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Reply to Cordaux and Stoneking

2003; Elsevier BV; Volume: 72; Issue: 6 Linguagem: Inglês

10.1086/375408

1537-6605

Phillip Endicott, Vincent Macaulay, Toomas Kivisild, Chris Stringer, Alan Cooper,

Genetic diversity and population structure

To the Editor: Cordaux and Stoneking (Cordaux and Stoneking, 2003Cordaux R Stoneking M South Asia, the Andamanese and the genetic evidence for an “early” human dispersal out of Africa.Am J Hum Genet. 2003; 72 (in this issue): xxxAbstract Full Text Full Text PDF Scopus (19) Google Scholar [in this issue]) have argued that although there is evidence of anatomically modern humans (AMH) reaching Australia ∼60,000 years ago (see also Bowler et al. Bowler et al., 2003Bowler JM Johnston H Olley JM Prescott JR Roberts RG Shawcross W Spooner NA New evidence for human occupation and climatic change at Lake Mungo, Australia.Nature. 2003; 421: 837-840Crossref PubMed Scopus (494) Google Scholar), there is no convincing genetic evidence that these early migrants passed through South Asia. They see this as obviating the need for a “southern migration” route for AMH out of Africa. They suggest that the ancestors of all known non-African mtDNA lineages (haplogroups M and N) entered Eurasia via the Levant ∼45,000 years ago, prior to differentiating and dispersing to all land areas outside of Africa. Cordaux and Stoneking also seek to use estimated dates for the colonization of the Andaman Islands to lend support to their position. The “crucial points” of evidence cited by Cordaux and Stoneking for their view on the settlement of South Asia are that “the South Asian mtDNA gene pool does not show close affinities to either Africa or PNG” (Papua New Guinea), and that “the archeological record does not show evidence for the presence of modern humans in South Asia before ∼30,000 years ago.” This position is inconsistent, since they first equate “modern” humans with Middle Paleolithic tools in Australia at ∼50,000 years ago (Bowler et al. Bowler et al., 2003Bowler JM Johnston H Olley JM Prescott JR Roberts RG Shawcross W Spooner NA New evidence for human occupation and climatic change at Lake Mungo, Australia.Nature. 2003; 421: 837-840Crossref PubMed Scopus (494) Google Scholar) but later exclude South Asian settlers within the same time frame from being “modern” on the basis of their lithic industries. Here we re-evaluate the evidence for this position and show that the distributions and characteristics of mtDNA and Y-chromosome data actually accord better with a dispersal of AMH into South Asia from Africa >30,000 years ago. The same data also argue for the hypothesized “southern route” “out of Africa,” leaving through Ethiopia via Arabia. We agree with Cordaux and Stoneking that the diversity within Andamanese M2 is potentially useful for giving some idea of the settlement time for the Andaman Islands, because it is plausible that a regionally specific clade in the mtDNA genealogy (in this case, Andamanese M2) had its most recent common ancestor (MRCA) in that region. Of course, it is possible that related mtDNAs in the source population may have disappeared because of drift, but, in that case, the MRCA of the cluster in the settled region could either pre- or postdate the colonization event (for a careful discussion of the issues, see Richards et al. [Richards et al., 2000Richards M Macaulay V Hickey E Vega E Sykes B Guida V Rengo C et al.Tracing European founder lineages in the Near Eastern mtDNA pool.Am J Hum Genet. 2000; 67: 1251-1276Abstract Full Text Full Text PDF PubMed Scopus (745) Google Scholar]). An estimate of the time to the MRCA of the clade, with the available Andamanese data, provides an idea of the latest possible settlement time and not the earliest (contra Barbujani Barbujani et al., 1998Barbujani G Bertorelle G Chikhi L Evidence for Paleolithic and Neolithic gene flow in Europe.Am J Hum Genet. 