~~~~~~~~~~~~~~~~~H -7040

H-010 02neH~-0405

- H.OI CIs, btut the D)RB1 genies are Stibject toPt-Ole ~~~ov-erdominanit natural selection, that its, het-

~~~~~~~~~~~Hi0411H erO_-v,,,'otes for- HLA genes are better off than -02

-0702 ~ are homiozyg,otes (3, 14); for instance, bect-H

t0701 Hs-1.1090cro:ygotes display enhanced resistanCe to Bias- H-83

M-011 1modium f,alciporum, thei parasite tha,t CauLSeS H-83

L~~~~ alignat (H-0400 Hitis:if1402

increaises th -poability that gene polymor- Hs:B021phiismis will persist ovecr time, and thuIS itH 1 1

Gog0201 edc te0o0l iP-0205 r~ed.cstl ni-Lmber o individUatas reqItirted tot -- It-lOOI-Pt-0213H.10Pt-0212 their persisten-ce. -H-150j

PP00201 H-10

Pt -0209 In thec case of balancing selection, thec .P 0150Pt 0209 "I~~1 H.- 1602Pt -0202 coaiescenice process nas the samie struictuire ais H.-1301Pt -0204.1

f7 PP0202 ii rctitt1-ilgene geneaiogy, except to- SCA- H10

P t -0203 ing factor, J,so that thei tim-ie to coa,lescence H-10Pt-020 1 Hit-1 102Pt72i7p ~~~~~ingenerations is esImae y f 16-

il).inc scaling tactor depnd ontheN0Gg3030 H 0

1,-30H120 1 ecitud tluutatOn ra~te as weii as on tmt etc H.-I

141'40, -0301 t 1-il~~5rageto ecle(t .1 / ~f~-e0302214

C,9-030 111~lts fwe rassumefr f1000 to 0.039(,1, -

H.0603 the popuLtation si:e reqtiUired for maintaining, -, l,

PtO03 thei I)RBJ polymorphism- is -125,000 toPt-009 i p 0/i 5 1117

Pt -0307 ~ [LIILd7mai ,xv c.15 6 1.7The rimei to coalescenice has beeni esti-P~~~~~~1701 ma~~~~~~~~~~~~~~~1,ted ait 60 My on thec bsis of the g,eneat- 60 50 4'0 30 20 10 0

H.- I 1 0 ~~~3 ogy reconstrriCted in Fig. 5. We can recachi My

H.-IlaI14thsaeetmtbyasmwadifrn Fig. 5. Genealogical tree of 59 human DRB1HP--I 1 rorite. According to the theory of coal__[-Hs - 1 30 3

1 ~~~~~~~~~~~~~~~~genes(exon 2), constructed according to the ''av-~~~~cence,i we amlple anly two genles at ran erage linkage'' method [(39). p. 31; also known asM."-0303 ~~dom, the expected v,alLie for theiir coales- the unweighted pi-ru methodusn arith-Mi 0301 pi-ru sn03 0 1 ~~~cence is 2N. Figure 6 displays thei distribul- m-etic averages (UPGMA) (43)], on the hasis of

1 305 ti~~~~~~onof geonetic dlistance between pairs of thei genetic distances (D) estimated hy Kimura's two-Pt -0301paaeemehd42foth 711piwsPt -0302 59 htiman D)RB1 alleles. The miealn distance pamermthd(2fote171piws

Gg-0304 \alu is00? hc,o h ai i h comparisons hetween the genes. The averagePt-03075aeo h R vluinr lc,yed linkage method assumes equal rates of evolution~pt-0303 .1 ,1 along thebanhes. The time scale is hased on a

_L:Pt -03 06 an average coalescence timac of 2Ni - 3 1.6 thj__F_PP-O 301 ~~~~~~~~~~~~~~~~~~~rateof evolution of 1 .96 x 190 substitutions perL014 My hsvle si esnal gemn nucleotide site per year, estimated by the mini-

1407 mum method (8) on the hasis of genetic distancesH 1 4 1 0 b~~~~~~~~~~~~~~~~~etweenspecies that diverged at different times.

H . - 1 4 0 5 ~~Fig. 4. Genealogical tree of 1 19 DRB 1 genes (exon The species compared for estimating the rate ofH 1 4 0 2 ~~~~~~2)fromihmn (Hs) and other primates (Tahle 2). evolution are Homo-Ran, Homo-Gorilla, and Pan-

1406 ~~~~~~~~~~~~~Thetree wAs;1- Madei wAith the- uso-pf the neighhror- Go,rilla a7t 6 My;I Hnmn-Rongo, Ran-Rongo, and

