Department of Biosystems Science, Graduate University for Advanced Studies, Hayama, Kanagawa, Japan
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Abstract |
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Introduction |
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It is generally accepted that anatomically modern Homo sapiens appeared 130,000150,000 years ago. However, the origin and evolution of H. sapiens have not been fully recovered by the fossil record and have attracted much attention, particularly since the pioneer work on human mitochondrial (mt) DNAs and the proposal of the replacement hypothesis by Cann, Stoneking, and Wilson (1987)
. A number of population genetics analyses have been carried out, including sequence analyses of mtDNA (Vigilant et al. 1991
; Horai et al. 1995
; Krings et al. 1997, 1999
) and genomic regions of the haploid Y chromosome (Jobling 1994
; Hammer 1995
; Ruiz Linares et al. 1996
; Hammer et al. 1997, 1998
; Quintana-Murci et al. 1999
), as well as those of the haplo-diploid X chromosome (Nachman et al. 1998
; Zietkiewicz et al. 1998
; Anagnostopoulos et al. 1999
; Harris and Hey 1999
) and diploid autosomes (Harding et al. 1997
; Clark et al. 1998
; Nickerson et al. 1998
; Jin et al. 1999
). The gene genealogy inferred from these genetic data generally exceeds the tenure of modern H. sapiens and goes back to the Pleistocene (Takahata 1993
; Hammer 1995
). Although all of these DNA sequence data appear to favor the uniregionality (single-origin) of modern H. sapiens (Takahata 1995
; Jorde, Bamshad, and Rogers 1998
; Jorde et al. 2000
; Przeworski, Hudson, and Di Rienzo 2000
for reviews), no consensus has yet been reached (Harris and Hey 1999
; Hawks et al. 2000
; Yu and Li 2000
).
The purpose of this paper is to quantify an alternative hypothesis for the origin of modern H. sapiens, the multiregional hypothesis proposed by Wolpoff, Wu, and Thorne (1984)
. This hypothesis is an extension of that of Weidenreich (1946)
, which allows gene exchanges among multiple founding populations of modern H. sapiens. However, it has been difficult to test the multiregional hypothesis because of ambiguity in the assumed population structure (Takahata and Klein 1998
). In this paper, we draw several predictions solely from the very premise of multiple founding populations and examine whether these predictions are compatible with the pattern and degree of DNA polymorphism observed in various genomic regions. We collected all nucleotide sequences relevant to this end. To make our argument quantitative, we performed computer simulation based on a population genetics model for the multiregional origin of modern H. sapiens.
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Materials and Methods |
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With gene flow, purely neutral genes may not show extensive local differentiations. The FST value would be moderately small, and the gene genealogy would be intermediate in its timescale compared with that expected for globally and locally advantageous genes (fig. 2c ). Again, the birthplace of the MRCA of neutral genes is not unique. We do not know how often or where in the genome these three types of mutations occur. However, under multiregionality, we can make some important predictions largely irrespective of the kind of genes. Most importantly, the MRCA that is found during the Td period should not be restricted to any particular founding population. Second, the time back to the MRCA (TMRCA) may vary more greatly from locus to locus than that expected under a single randomly mating population. Third, the shorter the TMRCA, the smaller the FST.
By definition, the uniregional, or replacement, hypothesis posits that only one population during the Td period founded modern humans (fig. 1b ). Advantageous genes transformed the founding population of H. ergaster or H. erectus to modern H. sapiens via archaic Homo. Local adaptation in modern H. sapiens is assumed to have occurred during its tenure. As a result, the MRCA of locally advantageous genes is comparably recent. The genealogy of selectively neutral genes is even shorter than that of locally advantageous genes under the multiregional hypothesis, but it is deeper than that of globally advantageous genes. Importantly, the MRCA under the uniregional hypothesis must always be traced back to the single founding population, although this trace may be somewhat obscured by random distribution of the ancestral polymorphism into descendant populations, as well as gene flow between them, if present. In general, we do not know a priori which current local populations are more representative of the founding population or how polymorphism in the founding population was sorted out in individual local populations. Nevertheless, should we find such a population specificity in the genealogy at a number of loci, the uniregionality of founding populations appears to be an inevitable conclusion.