1998; 62: 488-491Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar and Cordaux and Stoneking Cordaux and Stoneking, 2003Cordaux R Stoneking M South Asia, the Andamanese and the genetic evidence for an “early” human dispersal out of Africa.Am J Hum Genet. 2003; 72 (in this issue): xxxAbstract Full Text Full Text PDF Scopus (19) Google Scholar [in this issue]). There are further statistical problems in the reply by Cordaux and Stoneking. In trying to justify a constant population size model for the Andamanese, they concentrate their calculations on a set of lineages chosen to fall within a particular clade, whereas the usual theory pertains to random sequences from the whole population, which, in the case of the Andamanese, contains the M4 clade. Thus, it is not clear what the sampling distributions of the test statistics under the null hypothesis would be for their approach. Therefore, it is not possible to assess the significance of the values computed. Further, their assertion that the point estimates of divergence are “almost certainly overestimated” because the varied sites are faster mutating than average is based on a misunderstanding of how mutations arise. The number of mutations accumulates proportionally to the average rate for the whole DNA stretch under consideration, irrespective of the individual site rates. Of course, some sites may be hit more than once, but this effect would lead to an underestimation of divergence times. Cordaux and Stoneking introduce the finding by Thangaraj et al. (Thangaraj et al., 2003Thangaraj K Singh L Reddy AG Rao VR Sehgal SC Underhil PA Pierson M Frame IG Hagelberg E Genetic affinities of the Andaman islanders, a vanishing population.Curr Biol. 2003; 13: 86-93Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar) that the present-day indigenous Andamanese belong to Y-chromosome haplogroup D, defined by the mutation M174. Although the date of haplogroup D is not incompatible with the Upper Paleolithic, they assume that both mtDNA and Y chromosome yield similar narratives regarding archeologically defined horizons. However, sex-specific processes may lead to more genetic drift in males than in females, so that the time depth of the Y genealogy would be more recent. Consequently, the apparently discordant Upper and Middle Paleolithic molecular dates, for Y and mtDNA, respectively, would not necessarily be incompatible. There are other reasons that the estimated date to the MRCA of the M174 Y-chromosome clade (27,000–34,000 years) of Cordaux and Stoneking requires clarification. (i) The authors have not provided CIs for their estimate from a sample of just nine M174 individuals from two derived clades, and so the dates given only reflect uncertainty in the mutation rate. (ii) The Y SNP data sets used suffer from strong ascertainment bias (Underhill et al. Underhill et al., 2000Underhill PA Shen P Lin AA Jin L Passarino G Yang WH Kauffman E Bonné-Tamir B Bertranpetit J Francalacci P Ibrahim M Jenkins T Kidd JR Medhi SQ Seielstad MT Wells RS Piazza A Davis RW Feldman MW Cavalli-Sforza LL Oefner PJ Y chromosome sequence variation and the history of human populations.Nat Genet. 2000; 26: 358-361Crossref PubMed Scopus (742) Google Scholar). Therefore, dating methods applicable to randomly selected mutations are likely to be seriously biased when applied to such data. Using the subset of 42 unambiguous Andamanese mtDNA sequences available (Thangaraj et al. Thangaraj et al., 2003Thangaraj K Singh L Reddy AG Rao VR Sehgal SC Underhil PA Pierson M Frame IG Hagelberg E Genetic affinities of the Andaman islanders, a vanishing population.Curr Biol. 2003; 13: 86-93Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar) and considering the region 16090–16365 (Andrews et al. Andrews et al., 1999Andrews RM Kubacka I Chinnery PF Lightowlers RN Turnbull DM Howell N Reanalysis and revision of the Cambridge reference sequence for human mitochondrial DNA.Nat Genet. 1999; 23: 147Crossref PubMed Scopus (2371) Google Scholar) for which a plausible average mutation rate estimate is available (Forster et al. Forster et al., 1996Forster P Harding R Torroni A Bandelt H-J Origin and evolution of Native American mtDNA variation: a reappraisal.Am J Hum Genet. 