The Molecular Dissection of mtDNA Haplogroup H Confirms That the Franco-Cantabrian Glacial Refuge Was a Major Source for the European Gene Pool
2004; Elsevier BV; Volume: 75; Issue: 5 Linguagem: Inglês
10.1086/425590
ISSN1537-6605
AutoresAlessandro Achilli, Chiara Rengo, Chiara Magri, Vincenza Battaglia, Anna Olivieri, Rosaria Scozzari, Fulvio Cruciani, Massimo Zeviani, Egill Briem, Valério Carelli, Pedro Moral, Jean-Michel Dugoujon, Urmas Roostalu, Eva‐Liis Loogväli, Toomas Kivisild, Hans-Jürgen Bandelt, Martin Richards, Richard Villems, A. Silvana Santachiara‐Benerecetti, Ornella Semino, Antonio Torroni,
Tópico(s)Genetic diversity and population structure
ResumoComplete sequencing of 62 mitochondrial DNAs (mtDNAs) belonging (or very closely related) to haplogroup H revealed that this mtDNA haplogroup—by far the most common in Europe—is subdivided into numerous subhaplogroups, with at least 15 of them (H1–H15) identifiable by characteristic mutations. All the haplogroup H mtDNAs found in 5,743 subjects from 43 populations were then screened for diagnostic markers of subhaplogroups H1 and H3. This survey showed that both subhaplogroups display frequency peaks, centered in Iberia and surrounding areas, with distributions declining toward the northeast and southeast—a pattern extremely similar to that previously reported for mtDNA haplogroup V. Furthermore, the coalescence ages of H1 and H3 (∼11,000 years) are close to that previously reported for V. These findings have major implications for the origin of Europeans, since they attest that the Franco-Cantabrian refuge area was indeed the source of late-glacial expansions of hunter-gatherers that repopulated much of Central and Northern Europe from ∼15,000 years ago. This has also some implications for disease studies. For instance, the high occurrence of H1 and H3 in Iberia led us to re-evaluate the haplogroup distribution in 50 Spanish families affected by nonsyndromic sensorineural deafness due to the A1555G mutation. The survey revealed that the previously reported excess of H among these families is caused entirely by H3 and is due to a major, probably nonrecent, founder event. Complete sequencing of 62 mitochondrial DNAs (mtDNAs) belonging (or very closely related) to haplogroup H revealed that this mtDNA haplogroup—by far the most common in Europe—is subdivided into numerous subhaplogroups, with at least 15 of them (H1–H15) identifiable by characteristic mutations. All the haplogroup H mtDNAs found in 5,743 subjects from 43 populations were then screened for diagnostic markers of subhaplogroups H1 and H3. This survey showed that both subhaplogroups display frequency peaks, centered in Iberia and surrounding areas, with distributions declining toward the northeast and southeast—a pattern extremely similar to that previously reported for mtDNA haplogroup V. Furthermore, the coalescence ages of H1 and H3 (∼11,000 years) are close to that previously reported for V. These findings have major implications for the origin of Europeans, since they attest that the Franco-Cantabrian refuge area was indeed the source of late-glacial expansions of hunter-gatherers that repopulated much of Central and Northern Europe from ∼15,000 years ago. This has also some implications for disease studies. For instance, the high occurrence of H1 and H3 in Iberia led us to re-evaluate the haplogroup distribution in 50 Spanish families affected by nonsyndromic sensorineural deafness due to the A1555G mutation. The survey revealed that the previously reported excess of H among these families is caused entirely by H3 and is due to a major, probably nonrecent, founder event. For most of human