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inferences can be tested by computer exper- persist at the end of the experim-ent. heritance of the mitochondrial DNAiments, in which the time direction is re- Mutation is ignored in the simulated (mtDNA) is distinctive and follows a pat-versed and the process is examined as it populations. If the mutation rate to alleles tern of maternal inheritance. Sons andproceeds from past to present conditions, favored by natural selection is 5 X 10' daughters inherit mtDNA from their moth-The experiments simulate populations con- mutations per gene per generation (8), a ers, but only the daughters transmit it tosisting of a certain nuImber of individuals new mutation appears every 100 genera- their progeny.that reproduce each generation by random tions in a population of N = 10,000 indi- Analyses of the mntDNA from >100 eth-reassortment of genes. Figuire 7 presents the viduals. The mutation process increases the nically diverse individuals have shown thatreSuiltS of three sets of experiments. The fate number of genes in the populations, but it the mtDNA sequences of modern humansof 60 different genes, initially in identical would not be nearly sufficient to maintain coalesce to one ancestral sequence, the "mi-frequencies, is examined over 100,000 gen- 60 genes if s 0.01 to 0.02. With N = tochondrial Eve" that existed in Africaerations, a rime approxim-ately equivalent 10,000 and s =0.01 or 0.02, the process of --200,000 years ago (21). This Eve, howev-to the 1.7 My from the emergence of Homo elimination of the first 40 genes is very fiast. er, is not the one mother from whom allerectus to the present. The probability of For populations of N = 100,000 individ- humans descend, buIt rather a mtDNA mol-reproduction is s = 0 to 0.2 higher for uals (Fig. 7, bottom panel), with s = 0.01 to ecule (or the woman carrier of that mole-heterozygotes than for homozygotes. 0.03, 30 to 50 genes remain at the end of cule) from which all modern mtDNA mol-

For populations of N =1000 individuals the experiment. If we assume, as above, a eCuIles descend. The inference that all hu-(Fig. 7, top panel), withouIt selection, all 60 selected mutation rate of 5 X 10'~muta- mans descend from only one or very fewgenes but one are rapidly eliminated, consis- tions per gene per generation, a new over- women (1) is based on a confusion betweentent with the theoretical expectation that dominant mutation will arise every 10 gen- gene genealogies and individual genealo-fixation for one gene will occur in 4N = erations. Most newly arisen mutations have gies. Gene genealogies gradually coalesce4000 generations. If the heterozygotes have s a high probability of being quickly lost by toward a single DNA ancestral sequence=0.01 to 0.02 advantage, which is the chance, even if they are favorably selected, (such as in Figs. 4 and 5), whereas individ-

magnitude operating in real populations, all but mutation would increase the number of ual genealogies increase by a factor of 2genes but two or three are eliminated. Even persisting genes. Depending on the muta- each generation: An individual has twowith uinrealistically large s advantages of 0.1 tion rate, the number of genes might ap- parents, four grandparents, and so on. (Theto 0.2, only 8 to 11I genes persist after proach or reach 60, the number of DRBJI100,000 generations. POPuIlations of 10,000 genes. In conclusion, these computer-simu- 20 n = 60individuals (Fig. 7, middle panel) are like- lated populations yield results consistent N= 1000wise incapable of maintaining 60 genes over with the theoretical calculation that to

0s=U

many generations. Without natural selec- maintain -60 DRBJ genes, human ances- 100tion, all genes but one are soonl eliminated. tral populations must have consisted of s____________________ -002With s = 0.01 to 0.02, only 9 to 11 genes 100,000 or more individuals over their long o0 s 08i

history. 0 10 20 30 40 50 60 70 80 90 10060 n=60

Table 3. Effective population size, N, as a function The Mitochondrial Eve 50 N= 10,000of various parameter values. T, time in genera-tions; s, selection advantage of the heterozy- Ms ftegntcifraini trdi 0s.gotes; u, mutation rate per gene per generation for Moto h eei nomaini trdi 010selected alleles. If the long-term generation time is the chromosomes inside the cell nucleuIS. -2 3015 years, then T =4.0 x 106 corresponds to 60 The total DNA in a human cell nucleus ~2My. If the mutation rate per nucleotide site per year amounts to 6 X 1 0' nucleotides or base 0.02is m =10 -9, half the sites yield selected alleles (n pairs (bp), half in each set of 23 chromo- 10 s000-135), and the generation time is g =-15 years, -oe htar neie fo ahpret 00

then u = 2.0 x 1066 the same value of u results soeIhtaeihrte rmec aetifin-=S x 10 , n =-40, andg =-10. A relatively small amount of DNA 0 10 20 30 40 50 60 70 80 90 100_____________________________________ ~(-16,569 bp) exists in the mitochondria, 60 .~ s=0

T N cell organelles outside the nucleus. The in- 50 -~--s-=0-04.0 x 106 0 1,000,000 4

4.5 x 10 6 0.01 297,789 10301- s-001V0.02 257,430 20n = 600.03 230,213 120N= 100 000

2.0 x 10 6 0.01 194,240 10-0.02 149,072 100 s -0000.03 125,343 __ _ _ _ _ _ __ _ _ _ _ _ _