Multiregionality may be untenable to population-specific genealogy. If everything is equal regarding the founding populations, there should not be any population specificity. The multiregionality becomes tenable only if one founding population had predominated over the others in terms of the number of breeding individuals. However, emphasizing the overwhelming genetic contribution of only one founding population is equivalent to uniregionality. To be concrete and quantitative, we supposed that during Td (fig. 1a
), there were three founding populations, with the relative population sizes being p1 : p2 : p3, where 3j=1 pj = 1. If there are n independent genealogies, the probability that we find n1, n2, and n3 MRCAs (
3j=1 nj = n) would be multinomially distributed with parameters pj. The most likely proportion of the three founding population sizes is given by
j = nj/n (j = 1, 2, and 3). For n1
1, n2
1, and n3 = 0, the probability distribution is binomial, and the maximum-likelihood ratio becomes L = (p1/
1)n1{(1 - p1)/
2}n2, since
3 = 0. The L ratio can be used to set a lower confidence limit for p1. For instance, if n1 = 9 and n2 = 1,
1 = 9/10 = 0.9, and the condition of L > 0.01 leads to 0.45 < p1. For n1 = 19 and n2 = 1,
1 = 19/20 = 0.95, and the 1% lower confidence limit for p1 is 0.68. The more MRCAs are found in only one founding population, the stronger the required asymmetry in founding population sizes.
In the following, we focus on three quantities; the time (TMRCA) and place (PMRCA) of the MRCA, and FST. We estimated TMRCA based on the nucleotide differences within humans relative to those between humans and chimpanzees and assuming their 5 Myr old divergence. This simple method provided estimates similar to those reported in some literature which used the coalescence method of Griffiths and Tavaré (1994a, 1994b
). FST may be estimated according to Wright (1931)
or Nei (1973)
. We have redefined it as 1 - dw/d, where dw is the average maximum nucleotide difference within local populations, and d is the maximum nucleotide difference in the whole sample taken from all local populations. This redefined FST value is necessarily nonnegative and has properties similar to those of FST in Slatkin (1991)
.
To infer PMRCA, we first tried the cladistic method of Slatkin and Maddison (1989)
. The principle is simple: if we label the sampled sequences in a reconstructed tree by their localities, we may determine the character state in a node by the majority rule. However, it is possible that this method might not work at all if a demography such as that in figure 1a
is not at equilibrium. In the case of little or no gene flow, three population-specific ancestral lineages remain distinct during Td and go back to the common ancestral population. In this situation, the method necessarily predicts that the PMRCA can be any founding population. Only with moderate or high levels of gene flow can the MRCA occur during Td so that the method may identify PMRCA. Another difficulty arises from the fact that the method assumes an accurate phylogeny reconstructed from DNA sequence differences. Actually, this requirement was hardly met in our data, which showed low levels of polymorphism and the presence of recombination or sequence convergence. In a few regions in our data set, the number of phylogenetically informative sites was discouragingly small, and the phylogenetic relationships among sequences became unreliable.
Instead, we used a parsimony method to infer the ancestral state for each nucleotide. If a particular nucleotide of a sample of human sequences was the same as the one in the chimpanzee, the nucleotide was assumed to have remained unchanged after the species divergence and to be the ancestral type. We determined the MRCA sequence as being the closest to the chimpanzee sequence and defined the population that contained this MRCA sequence as the PMRCA. In reality, it is possible that these MRCA sequences are shared by different populations. There are indeed three such genomic regions, as discussed below. In such case, we used the frequency data. Rare haplotypes in a population are likely to be migrants. If there was a large discrepancy in haplotype frequencies between populations, we assumed that the PMRCA was the population that exhibited the higher haplotype frequency.
Computer Simulation
To confirm the predictions in the preceding section, we carried out computer simulation. The simulation model (fig. 1a
) assumes that there was a single ancestral population in Africa that gave rise to three descendant populations, which founded modern H. sapiens. These founding populations are assumed to have evolved into the current African, European, and Asian populations. Each founding population may consist of local mating groups being connected by gene flow or undergoing extinction or recolonization. Further subdivision within a founding population increases the effective size, whereas extinction and recolonization by groups within the same founding population decrease the effective size (Takahata 1993, 1994
). However, since these effects of within-population subdivision are less important than those among founding populations (Takahata and Klein 1998
), we assume that each of the three founding populations is approximately panmictic. There are Nj breeding individuals in population j (j = 1, 2, and 3), and
3j=1 Nj = NT in the entire population. Unless specified, we consider genes in an autosomal region, so there are 2Nj genes in founding population j.