evolution, and particularly during the recent process of diffusion from Africa to the other continents, the relatively fast evolution of human mitochondrial DNAs (mtDNAs) has occurred in a context of small founding populations. Thus, founder events and genetic drift have played a major role in shaping haplotype frequencies, giving rise to haplogroups and subhaplogroups that are often restricted to specific geographic areas and/or population groups. In Europe, with the exception of U5 and V, which most likely arose in situ, all mtDNA haplogroups (H, I, J, K, T, U2e, U3, U4, X, and W) are most likely of Middle Eastern origin and were introduced by either the protocolonization ∼45–40 thousand years ago (kya), by later arrivals in the Middle/Late Upper Paleolithic, Neolithic dispersals, or by more recent contacts (Torroni et al. Torroni et al., 1998Torroni A Bandelt H-J D’Urbano L Lahermo P Moral P Sellitto D Rengo C Forster P Savontaus M-L Bonné-Tamir B Scozzari R MtDNA analysis reveals a major late Palaeolithic population expansion from southwestern to northeastern Europe.Am J Hum Genet. 1998; 62: 1137-1152Abstract Full Text Full Text PDF PubMed Scopus (295) Google Scholar; 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 (781) Google Scholar). For some haplogroups, particularly the more common ones, multiple chronologically distinct arrivals to Europe are extremely likely. In addition, the genetic landscape of Europe has probably been further confounded by the major climatic changes that have occurred since the arrival of the first modern humans. In particular, the early Paleolithic populations of Northern and Central Europe either became extinct or retreated to the south during the Last Glacial Maximum (LGM) ∼20 kya, and there was a gradual repeopling from southern refuge areas only when climatic conditions improved, from ∼15 kya. This scenario is supported not only by recent work on archaeological dating (Housley et al. Housley et al., 1997Housley RA Gamble CS Street M Pettitt P Radiocarbon evidence for the lateglacial human recolonisation of northern Europe.Proc Prehist Soc. 1997; 63: 25-54Crossref Google Scholar; Richards Richards, 2003Richards M The Neolithic invasion of Europe.Annu Rev Anthropol. 2003; 32: 135-162Crossref Scopus (102) Google Scholar) but also by the phylogeographic evidence provided by mtDNA haplogroup V (Torroni et al. Torroni et al., 1998Torroni A Bandelt H-J D’Urbano L Lahermo P Moral P Sellitto D Rengo C Forster P Savontaus M-L Bonné-Tamir B Scozzari R MtDNA analysis reveals a major late Palaeolithic population expansion from southwestern to northeastern Europe.Am J Hum Genet. 1998; 62: 1137-1152Abstract Full Text Full Text PDF PubMed Scopus (295) Google Scholar; 2001a) and Y-chromosome haplogroups R1b and I1b2 (Semino et al. Semino et al., 2000Semino O Passarino G Oefner PJ Lin AA Arbuzova S Beckman LE De Benedictis G Francalacci P Kouvatsi A Limborska S Marcikiae M Mika A Mika B Primorac D Santachiara-Benerecetti AS Cavalli-Sforza LL Underhill PA The genetic legacy of Paleolithic Homo sapiens sapiens in extant Europeans: a Y chromosome perspective.Science. 2000; 290: 1155-1159Crossref PubMed Scopus (639) Google Scholar; Cinnioğlu et al. Cinnioğlu et al., 2004Cinnioğlu C King R Kivisild T Kalfoglu E Atasoy S Cavalleri GL Lillie AS Roseman CC Lin AA Prince K Oefner PJ Shen P Semino O Cavalli-Sforza LL Underhill PA Excavating Y-chromosome haplotype strata in Anatolia.Hum Genet. 2004; 114: 127-148Crossref PubMed Scopus (298) Google Scholar; Rootsi et al. Rootsi et al., 2004Rootsi S Magri C Kivisild T Benuzzi G Help H Bermisheva M Kutuev I et al.Phylogeography of Y-chromosome haplogroup I reveals distinct domains of prehistoric gene flow in Europe.Am J Hum Genet. 