3.0 x 1060 750,000 80 [1~~~~~~~~~~ 0 10 20 30 40 50 60 70 80 90 10045x10 6 0.01 2173 Time (103 generations)

0.02 178,691 60 -Fig. 7. Loss of genetic polymorphism in comput-0.03 157,795 er-simulated populations initiated with 60 genes

2.0 x 10 6 0.01 131,196 40 -(alleles) at identical frequencies. The 100,000 gen-0.02 98,992 20 eaton corspn to -1 .7 My-k,the time e~lapsedn

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theoretical niumiber of ancestors for any one mnean population size that ranges between history. We want, nevertheless, to explore theindividuial becomes enormiotis after somie 1 0,000 and >50,000 Individuals throtigh- likelih-ood that a bottleneck did occuir. Wh-entens of generations, buit 'inbreedling oc- oLIt theC Pleistocene. This finding is Con1- the numtiber of Individtials in a populationcuirs; that is, alfter some-i generations, ainces- 'sistenlt wNltit the estimate based on thei oscillates fromi- generation to genieration, smnalltorsappear mre than once in th gneal- I)RB 1 polymnorphism of a population size numbiiers have a disproportionately large effect

ogy. Coalescence to one ancestral gecne on the order of 100,000 Individuals over on the VALue Of N, becaulse N is the harmionicoriginally present 'in one indiVidUal does thei last60 My.iean othppilinszevrtIm.Te-not disallow thei contemporary existeceic Of fore, very niarrow or long-lasting bottlenecksmany o)ther ancestors from whiomi wec have The ZFY Adam are iniconisistenit with the DRB 1 reSuIlts. Howv-inhierited thei other genes. eVeC, theC queIStion remiains whether an occa-

The concILuSion warranted by thei A genetic gender counterpart of thei sitonal population bottleneck miay have oc-m--tDNA analysis is that thei mitoch-ondrial mitDNA is thei Y ch-rom-iosomie, which is cuirred, and if so, how smiall it could be. It h-asEve is thle ancestor of miodern hLtimans in thec transmiittedi fromi fathers to sons. Regions of been stiggested that a popuilation bottleneckmaternal line. Any petson has a sinigle an- the Y chiromiosome do n-ot have homologs occurred at thei ttansition from archaic to

cestor i the maernal lne in ay given in the X chromiosomie andi thuis are tranis- miodlern H1. saOilii,oe 100,000 to 200,000gen-eration. ThuLs, a person inhlerits thei miiltted through1 the Paternal ineII, julSt as thei yeaIrs ago (1, 21, 24).mitD)NA fromi thei great-grandmother in thei mtDiNA is inheritedi thiroughl- the maternal Thei conseqtience-CS of a population bot-maternal lIneI, bUt aSOlsoiniherits other genies linie. A 729-bT fragmient of the Y-clhromio- tleneick dependi not onily on the Size of thefromi thec three other g,reat-grandmothers and sonice ZFY gene (thiought to be Involved In bottleneck, Nb,, buit also on the ni-Lmber ofthei fotir great-grandfathers (abouit one- the matuirationi of testes ot spermi) has been- bottleneick generations, t .Auelmasreighith of the total DNA from each great- sequenced in 38 meni, of diverse geographic for`evltiating thei effects of a bottleneck isgrandparent). The mitDNA th-at wve have origHins and representative of- major ethniic the ratio N1j/t1), wh1ilch if <10 leads to ainherited fromi the miitochoncirial Eve repre- grouIps, an11d no vaniation was observed (24). drastic recducction in genetic polymiorphiismlsents a foUr-hUndred-thIOUsandth part of thei Comparison wvith the homlo01gous regi(on of (18). Thus, a bottleneck of 1 00 individulKISDNA present In any m--odern- htIiman. Thei th-e great apes ylields a rate Of subStitUtion (of would suibstantially redLice genetic variationrest of thec DNA, 400,000 times thei amtIlint 1.35 X 10" nucleotides per site per year. if it lasted 10 ot mi-ore generations, butiof mtDNA, wasInhrie fromi- otheir con-- Assuiiing, thait substitutions in thits DNA balancing selection facilitates the pers'is-tmoaisof the niitochondrial Eve,C segmientar neutral, coalescence theory tence fPtmrhsstrtg ote