1996; 59: 935-945PubMed Google Scholar), we estimate the time to the MRCA of the clade with motif 16223/16319/16357 as 33,000 years (SE 22,000) and to 16223/16319 as 53,000 years (SE 30,000). This method is based on the average number of mutations of each sequence from the ancestral one and an estimate of its SE (Saillard et al. Saillard et al., 2000Saillard J Forster P Lynnerup N Bandelt H-J Nørby S mtDNA variation among Greenland Eskimos: the edge of the Beringian expansion.Am J Hum Genet. 2000; 67: 718-726Abstract Full Text Full Text PDF PubMed Scopus (400) Google Scholar). Given the large SEs of these estimates, the statement of Cordaux and Stoneking that this “suggests a colonization event…at most 40,000 years ago” cannot be sustained. In fact, the diversity of Andamanese M2 allows us to pin it down only to the last 100,000 years, but it must necessarily postdate the MRCA of haplogroup M, which is 65,000 years old (SE 7,000), on the basis of a recent dating from complete mtDNA sequences (Mishmar et al. Mishmar et al., 2003Mishmar D Ruiz-Pesini E Golik P Macaulay V Clark AG Hosseini S Brandon M Easley K Chen E Brown MD Sukernik RI Olckers A Wallace DC Natural selection shaped regional mtDNA variation in humans.Proc Natl Acad Sci USA. 2003; 100: 171-176Crossref PubMed Scopus (739) Google Scholar). The current estimate of coalescence for M2, on the basis of HVS-I variation, of 73,000 years (SE 22,900) does not further restrict its age (Kivisild et al. Kivisild et al., 2003Kivisild T Rootsi S Metspalu M Mastana S Kaldma K Parik J Metspalu E Adojaan M Tolk H-V Stepanov V Gölge M Usanga E Papiha SS Cinnioğlu C King R Cavalli-Sforza L Underhill PA Villems R The genetic heritage of the earliest settlers persists in both the Indian tribal and caste populations.Am J Hum Genet. 2003; 72: 313-332Abstract Full Text Full Text PDF PubMed Scopus (279) Google Scholar). Cordaux and Stoneking place their estimates of the first appearance of haplogroup M in South Asia within the context of a “southern route” of dispersal for AMH from Africa to Oceania. This hypothesis is directly linked to the absence of AMH in the Levantine corridor at the time of their putative presence in Australia ∼60,000 years ago. On the other hand, Endicott et al. (Endicott et al., 2003Endicott P Gilbert MTP Stringer C Lalueza-Fox C Willerslev E Hansen AJ Cooper A The genetic origins of the Andaman Islanders.Am J Hum Genet. 2003; 72: 178-184Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar) said “that haplogroup M may represent the phylogenetic signature of an early, southern colonization route in Asia.” Neither the references for this statement nor the authors invoked an early settlement of Australia (contra Cordaux and Stoneking) to explain an African exodus leaving by a southern route (i.e., from Ethiopia via Arabia). Rather, it is the distribution and estimates of coalescence for mtDNA haplogroup M that are the basis for suggesting its early presence in South Asia. All non-Africans have inherited a subset of African mtDNA haplogroup L3 lineages, differentiated into haplogroups M and N. The lack of other L3 lineages among all non-African mitochondria suggests that the earliest migration(s) of AMH already carried those two mtDNA ancestors or that they have replaced previously extant lineages. Haplogroup M is present in Ethiopia, but the rest of M is densely distributed throughout South and East Asia and is absent in the Near East and Europe. If the settlement of Asia by haplogroup M–bearing populations was delayed by the ∼30,000 years alluded to by Cordaux and Stoneking, there is, as yet, no evidence of the source population, either inside or outside of Africa. Since haplogroup M is not present along their hypothesized “northern route” “out-of-Africa,” it seems likely to have been dispersed along the “southern route” and necessarily “early,” since the MRCA of Asian M is ∼65,000 years old (Quintana-Murci et al. Quintana-Murci et al., 1999Quintana-Murci L Semino O Bandelt H-J Passarino G McElreavey K Santachiara-Benerecetti AS Genetic evidence of an early exit of Homo sapiens sapiens from Africa through eastern Africa.Nat Genet. 