2004; 75: 128-137Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar). Among the mtDNA haplogroups of Europe, haplogroup H displays two unique features: an extremely wide geographic distribution and a very high frequency in most of its range. Indeed, it is by far the most prevalent haplogroup in all European populations except the Saami, is very common in North Africa and the Middle East, and retains frequencies of 5%–10% even in northern India and Central Asia, at the edges of its distribution range (Richards et al. Richards et al., 2002Richards M Macaulay V Torroni A Bandelt H-J In search of geographical patterns in European mitochondrial DNA.Am J Hum Genet. 2002; 71: 1168-1174Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar). Previous studies have proposed that haplogroup H (i) originated in the Middle East ∼30–25 kya; (ii) expanded into Europe in association with a second Paleolithic wave, possibly contemporary with the diffusion of the Gravettian technology (25–20 kya); and (iii) was strongly involved in the late-glacial expansions from ice-age refugia after the LGM (Torroni et al. Torroni et al., 1998Torroni A Bandelt H-J D’Urbano L Lahermo P Moral P Sellitto D Rengo C Forster P Savontaus M-L Bonné-Tamir B Scozzari R MtDNA analysis reveals a major late Palaeolithic population expansion from southwestern to northeastern Europe.Am J Hum Genet. 1998; 62: 1137-1152Abstract Full Text Full Text PDF PubMed Scopus (295) Google Scholar; 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 (781) Google Scholar). In addition, because of its high frequency and wide distribution, haplogroup H most likely participated in all subsequent episodes of putative gene flow in western Eurasia, such as the Neolithic diffusion of agriculture from the Near East, the expansion of the Kurgan culture from southern Ukraine, and the recent events of gene flow to northern India. As a result, it is likely that the dissection of H into subhaplogroups of younger age might reveal previously unidentified spatial frequency patterns, which in turn could be correlated to prehistoric and historical migratory events. However, until now, haplogroup H has been only partially resolved genealogically (Herrnstadt et al. Herrnstadt et al., 2002Herrnstadt C Elson JL Fahy E Preston G Turnbull DM Anderson C Ghosh SS Olefsky JM Beal FM Davis RE Howell N Reduced-median-network analysis of complete mitochondrial DNA coding-region sequences for the major African, Asian, and European haplogroups.Am J Hum Genet. 2002; 70 (erratum 71:448–449): 1152-1171Abstract Full Text Full Text PDF PubMed Scopus (446) Google Scholar) allowing for the identification of 11 subclades (H1–H11) (Quintáns et al. Quintáns et al., 2004Quintáns B Álvarez-Iglesias V Salas A Phillips C Lareu MV Carracedo A Typing of mitochondrial DNA coding region SNPs of forensic and anthropological interest using SNaPshot minisequencing.Forensic Sci Int. 2004; 140: 251-257Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar; Loogväli et al. Loogväli et al., in pressLoogväli EL, Roostalu U, Malyarchuk BA, Derenko MV, Kivisild T, Metspalu E, Tambets K, et al (2004) Disuniting uniformity: a pied cladistic canvas of mtDNA haplogroup H in Eurasia. Mol Biol Evol (in press)Google Scholar), the phylogeography of which has been evaluated only in rare instances (Tambets et al. Tambets et al., 2004Tambets K Rootsi S Kivisild T Help H Serk P Loogväli EL Tolk HV et al.The western and eastern roots of the Saami—the story of genetic “outliers” told by mitochondrial DNA and Y chromosomes.Am J Hum Genet. 