The theory of gene coalescence makes it yields 270,000 vears as the expected date for nieck (25). Thei persistence of HLA poly-p(ssble to estimate the numtiber of an-cestors the last commiion ancestor of thei ZY gee m)pim vr mi-illions of years requLires

who were con-tem--poraries of the mitoch-on-- of m-iodern- lhumans, with 95% confidence th-at thei size of htiman ancestral poptilationsdrial Eve. The mtDNA is inheritedi as a limiits fromi 0 to 800,000 years (24). The be at least Ns 10I at all timies (7, 1 7). Ifssingle copy, fromi (wily one parent, alnd thei Carrier ofIth-e ancestra(l ZFY gene predictedi 0.01, th-e miinimumItI popuilation size pos-mntDNAPI ylymorphilsmi is largely neuitral. byW theCSe CAlCUlationS is the anicestor of all sible at anly timei WOUld thecrefore be N1According to thei theory, thei coalescence iiiodern huIMan'1-S In thei paternal line. As wvas 1000. The iiiinimulLm ntiiiiber mtist haveinito a single ancestral miolecuile is expected the case for- the mtitochondrial Evc, thils beenI_ in falCt mu1Lch larger, because htimanto be T =2N1 genera-~tions ago, where N~is "ZFY Adam" is the indiVidUal from which poptilation bottlenecks cannot last jsthe numtiber of m-itheirs per g,eneration. Th-is all humans have Inherited thei ZFY g,ene, few generatitons. Many generations are re-inference aSStUiieS constant poptilation slize butit e is not out only ancestor in hiis gyen- quLired for a humtian popuilation t(o growand other conditions that are tinlikely in eration. We have inherited the other thiou- fromi 1000 to its long-termi miean, whichreality, so that the concILuSions reached are sands of genes fromi many othier conitemipo- we have estimi-ated to be -100,000 mndi-only roughyl approximllationls. If we aSSumiie 20 r-aries of th-is Adami-. vidtUals. Thei rate of g,rowth of humi-an pop-years per generation, thei 200,000 years of The expected coalescence of a DNA ullationis thiroughouit the Pleistocene ha-sthe mi-tDNA coalescence yield T 10,000 polymiorphism that is transmiitted in a single been estimiated to be 0.02(Yo per- genera-generations; theirefore, N,. 5000 mothers copy and paternallyT inhrtedi 2 , nn(26).aind N =1 0,000 Individuails, whitch- is al1- where N,,, is thei number of miales. If we Computer-siiMiiuated populiations are uISe-m-iost certainly an uinderestiniiate (22). assumiie 210 yea,-rs per generation, the coales- fuil for exploring the minimu-nm bottleneck

Otheir estimrates place thei coalescence (if cence to thei ancestral ZFY' gene yields an size that WOUld allowv thei persistence of th-ethe mitDNA at 143,000 and 298,000 years effect'Ive Population siz-e of 6750 fathers, ot DRBJ polymorphism. The resuilts in Fig.1 8ago (23). One recen-t anillysis, which takes 13,500 indi'Viduals, with a 95(,~, conifidenice aIre based oni 200 separate COmIpulter run1s. Ifin-to aICCounlt VMarible Substitution rates for ul-pper limiit of N = 40,000 indtiVIdualIS. If We theire is n-o selection (s --0) aind we ig,,noredifferent sites (if the mrlDNA gen-omie andI is aIcc(iunt for thec standard dleviation of thei th-e rimei required for- a population toi growvsuppoirtedl by com-iputer SIMuLtation-s, yields mnean coalescence, the 95(% Upper limiit for back to its long-term poipulation size, and ifMan estimlate of 622,000 to 889,000 years ago N wVould- Iincr-ease to 80,000 in-dividualIS, easm that 70 genei lineiages were(22) and corresponids to N =31,100 to Thei ZFY results are thuIS COn-SISten-t wNith- theI presen-t before thei bottleneck, thei smallest44,450 individuals. As n-oted earlier, esti- mttDNA-derived anid DRB 1-derived esti- bottleneck tha(_t WOUld allow the persistencem,ates of me-ian coalescence rimie as a fuinc- niates that huLman ancestral populatiOn-s (if 60 (if these 70 gene lineages is 510 to 550tnon of N, an-d vice versa, have large vanl- have been -100,000 individuals for mil- Individuals (Fig. 8, top paniel). Wheni weane.x(hnteapeoVee isL,cLare in fyas accuntforth tie eq Ire fo th pp

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growth to 100,000 individuals, 4490 to 4590 Census Populations anderthals have been thought to be ances-individuals are the minimum bottleneck for tral to anatomically modern humans, butpassing 60 alleles (Fig. 8, top panel). The parameter N that I have used for estimat- now we know that modern humans ap-