In simulation, we measured time in units of generations. If one generation spans 20 years, Td would be 50,000100,000 generations. Migration occurs from founding population i to population j with a per-generation rate of mij. In order to keep Nj constant throughout generations, we imposed the condition of Nimij = Njmji; the numbers of immigrants and emigrants between a pair of founding populations were assumed to be the same. We further assumed that N1 N2 = N3, where founding populations 1, 2, and 3 are the African, European, and Asian populations, respectively. The African founding population thus assumed to have been no smaller than the European or Asian founding population. Because of these assumptions, there were only three independent parameters among the six mijs: m21 = m31, m23 = m32, and m12 = m13. In the following simulation, we further assume that m21 = m23, so that when the ratio of N1 to N2 and N3 is specified, only one migration parameter is free to vary. If we designate m12 = m13 by m, m21 = m31 = m23 = m32 = N1m/N2 (=N1m/N3). First, we examined the genealogy of kj neutral genes sampled from the current population of breeding size Nj. Simulation (with 1,000 repeats) was done backward in time to trace the ancestral lines of the sampled genes under genetic drift and migration. Mutations were not superimposed on the genealogical tree. The FORTRAN simulation program (available on request) is a slight extension of that of Takahata (1989)
with respect to migration.
Second, based on the infinite-alleles model (Kimura and Crow 1964
), we developed forward simulation programs for globally and locally advantageous mutations (also available on request). For globally advantageous mutations, we recorded when and in which population new mutations occurred. A new mutation always had relative fitness 1 + s over its parent, (1 + s)2 over its grandparent, and so on. Mutant offspring of the same parent were assumed to be equally advantageous but mutually neutral. Since fitness exceeded 1, we divided individual fitness by the maximum fitness found within each population at a generation and used the results as relative probabilities for 2Nj genes to be chosen for the next generation. This scheme of selection and genetic drift was applied to all three founding populations. A similar but slightly different fitness scheme can be used for locally advantageous mutations. As long as they remain in the birthplace, they are advantageous in exactly the same way as for globally advantageous mutations. However, once locally advantageous mutations move out by migration, they are assumed to become disadvantageous. For an individual gene lineage within each population, we counted the number of mutations which occurred in that population (a), as well as the number of mutations which occurred in the other populations (b). The relative fitness of this gene lineage was determined to be (1 + s)a(1 - s)b. The relative probability was then computed for simulating selection and genetic drift for the next generation. The selected mutation rate was designated u per gene per generation. To save computer time, we assumed relatively small Nj and correspondingly large s, mij, and u. Because of this scaling, Td was also shortened, but Td = 10 NT was kept throughout to imitate a plausible situation. Each simulation starting with three monomorphic populations was repeated 100 times. As under neutrality, we measured TMRCA, PMRCA, and FST, where Td = 10NT generations.
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Results |
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Data Analyses
We examined the currently available DNA sequence data for 10 X-linked and 5 autosomal regions (table 2
): Zfx (Jaruzelska et al. 1999
), dys44 (Zietkiewicz et al. 1997, 1998
; Nachman et al. 1998
), Pdha1 (Nachman et al. 1998
; Harris and Hey 1999
), Xq13.3 (Kaessmann et al. 1999
), Gk, Il2rg, Plp, Hprt, and Ids (Nachman et al. 1998
), Xq22 (Anagnostopoulos et al. 1999
), Ace (Rieder et al. 1999
), a small intergenic region near Mx1 (Jin et al. 1999
), Lpl (Clark et al. 1998
; Nickerson et al. 1998
), ß-globin (Harding et al. 1997
), and Mc1r (Rana et al. 1999
). We also included a Y-linked region (Hammer 1995
) and an mtDNA control region (Vigilant et al. 1991
). Table 2
lists all of these regions, estimates of TMRCA and PMRCA wherever possible, the pattern and degree of nucleotide differences, and FST.