2004; 74: 661-682Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar). Therefore, the objective of this study is to provide new information concerning the molecular dissection of haplogroup H and to determine whether its subhaplogroups do indeed show such spatial patterns. To achieve this objective, the first step consisted in the complete sequencing of 62 mtDNAs performed as described by Torroni et al. (Torroni et al., 2001bTorroni A Rengo C Guida V Cruciani F Sellitto D Coppa A Calderon FL Simionati B Valle G Richards M Macaulay V Scozzari R Do the four clades of the mtDNA haplogroup L2 evolve at different rates?.Am J Hum Genet. 2001b; 69: 1348-1356Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar). Fifty-four of the mtDNAs that were chosen for complete sequencing harbored −7025 AluI and −14766 MseI, two well-known diagnostic RFLP markers of haplogroup H. In addition, for the choice of these mtDNAs, we also took into account the nature and extent of the sequence variation observed in a preliminary sequence analysis restricted to the control region; the objective being to include the widest possible range of haplogroup H internal variation. The remaining eight mtDNAs were chosen because the RFLP analysis and control-region sequencing had suggested that they belonged to haplogroups that were closely related to H. Thus, their complete sequences would allow the definition of the branching order of the entire superhaplogroup HV. A tree of the 62 complete mtDNA sequences (authors' Web site; GenBank) is illustrated in figure 1, which also incorporates information from previous studies about shared mutations in minor subbranches (Ingman et al. Ingman et al., 2000Ingman M Kaessmann H Pääbo S Gyllensten U Mitochondrial genome variation and the origin of modern humans.Nature. 2000; 408: 708-713Crossref PubMed Scopus (1026) Google Scholar; Finnilä et al. Finnilä et al., 2001Finnilä S Lehtonen MS Majamaa K Phylogenetic network for European mtDNA.Am J Hum Genet. 2001; 68: 1475-1484Abstract Full Text Full Text PDF PubMed Scopus (289) Google Scholar; Herrnstadt et al. Herrnstadt et al., 2002Herrnstadt C Elson JL Fahy E Preston G Turnbull DM Anderson C Ghosh SS Olefsky JM Beal FM Davis RE Howell N Reduced-median-network analysis of complete mitochondrial DNA coding-region sequences for the major African, Asian, and European haplogroups.Am J Hum Genet. 2002; 70 (erratum 71:448–449): 1152-1171Abstract Full Text Full Text PDF PubMed Scopus (446) Google Scholar, Herrnstadt et al., 2003Herrnstadt C Preston G Howell N Errors, phantom and otherwise, in human mtDNA sequences.Am J Hum Genet. 2003; 72: 1585-1586Abstract Full Text Full Text PDF PubMed Scopus (42) 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 (786) Google Scholar; Coble et al. Coble et al., 2004Coble MD Just RS O’Callaghan JE Letmanyi IH Peterson CT Irwin JA Parsons TJ Single nucleotide polymorphisms over the entire mtDNA genome that increase the power of forensic testing in Caucasians.Int J Legal Med. 2004; 118: 137-146Crossref PubMed Scopus (186) Google Scholar). The phylogeny reveals that superhaplogroup pre-HV first splits into the minor haplogroup (pre-HV)1 and the major haplogroup HV, in which pre-V, HV1, and other branches of HV are all sister haplogroups of H (Macaulay et al. Macaulay et al., 1999Macaulay V Richards M Hickey E Vega E Cruciani F Guida V Scozzari R Bonne-Tamir B Sykes B Torroni A The emerging tree of West Eurasian mtDNAs: a synthesis of control-region sequences and RFLPs.Am J Hum Genet. 1999; 64: 232-249Abstract Full Text Full Text PDF PubMed Scopus (509) Google Scholar; Torroni et al. Torroni et al., 2001aTorroni A Bandelt H-J Macaulay V Richards M Cruciani F Rengo C Martinez-Cabrera V et al.A signal, from human mtDNA, of postglacial recolonization in Europe.Am J Hum Genet. 