Overdominant selection reduces only ing the size of human populations is a theo- peared at least 100,000 years ago, muchslightly the minimum number of individuals retical construct that corresponds approxi- before the disappearance of Neanderthalrequired at the bottleneck. When s = 0.01, mately to the number of synchronously repro- fossils. It is puzzling that in caves in thethe minimum bottleneck size for passing 60 ducing individuals. The census number is like- Middle East, fossils of anatomically modernof the 70 alleles is 500 to 540 individuals if ly to be about four or five times greater. In humans precede as well as follow Neander-we ignore the required growth back to long- humans and in other primates, a number of thal fossils. Some modern humans are datedterm numbers, but 4310 to 4380 when we individuals, possibly one-third of the total, do at 120,000 to 100,000 years ago, whereastake population growth to 100,000 individ- not reproduce at all. Of the females who Neanderthals are dated at 60,000 anduals into account (Fig. 8, middle panel). reproduce, only about one-third are actively 70,000 years, followed by modern humansEven with the unrealistically high s = 0.1, reproducing at any given time; the others are dated at 40,000 years (34). It is unclearthe corresponding values become 490 to juveniles or are beyond reproductive age. whether the two forms repeatedly replaced530 and 3410 to 3510 (Fig. 8, bottom pan- With the use of these rough approximations, one another by migration from other re-el). It may be concluded that, to account for we can conclude that N is about two-ninths of gions, or whether they coexisted, or indeedthe DRBI polymorphism, the minimum the census population. A long-term effective whether interbreeding may have occurred.possible number of individuals at a bottle- population size of N = 100,000 corresponds, There is considerable controversy aboutneck is at least 4000; this number is consis- therefore, to a census population of 400,000 to the origin of modern humans (22, 33-36).tent with the lower estimates derived from 500,000 individuals. A bottleneck population Some anthropologists argue that the transi-the mtDNA and the ZFY gene. of N = 4000 similarly corresponds to 15,000 tion from H. erectus to archaic H. sapiens,

to 20,000 census individuals. Population sub- and later to anatomically modern humans,division would affect the value ofN estimated occurred consonantly in various parts of the

1.0-Ar- B c from the DRBI genealogy. If human ancestral Old World. Proponents of this "multire-0.8 pY , populations consisted of several synchronous gional model" emphasize fossil regional

but relatively isolated populations, fewer indi- continuity in the transition from H. erectus0.6 viduals than were estimated above would be to archaic and then modern H. sapiens.

04 required to account for the DRBI polymor- However, they postulate that genetic ex-

phisms, although the order of magnitude change occurred from time to time between0.2 s 000 would not change (18). populations, so that the species evolved as a

l__ R=1.01 single gene pool, even though geographic. The Origin of Modern Humans differentiation occurred and persisted, just

0 1000 2000 3000 4000 as geographically differentiated populationsThe hominid lineage diverged from the exist in other animal species (29, 35). This

1.0 A B C chimpanzee lineage at -6 Ma, and it explanation is dependent on the postulate0.8 , evolved exclusively in the African continent of persistent migrations and interbreeding

until the emergence of Homo erectus some- between populations from different conti-0.6 what before 1.7 Ma. The first known homi- nents, of which no direct evidence exists.

¢ 0.4 nid, Ardipithecus ramidus, lived around 4.4 Moreover, it is difficult to reconcile theMa, but it is uncertain whether it was bipe- multiregional model with the contemporary

0.2 s= 0.01 dal or in the direct line of descent to modern existence of different species or forms in

O.0O [R=1.01 humans (27). The recently described Austra- different regions.

0.C Iopithecus anamensis, dated at 3.9 to 4.2 Ma, Other scientists argue instead that modern0 1000 2000 3000 4000 was bipedal and has been placed in the line humans first arose in Africa or in the Middle

1.0 Aof descent to A. afarensis, H. habilis, H. East somewhat earlier than 100,000 years ago

B c erectus, and H. sapiens (28). and spread from there throughout the world,0.8t Shortly after its emergence in Africa, H. replacing the preexisting populations of H.0.6 erectus spread to other continents. Fossil re- erectus or archaic H. sapiens (21, 23, 37-39).

mains of H. erectus have been found in Africa, Some proponents of this African replacement0.4 Indonesia (Java), China, the Middle East, and model argue further that the transition from

Europe (29-33). Homo erectus fossils from archaic to modern H. sapiens was associated0.2 s= 0.1 Java have been dated at 1.81 ± 0.04 and 1.66 with a very narrow bottleneck, and that this0.0 R 1.01 + 0.04 Ma (30), and from Georgia between bottleneck consisted of a small number of

1.6 and 1.8 Ma (31 ). Anatomically distinctive individuals who are the ancestors of all mod-0 1000 2000 3000 4000 H. erectus fossils deposited before 780,000 ern humans. The postulate of a narrow pop-Effective population size years ago have been found in Spain (32). ulation bottleneck derives from a misunder-

Fig. 8. Minimum size of bottleneck populations. The transition from H. erectus to H. sapi- standing and need not be entertained. TheThe ordinate displays the average probability ens occurred around 400,000 years ago, but most serious difficulty with the replacementP60/70 (based on 200 computer-simulated PoP- there is uncertainty as to whether some fossils model is that it leaves unexplained the appar-ulations) that 60 of the initial 70 genes will per- are H. erectus or "iarchaic" formus of H. sapiens ent morphoalogical continuity observed insist. The selective advantage of the heterozy- (33). Moreover, H. erectus persisted further in somne regions, most notably in Australasiagotes IS S, and the rate of population growth per Asiageneration is R = 1 .01. The bottleneck lasts 10 Aa, until 250,000 years ago in China and (29, 35).generations. A gives the probability of survival at perhaps until 100,000 years algo in Java (33). The reconstruction of the mtDNA gene-the end of the bottleneck; B and C take into The subspecies H. sapiens neanderrhalensis ap- alogical tree places its root in Africal (21,account the growth of the population to N = peared in Europre around 200,000 years ago 23), consistent with the African origin fa-10,000 and 100,000 individuals, respectively, and persisted until 30,000 years ago. The Ne- vored by proponents of the replacemnent