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Second, based on the parsimony method, which allows polychotomy, we inferred the ancestral sequences and the PMRCAs. There were seven regions to which this method was not applied. Both Il2rg and Ids were monomorphic, Ace and Mx1 lacked chimpanzee orthologs, and the Xq22 sequences were not available. For these five regions, we could not infer the PMRCAs. There were two other regions for which we failed to determine the PMRCAs. In the Hprt region, all three ethnic groups possessed the ancestral-type sequences in similar frequencies, and in the Lpl region, recombination occurred too frequently (Templeton et al. 2000
). Figure 5
shows 10 parsimony trees for 9 other regions in which the ancestral sequences (boxed) could be inferred. The PMRCAs at all but Gk loci were determined as Africa. In Gk, there was only one informative site, and the ancestral nucleotide at this site was shared by two Asians and the chimpanzee. We therefore assigned Asia as its PMRCA. For Xq13.3, sequence A (four from Africans and four from Asians) and sequence S (from Biaka Pygmy) were the closest to the chimpanzee sequence, but they differed from each other. Since sequence S branched off earlier than sequence A (fig. 5 ), we assigned Africa as the PMRCA. The MRCA-type sequences for the Plp, ß-globin, and Mc1r regions occurred in more than one population. As mentioned, we used the haplotype frequency data. In each case, the highest frequency (80%, 49%, and 42%) was observed for Africans, so these three PMRCAs were assigned as Africa.
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In any event, there were six X-linked regions (Plp, Gk, Pdha1, Dys44, Zfx, and Xq13.3), two autosomal regions (ß-globin, Mc1r), and one Y-linked region, as well as mtDNA, in which PMRCAs could be inferred. For these 10 regions, there were 9 African PMRCAs and 1 Asian PMRCA (table 2 ). If we ignored the Gk region because it contained only one informative site, then all 9 regions favored the African PMRCA, and the 1% confidence limit of p1 was 0.6. This was significantly greater than 0.45 when the Gk region was included. To be conservative, however, we considered all 10 regions.
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Discussion |
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Assuming neutrality, we carried out fairly extensive simulation to set a lower bound of the African population size. Excluding the cases in which PMRCA went back to the ancestral population (fig. 1 ), simulation yielded the probability of African PMRCAs for various ratios of r. We then compared this probability with the observed value of 9/10 = 0.9. The probability of 90% African PMRCA is as low as 0.01 even for r = 1.5 and becomes nearly 0.4 for r = 1050 (fig. 6 ). These values are slightly different from those discussed based on the binomial distribution. We note two points regarding the simulation. First, when r > 0.5 or N1 > N2 and N3, migration becomes asymmetrical, and the ancestral lineages in smaller founding populations tend to come from a larger founding population. Second, simulation is based on fig. 1a, so there are quite a few cases in which the MRCA occurs in the ancestral population, whereas the previous argument, based on the binomial distribution, assumes no such case.
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Thus, Ne is always greater than NT in a structured population without extinction and recolonization (Nei and Takahata 1993
; Takahata 1993, 1995
). Since the estimated Ne in humans is on the order of 10,000, and FST is about 10% (Takahata 1993
), the total number of breeding individuals is also on this order. For simplicity, we assume that FST = 0.1, as observed for three major ethnic groups (Nei and Roychoudhury 1974
), and Ne = 11,000. We then have NT = 10,000 from the above formula. Therefore, when r = 1.5, we obtain N1 = 6,000 and N2 + N3 = 4,000. On the other hand, for a more likely value of r = 10, N1 is 9,000 and N2 + N3 is only 1,000. Whatever the cause of this small population size in Europe and Asia is, the extent of DNA polymorphism in these geographic areas becomes extremely low, such that it seems difficult to establish regional continuity.
According to the uniregional hypothesis, the transition from H. erectus to anatomically modern H. sapiens had completed in a single founding population by the end of the Td period (fig. 1b ). This transition may have stemmed from globally advantageous mutations. Concerning local differentiation, the hypothesis assumes that a rapid process occurred after modern H. sapiens evolved. Local differentiation might result from locally advantageous mutations, and this process might be facilitated by limited amounts of gene flow and population expansion. The MRCA of those mutations must have occurred in the single founding population from which modern H. sapiens emerged. This also applies to neutral genes in the case of a short tenure of modern H. sapiens relative to the coalescence time. The population-specific pattern of allelic lineages is thus in better agreement with uniregionality than with multiregionality.