1999; 23: 437-441Crossref PubMed Scopus (388) Google Scholar; Stringer Stringer, 2000Stringer C Coasting out of Africa.Nature. 2000; 405: 24-27Crossref PubMed Scopus (252) Google Scholar; Mishmar et al. Mishmar et al., 2003Mishmar D Ruiz-Pesini E Golik P Macaulay V Clark AG Hosseini S Brandon M Easley K Chen E Brown MD Sukernik RI Olckers A Wallace DC Natural selection shaped regional mtDNA variation in humans.Proc Natl Acad Sci USA. 2003; 100: 171-176Crossref PubMed Scopus (739) Google Scholar). The distributions, diversity, and ages of haplogroups M and N in India are consistent with this region providing the inocula for the subsequent differentiation of both the distinctive eastern and western Eurasian gene pools (Kivisild et al. Kivisild et al., 2003Kivisild T Rootsi S Metspalu M Mastana S Kaldma K Parik J Metspalu E Adojaan M Tolk H-V Stepanov V Gölge M Usanga E Papiha SS Cinnioğlu C King R Cavalli-Sforza L Underhill PA Villems R The genetic heritage of the earliest settlers persists in both the Indian tribal and caste populations.Am J Hum Genet. 2003; 72: 313-332Abstract Full Text Full Text PDF PubMed Scopus (279) Google Scholar). This is because (i) the percentages of typically eastern and western Eurasian mtDNA lineages present in India are moderately low, (ii) the majority of these lineages are specific to India, and (iii) they contain all the founding haplotypes for the non-African mtDNA gene pool. The time to coalescence of the major M subclusters on the Indian subcontinent center on 47,000 years (SE 2,500 years) and not the ∼30,000 years that Cordaux and Stoneking (Cordaux and Stoneking, 2003Cordaux R Stoneking M South Asia, the Andamanese and the genetic evidence for an “early” human dispersal out of Africa.Am J Hum Genet. 2003; 72 (in this issue): xxxAbstract Full Text Full Text PDF Scopus (19) Google Scholar [in this issue]) allude to (Kivisild et al. Kivisild et al., 1999Kivisild T Kaldma K Metspalu M Parik J Papiha SS Villems R The place of the Indian mitochondrial DNA variants in the global network of maternal lineages and the peopling of the old world.in: Papiha SS Deka R Chakraborty R Genomic diversity: applications in human population genetics. Kluwer/Academic/Plenum, New York1999: 135-152Crossref Google Scholar). These Indian components are comparable in diversity and are older than most eastern Asian and Papuan haplogroup M clusters (Forster et al. Forster et al., 2001Forster P Torroni A Renfrew C Rohl A Phylogenetic star contraction applied to Asian and Papuan mtDNA evolution.Mol Biol Evol. 2001; 18: 1864-1881Crossref PubMed Scopus (187) Google Scholar). This suggests that the Indian subcontinent was settled soon after the African exodus and that there has been no complete extinction, or replacement, of the initial settlers (Kivisild et al. Kivisild et al., 2003Kivisild T Rootsi S Metspalu M Mastana S Kaldma K Parik J Metspalu E Adojaan M Tolk H-V Stepanov V Gölge M Usanga E Papiha SS Cinnioğlu C King R Cavalli-Sforza L Underhill PA Villems R The genetic heritage of the earliest settlers persists in both the Indian tribal and caste populations.Am J Hum Genet. 2003; 72: 313-332Abstract Full Text Full Text PDF PubMed Scopus (279) Google Scholar). Of the Indian haplogroup M lineages, M2 is significant because of its estimated age (73,000 years, SE 20,000), southerly distribution, and frequency (∼10% of caste populations and ∼23% of noncaste populations) (Kivisild et al. Kivisild et al., 1999Kivisild T Kaldma K Metspalu M Parik J Papiha SS Villems R The place of the Indian mitochondrial DNA variants in the global network of maternal lineages and the peopling of the old world.in: Papiha SS Deka R Chakraborty R Genomic diversity: applications in human population genetics. Kluwer/Academic/Plenum, New York1999: 135-152Crossref Google Scholar; Bamshad et al. Bamshad et al., 2001Bamshad M Kivisild T Watkins S Dixon M Ricker C Rao B Naidu J Prasad B Reddy P Rasanayagam A Papiha S Villems R Redd A Hammer M Nguyen S Carroll M Batzer M Jorde L Genetic evidence on the origins of Indian caste populations.Genome Res. 2001; 11: 994-1004Crossref PubMed Scopus (271) Google Scholar; Endicott et al. Endicott et al., 2003Endicott P Gilbert MTP Stringer C Lalueza-Fox C Willerslev E Hansen AJ Cooper A The genetic origins of the Andaman Islanders.Am J Hum Genet. 