SC'IENC'E * VOL. 270 * 22 LDECEMB3ER 1995 1935

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model (37-39). Thils evidlence is, however, 5. R. E. Bontrop, lmmuncogenetics 39, 81 (1994): R. F. a different Y chrumounosiie fragmient truorj five ioner,far froim concluisive. The mtlitDNA root pi-- Bontrop et a).. Immunol. Rev. 143,33 )1 995(;J. Klein have estimated the coalescence at 37,000 to 49,000Pi- and F. Figueroa, Cri't. Rev. lmrmonol. 6, 295 (1 986); S. years ago. The discrepanicy betweeni these two es-

Poin1ts oily thei ancestor in thei mnaternal 0. E. Marsh and J. G. Bodmer, fmnmunogenetics 33, 1imates and Dorit et a!.s estimate uinderscores theline, bitt the itchIILI larger nuclear DNA mnay 321 (19911: hibd. 37. 79 11993); H. McDevitt, lmmuo nieed tor m-ore extensive and accurate data. Thesohave genealotjical roots in i)ther palrts of thec no). Rev. 1 43, 11 3 (1 995); C. O'hUigin et a!., rornmu niew estimates are consistent with the conclusionisnogenetics 38, 165 (1993); World Health Organiza- reached hiere concerning the size of anicestral hu-wvorld. tioni, Boill. WHO 70, 801 (1992). roian popuilations.

Additional molecular evidence tavoT)ing 6. 1. BergstrOmi and 0. Gyllenstein, lmmnsooo. Rev. 143. 257 Becarise alleles behave as n'eutral whenever NaAfrican ancestry derives, however, fromi the 13 (19951:l W. Fan et a)., Humn. lmmunool. 26, 107 if the selection is weak (for examiple, s 0.01), N

analsis f 30DNA poyirhsi rti1 11989); 0. B. Gyllenstein and H. A. Erlich, Proc. Nat). rooLst he correspondingly large (at least 1 00) for se-analysis of 3opOlymorphismS front 14 ~Acad. Sci. U.S.A. 86, 9986 (1989): 0. 8. Gyllenstein l-ctroni to play a role.worldwide populations (38). Thei genealogical eta).,ibid. 87. 1835(1990); 0. A. Lawloretal.,Nature 26. J. N. Spuhler. in Geneti'Cs of Cellullar, Indivi'dual, Fani

tree derivedfrom aveage generic distances 335, 268)(1988):- W. F. Mayeret al.. EMBOUJ. 7. 2765 il/y, lrrd Populatiorr Variability, C. F. Sing and C. L.treeder'Tedroii aveaclegeneic dstanes1988). Hanis, Fda. (Oxford Univ. Press, New York, 1993).

separates ancestral African from derived non- 7 .2 vl f3.Po.Nt.Aa.SiLS.9. p.2227African populations. The deepest split 'in the 6707(1994). 797. T. 0. White, 0. Suwa, B. Astaw, Nature 371. 306

genealogy isdared at 156000 years ~, 8. F. J. Ayala and A. A. Escalar-ite, Mol. Phylogenet. 11994); ibid. 375, 88 (1995); G. WoldeGabriel et a).,wh'clitusestmaesthe titie when mnodern Evol.. in pross ibid. 371 330 (1994).whichthusestimates ~ ~ ~ ~ ~~~~9.B. Ardeni and 3. Klein, Proc. Nat). Acad. Sci'. U.S.A. 28. M. G. Leakey et a)., ibi'd. 376, 565 (1995).

hunIMians spread from Africa throughou-0Lt theI 79, 2342 (1982); F. Figueroa et a)., Nature 335, 265 119. U. A. Clark, in The Mi'ddle Paleolithic: Adaptation.world. These resulits are partiCUlarly notewor- (11988); T. 3. McConnell eta).. i'bid. 332, 651 (1988). Befravi'Or anrd Variability, H. Dibble and P. Mellars,thy be)cauRSe the analysis souight to determine 0. This rate is obtained by thc 'minirmumii' m-ethod de- Eds. (Univ. of Perrosylvania Museumi, Philadelphiia.scrbed 'n (5). See also Y. Satta at al., ini Molecular 1002), pp. 183-205;- Recherche (Panis1 263. 316the history of humian popuilations rather than Evolution of the Major Histocompatibill'ty Complex. 3. (March 1 994); and 3. M. Lindly, Ami. An-ithei ancestry of individual genes [see also Klein and 0. Klein, Fda. (Springer, Heidelberg. 1991/. thropol. 9. 902 11989).