Uniregionality does not imply that there was only one population at a given time during Td, but it assumes that one population predominated and the rest played minor roles in the evolution of anatomically modern H. sapiens. Regarding this assumption, it would be of particular interest to compare current human DNA sequences with those extracted from extinct Homo species. Hypervariable regions I and II of the Neanderthal mtDNA were sequenced and compared with the homologous sequences of 689 humans as well as 7 chimpanzees and 2 bonobos (Krings et al. 1997, 1999
). Although some contemporary human sequences are more divergent from each other than from the Neanderthal, the phylogenetic analysis shows that the Neanderthal sequence diverged before the MRCA in the modern human mtDNA pool, followed by divergences of two distinct African lineages. It appears that the Neanderthal and modern human mtDNA lineages separated 465,000 years ago and the MRCA of the present-day human mtDNA occurred 163,000 years ago. The recent analysis of the second Neanderthal specimen from Caucasus also shows an isolated clade of the two Neanderthal mtDNAs (Ovchinnikov et al. 2000
). The long coexistence of the Neanderthal and modern humans has raised questions about the absence of admixture or the possibility that these two species were really reproductively isolated. It turns out that the conditions for detecting admixture are stringent (Nordborg 2001). It is necessary that the population divergence is ancient and the time of admixture is recent. The power of detection of admixture also depends on the extent of admixture. If extensive admixture between Neanderthals and modern human ancestors occurred 30,000 years ago, close to the extinction time of the Neanderthals, and if they diverged 450,000 years ago, close to the estimate of the Neanderthal mtDNA divergence, it may be possible to detect admixture in a sample of current human mtDNAs. However, our inability to detect ancient admixture results largely from single-locus information, and many independent regions are needed to improve the power. This is only possible with autosomal regions, but unfortunately, they may not work at all for the Neanderthals. TMRCA at autosomal regions is on average four times as old as that of mtDNA (table 2
). Because of weaker genetic drift for autosomal regions than for mtDNA, the time of admixture can be as ancient as 100,000 years ago. Yet, the population divergence time must be as long as >1 MYA in order to obtain the same power of detection of ancient admixture. Whereas this is feasible for H. erectus, it is not feasible for Neanderthals.
Finally, we would like to discuss one evolutionary feature of 10 X-chromosomal regions. The mean amount of sequence differences between humans and chimpanzees over the regions was 0.87%. This is nearly one half of either 1.58% of the three autosomal regions examined here or 1.75% over 37 autosomal regions of about 6,500 silent sites (N.T. at Dual Congress 1998, South Africa). Concerning the X-chromosomal regions, we examined the extent of polymorphism in the ancestral population between humans and chimpanzees. It turns out that of the average 0.87% sequence differences, 0.17% were attributed to the ancestral polymorphism, and the remaining 0.68% were attributed to the sequence differences during the past 5 Myr. On the other hand, the 37 autosomal regions divided the 1.75% sequence differences into 0.45% and 1.32%, respectively. Thus, both quantities in the X-chromosomal regions were one half of those in the 37 autosomal regions. One possible cause is a reduction in mutation rates in X chromosomes. The ratio of the X-chromosomal to autosomal sequence differences, however, is even smaller than that expected under the male-driven mutation hypothesis (Miyata et al. 1987
). Although the small extent of ancestral polymorphism at the X-chromosomal regions may be accounted for by a smaller effective size than for the autosomal regions, the reduced substitution rate remains to be elucidated. Despite this, most regions have supported the concept of the uniregionality of modern H. sapiens.
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Acknowledgements |
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Footnotes |
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1 Keywords: Homo sapiens, human evolution
multiregional evolution
recent African origin
population genetics
2 Address for correspondence and reprints: Naoyuki Takahata, Department of Biosystems Science, Graduate University for Advanced Studies, Hayama, Kanagawa 240-0193, Japan. E-mail: takahata{at}soken.ac.jp
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