2003; 72: 178-184Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). The phylogeography of the four non-African Y-chromosomal founder haplogroups C, D, F, and K is also more consistent with the southern route migration than one through the Levantine corridor. This is because (i) the presence of the D lineage in the Andaman Islands completes the package of the postulated founder lineages detected in or around India, and (ii) C and D are spread, like mitochondrial haplogroup M, only in the Asian continent and Oceania (Underhill et al. Underhill et al., 2001Underhill PA Passarino G Lin AA Shen P Lahr MM Foley RA Oefner PJ Cavalli-Sforza LL The phylogeography of Y chromosome binary haplotypes and the origins of modern human populations.Ann Hum Genet. 2001; 65: 43-62Crossref PubMed Scopus (551) Google Scholar; Kivisild et al. Kivisild et al., 2003Kivisild T Rootsi S Metspalu M Mastana S Kaldma K Parik J Metspalu E Adojaan M Tolk H-V Stepanov V Gölge M Usanga E Papiha SS Cinnioğlu C King R Cavalli-Sforza L Underhill PA Villems R The genetic heritage of the earliest settlers persists in both the Indian tribal and caste populations.Am J Hum Genet. 2003; 72: 313-332Abstract Full Text Full Text PDF PubMed Scopus (279) Google Scholar) and not in western Eurasia and North Africa. Further, the upper limit (contra Cordaux and Stoneking Cordaux and Stoneking, 2003Cordaux R Stoneking M South Asia, the Andamanese and the genetic evidence for an “early” human dispersal out of Africa.Am J Hum Genet. 2003; 72 (in this issue): xxxAbstract Full Text Full Text PDF Scopus (19) Google Scholar [in this issue]) for the time of their spread out of Africa would be the coalescent of all three main branches and not of only one of them, D-M174. On the basis of the mtDNA and Y-chromosome data presented here, we see no need to accept the view of Cordaux and Stoneking regarding the settlement of South Asia. To suggest that in this region “the archeological record does not show evidence for the presence of modern humans…before ∼30,000 years ago” is not sustainable if they accept their presence in Australia at ∼60,000 years ago. This Eurocentric view of equating AMH with Upper Paleolithic tools has already been abandoned in the Middle East and Africa (McBrearty and Brooks McBrearty and Brooks, 2000McBrearty S Brooks A The revolution that wasn't: a new interpretation of the origin of modern human behaviour.J Hum Evol. 2000; 39: 453-563Crossref PubMed Scopus (1594) Google Scholar) and, given the Australasian evidence, should be discarded in South Asia, too. We must infer an early dispersal of AMH with non–Upper Paleolithic technology through Asia to explain the early Australian evidence (Stringer Stringer, 2000Stringer C Coasting out of Africa.Nature. 2000; 405: 24-27Crossref PubMed Scopus (252) Google Scholar), although we agree with Cordaux and Stoneking that the precise route(s) taken is still unclear (Stringer Stringer, 2002Stringer C Modern human origins: progress and prospects.Philos Trans R Soc Lond B Biol Sci. 2002; 357: 563-579Crossref PubMed Scopus (364) Google Scholar). But we see no requirement for the South Asian mtDNA gene pool to demonstrate close affinities with either PNG or Africa to discuss an early settlement of this region. Given the continuity of the archeological record within India, from the Middle Paleolithic onward, and the range of estimated dates for Indian haplogroup M, there is no clear reason to preclude the presence of modern humans in this region prior to ∼30,000 years ago. A.C. and V.M. are supported by the Wellcome Trust. The authors thank Martin Richards for a critical reading of the manuscript.