(39)1. venso thereseems o be n defintivTe oo 502.. C. C. Swasher Ill et a)., Science 263, 1118 (1994).11.R.C. Griftiths, Theor. Popuil. Ri'o). 17. 37 1980); 0.0R. 31. F. Gabunia and A. Vekua, Nature 373, 509 (1995).resnto excludec the possibility that different HLudsaol, Oxf Suirv. Evol. Biol. 7, 1)1990). 37F'-. Carbonell at a).. Science 269, 826 (1995) 3. M.

goenes miay have different popuilationat originls. 1 2 3. F. C. Kingman, Stochast. Processes App). 13. 235 Pares and A. Perez-Gonlzalez, ibi'd., p. 830.

Thei average distances Wvould thein reflect thei (1982); 3. App). Prohab. 19, 27 (1982); F. Talima. 33. S. Jonies, H. Martnt, 0. Pilbeam, Fda., The CambridgcGerletl/cs 105, 437 (1983); N. Takahata anid M. Nei, Errcyclopedia of Human Evoluition) (Cam-bridge Univ.

re~at1xe .,contrlnutlo Oi \'i§ttl.)tIs 011- ibi'd 1 10, 325 (1985);51. Tavare, Theor. Popt1l. Bin!l. PresS, Cafi//bridge. 1992), pp. 246-257.cestral popuilations. The resuLts WOUld thuLS be 26. 119 (1984). 34. C. B. Stringer. Sci'. Ami. 263, 98 (Decemiber 1990).copaIbl wihamdli hc oen 13. In the case of nuclear genes, the stanldard deviatiorir 35. M. It. Wolpoff eta)., Sciernce 241, 772 (1988); A. G.Africani r)epldiacmn wasdc conwhcmian withdci for the rilleal is ON/\ (see M. Nei, Molecular Eva/Li Thiorrie anld M. H. Wolpoff, Scl!. Aol. 266, 76 (AprilAfficanrepl.aenientwas conomitan with tioarlar Genetics (Columbia Unilv. Presse New York. 1992); 0. M. Waddle, Nature 368, 452 (1994);l G.

somie regional continuity (40). 1987/, p. 395. eq. 13.74). Br3'uer, ini ConrtinruityorPReplac erment?ControversiesIn Con1CILuSion, thle weight of thei moAClec- 14. P. W. Hedrick, Am. Nat. 143, 945 11994); A. L. in Hor/lu sapienls Evolution. 0. Brauer aild F. H.

lot evidence favors a recent African origin Hughles aild M. Nei, Natrire 335. 167 11988);l itbid. Sirith. FEds. (Balkemla, Rotterdanl,. Nethlerlainds355. 402 (1992);- 3. Klein and C. OUl-lbigin. Philas. 1992), pIp. 83-98.for 1Tihiderin hum1i-ans. Ethniiic differentiation Trans. P. Soc. London Ser. B 346, 351 (1 994); W. 0. 36. Thle coriltroversy about tIle origin of illodernl hunliallsbetween nmodern humtian popuLtatiomns WOUld Potts and P. R. Slev, Imoluno!. Rev. 143, 181 11995); hias aft/n/-res been heated and prone to overstate-

therefore be CVOIlutionarily recent, a reSuilt O~f Y. Sattalet al., Proc. Nat). Acad. Sci'. UiS.A. 90. 7490/ trrierlt. Recently, a sciellce jlarlrlalist guuoted wittl il/i-(1993). plrcit approval a distinguilstled scletitist sayling tIlaLtdivergent eVo1lution Iletween geo)graplhically 17. A. V. S. Hill eta!., Nature 352, 595 11991); A. V. S. Hi)l ''there is r10 genletic data Ithat is Caonsistenlt witfl Itheseparated popUlations duiring the last 50,000 et a!., hild. 355. 403 (1992); A. V. S. Hill et a!.. Ibid. rnlultkregionai hypothesis'' (A. Gibburns, Scierrce 267.t(o 100,000 years. However, the replacemnirt 360, 434 11992); L. H. Miller, Proc. Nat/. Acad. 5Cr. 1272 11995);- my italics). Apparently, leelther thle sci-U.S.A. 91, 2415 (1994). eniist rnor tIre Jouriralist reflected tflat Menidel's laws,of archaic I I. scIlrics by anatomically itiird- 16. If uris thle selected muitatioll rate per genie per geri- thle tdouble helix, anld the iilllllense mnajority of gellet-eri hutmans mi-ay n-ot have Ibeen comipltet eratoim arlr s is the selection coefficient. fthern ic data are conna'stenlt withl the mlurltiregional bypath-ev'erywhere. Sonice interbreeding Iletween uN N sia, 15 well as wittli the Africanl replacerllerlt or ally

the coloni:ingmi)dern humans and local~~~~ Inttlier illodel of hlurllan originls.T.A. P. Rogers aild L. B. Jorde. Hurrr. Ri'o!. 67.popuIlations WOuld- aIccouint for the apparent (see(7, B.8. /, 16)). (11995);- C. B. Strinlger, P-hi!os. Tranls. H. Sac. Lorndonrmiorphological continuity in soicm regions, 1 7. N. Takahata, Pr-oc. Nat). Acad. Sci'. U.S.A. 87. 2419 Ser. B 337, 217 (1992);: _ arrd P. Arlrtrew,"partiCu_larlyT AuIstralasia (29, 35, 39). The (11990)! anld M. Nei, Genletics 124. 9JOr Sciernce 239, 1263 (1988).

(11990). 38. U. B. Coldsteill et al!., Piarc. Nat). Acadi. Sci. U.S,A.cuirrent lllissomitng of mnOleCUlar ev-OlUtion- 13. N. Takahata. Ma). Bra!. Evol. 10, 2 (1993). 92, 6723)(1995). TIle polymairpt 51115i are for aLlaOary an1thro1_pology SUrely wxill soon- provide 19. Arllurng tlhevaluLes in Table 3, mare ilearly apprapri- so hal rrricrosatellite luci

definitiveandIlrecise answers. a-te far ORB! Iare T -4.0 x 10' )wtl 1c corresponlds 32. L. L. Cavallli-Sforza, P. Merlozzi, A. Piazza, Ole His-niore ~~~~~~~~~~~~~~~to60 My at 1 5 years per general iarll, ui 2.0 a 10 ' tory aid Geographry af Hiumanr Genes )Prirlcetori

olr 4.5 x10 . and a 0.01 or 0.02. TIle ranige Oniv. Pre'ss Princeton, NJ. 1994).REFERENCES AND NOTES correspondirlg to these valuies Is N --149.072 ta 40. Regrorala colltinuity is supplorted by sollle mlolecuilar

297,789 (Table. 3). evidorlce (W. Fl. Li et a)., lil Ge/let/Cs af Cellular. Ir-1 The clia/a tllat evoluitionists have shown that all modern 20. EFatillates 011 tlIre order at N -100,017)1aoracestral Jivi'dtial. Ehtir/y, and Populatiarn Variability, C. F. Sillg

hurllarls descerld froill onie or few womern has repeat- hlniran populatrarla over Ithe last 60 My are a/so aIr alid C. L. Harlis, Eds. (Oxford Urriv. Press, New Yorrk.edly been m-ade ril the m-edia, as well as irr popular famned oy analyzing the HLADQB!I polynlorphislns (B). 1993). pp. 253-261; 5 5. Deeb et a!., Praoc. Nat!.scientific publications (3. M. Lowenstein, Pac. Discovery 21. R. F. Canrl et r!l., Nature 325, 31)(1987); M. Storle- Acad. Scli. UJ.S.A. 91, 7262 (1994); see 17)).39, .12 (19801) and by scientists [W. M. Brown, Proc. k/ng etal!., Gernetics 124. 717 1199001; F. Vigrlarlt etal/., 41. N. SaitouIalrIi M. Nei, Mol/ Rio! CEvol! 4. 406 /1987/.Nat). Acad. Sci'. U.S.A. 77, 3605 (1980)). Screnlce 253. 1503 (1991). 42. M. Kinlura, T/le Neurael Thleory oft Molecuilar Eva/ri-

2. A good introdUCtion to variouis methodS ulsed in the 22. C. Wills, Evolutiarn 49, 593 11995). ti'ori )Carllbridge Univ. Press, Cam-bridge, 1983/.r-iolecular reconstruction of phylogeny is D. F. Swof- 23. 5. Horai et a!., Proc. Nat!. Acad. Sci. U.S.A. 92. 532 43. P. Ft. A. Sneath and B. A. Sokal, Ndrrrerrca! Taxarrford and 0. 3. Olsenl, inl MolecularSystemratlrcs. D. M. 11995);- M. Ruvolo et a!., Ma!. Bic!l. Eva!. 1 0. 1 1 1 arrry )Freerllanl, Saril Franlcisco, 1373).Hillis and C. Moritz, Fda. )Sinauer Associates, Surir (1993). .14. arll gratefuil to A. Facalante for help with the corIllderland, MA. 1990), pp. 411 501. 24. R. F. Dorit. H. Akashil, W. Gilbert. Sclrerlce 268, 11 83 pditer simulations and dlata analysis. and to [11111 and

3. 3. Klein, Natra! HisQtory at thAleMjonr His'tacoralpnati' (1995). MA F. H-1rllrller (NatLire 378. 3~76 (199))las1hi RP B. Hudsorr fo-r Iheiptu l dAoriscussiorla`1 amr pairt icu

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The Myth of Eve: Molecular Biology and Human Origins: F. J. AyalaFrancisco J. Ayala

DOI: 10.1126/science.270.5244.1930 (5244), 1930-1936.270Science 

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