2001a; 69: 844-852Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar). As for the haplogroup H mtDNAs, the phylogenetic analysis confirmed a very large number of independent basal branches, some giving rise to subclades that have several basal subbranches themselves (fig. 1). Among these subclades, representatives of all previously proposed subhaplogroups (H1–H11) were present. However, we noticed that subhaplogroup H9 of Loogväli et al. (Loogväli et al., in pressLoogväli EL, Roostalu U, Malyarchuk BA, Derenko MV, Kivisild T, Metspalu E, Tambets K, et al (2004) Disuniting uniformity: a pied cladistic canvas of mtDNA haplogroup H in Eurasia. Mol Biol Evol (in press)Google Scholar), is actually a subclade of H6, as attested by the control-region mutational motif of sequence S092 reported by Howell et al. (Howell et al., 2003Howell N Oostra RJ Bolhuis PA Spruijt L Clarke LA Mackey DA Preston G Herrnstadt C Sequence analysis of the mitochondrial genomes from Dutch pedigrees with Leber hereditary optic neuropathy.Am J Hum Genet. 2003; 72: 1460-1469Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar). In addition, 18 of our H sequences did not fit in any of the known subhaplogroups, but 7 harbored control-region and/or coding-region mutations already seen in H mtDNAs from published and unpublished data sets, thus suggesting that those mutations might characterize additional relatively common clades. To these clades, we assigned the following novel subhaplogroup names: H9 (3591-4310-13020-16168), thus replacing the H9 proposed by Loogväli et al. (Loogväli et al., in pressLoogväli EL, Roostalu U, Malyarchuk BA, Derenko MV, Kivisild T, Metspalu E, Tambets K, et al (2004) Disuniting uniformity: a pied cladistic canvas of mtDNA haplogroup H in Eurasia. Mol Biol Evol (in press)Google Scholar); H12 (3936-14552-16287); H13 (2259-4745-13680-14872); H14 (7645-11377); and H15 (55-57-6253). For the time being, taking into account the possibility that their mutational motifs could be very uncommon, no names were assigned to the remaining 11 H sequences shown in figure 1. Among the 15 defined subhaplogroups of H, 2 appeared by far the most frequently in our sample; these were H1 and H3, encompassing 12 and 10 mtDNAs, respectively. This suggested that, if the high incidence of H1 and H3 was a real feature of haplogroup H and was not restricted to our selected H sample, a detailed phylogeographic analysis focused on these two subhaplogroups could be particularly informative in revealing spatial patterns. To evaluate this possibility, we performed a detailed molecular survey of all the H mtDNAs found in 5,743 subjects (who had signed appropriate informed consents) from 43 populations of Europe, North Africa, the Middle East, the Caucasus, and Central Asia (table 1 and fig. 2). The H mtDNAs were screened for the presence of the transitions G3010A and T6776C, which mark haplogroups H1 and H3, respectively. The 3010 mutation was detected as a TaqI site loss at np 3008 by use of the mismatched primer 2988FOR (5′-cgatgttggatcaggacatctc), whereas the 6776 mutation was identified as an NlaIII site gain at np 6773 by use of the mismatched primer 6807REV (5′-gtgtgtctacgtctattcctactgtaaaca).Table 1Population Distribution and Frequencies of Haplogroup H, H1, and H3 mtDNAsSubhaplogroup Frequency (%)Region, ID Number, and PopulationNo. of SubjectsH Frequency (%)H1H3Africa: 1. Senegal100……… 2. Berbers (Morocco)12536.819.21.6 3. Algeria8225.69.8… 4. Tunisia8326.59.61.2 5. Berbers (Egypt)711.41.4…Europe: 6. Andalusia10343.724.34.9 7. Spain (miscellaneous)13239.418.93.8 8. GaliciaaFrom Quintáns et al. (2004).26645.117.78.3 9. Pasiegos (Cantabria)5135.323.52.0 10. Basques (Spain)10851.927.813.9 11. Basques (France)4040.017.55.0 12. Béarnaise2725.914.87.4 13. FrancebThis data set is from Loogväli et al. (2004).10647.212.35.7 14. Netherlands3438.28.82.9 15. AustriacFrom Brandstätter et al. (2003).27744.814.42.2 16. Italy (north)32246.911.55.0 17. Italy (center)20835.66.33.8 18. Sardinia10642.517.98.5 19. Italy (south)20637.98.72.4 20. Sicily9048.910.02.2 21. Greece (mainland)7941.86.31.3 22. Greece (Aegean islands)24744.11.6.4 23. Macedonia (Northern Greece)5240.47.7… 24. Albania10548.62.9… 25. Croatia8444.08.36.0 26. Hungary13042.312.36.2 27. SlovaksbThis data set is from Loogväli et al. (2004).11942.07.6.8 28. Czech Republic10241.210.82.0 29. Poland8637.29.33.5 30. UkrainedIncludes 100 mtDNAs from Loogväli et al. (2004).19140.89.92.1 31. RussiabThis data set is from Loogväli et al. (2004).31240.113.51.6 32. EstoniabThis data set is from Loogväli et al. (2004).11443.916.72.6 33. Saami575.3…… 34. Volga-Ural Finnic speakersbThis data set is from Loogväli et al. (2004).12540.013.6…Caucasus: 35. Caucasus (north)6827.98.8… 36. Caucasus (south)13221.22.3.8Middle East: 37. TurkeyeIncludes 192 mtDNAs from Loogväli et al. (2004).24226.05.0… 38. Druze5817.23.4… 39. Iraq20619.91.9… 40. Arabian Peninsula9410.6……Asia: 41. Pakistan10012.0…… 42. Central AsiabThis data set is from Loogväli et al. (2004).44511.2.7.2 43. Yakutia588.61.71.7a From Quintáns et al. (Quintáns et al., 2004Quintáns B Álvarez-Iglesias V Salas A Phillips C Lareu MV Carracedo A Typing of mitochondrial DNA coding region SNPs of forensic and anthropological interest using SNaPshot minisequencing.Forensic Sci Int. 2004; 140: 251-257Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar).b This data set is from Loogväli et al. (Loogväli et al., in pressLoogväli EL, Roostalu U, Malyarchuk BA, Derenko MV, Kivisild T, Metspalu E, Tambets K, et al (2004) Disuniting uniformity: a pied cladistic canvas of mtDNA haplogroup H in Eurasia. Mol Biol Evol (in press)Google Scholar).c From Brandstätter et al. (Brandstätter et al., 2003Brandstätter A Parsons TJ Parson W Rapid screening of mtDNA coding region SNPs for the identification of west European Caucasian haplogroups.Int J Legal Med. 2003; 117: 291-298Crossref PubMed Scopus (112) Google Scholar).d Includes 100 mtDNAs from Loogväli et al. (Loogväli et al., in pressLoogväli EL, Roostalu U, Malyarchuk BA, Derenko MV, Kivisild T, Metspalu E, Tambets K, et al (2004) Disuniting uniformity: a pied cladistic canvas of mtDNA haplogroup H in Eurasia. Mol Biol Evol (in press)Google Scholar).e Includes 192 mtDNAs from Loogväli et al. (Loogväli et al., in pressLoogväli EL, Roostalu U, Malyarchuk BA, Derenko MV, Kivisild T, Metspalu E, Tambets K, et al (2004) Disuniting uniformity: a pied cladistic canvas of mtDNA haplogroup H in Eurasia. Mol Biol Evol (in press)Google Scholar). Open table in a new tab The results of this survey are reported in table 1 and are illustrated in the spatial distribution of figure 3. Subhaplogroup H1 turned out to encompass a large proportion of H in the western part of its distribution range. It has a frequency peak among the Basques of Spain (27.8%) and very high frequencies in the rest of Iberia (17.7%–24.3%), Morocco (19.2%), and Sardinia (17.9%). The spatial pattern depicted in figure 3 appears to indicate the presence of an overall gradient for H1, with a peak centered at the most southwestern edge of Europe and in Morocco and declining frequencies towards both the northeast and southeast. Compared to H1, subhaplogroup H3 represents a much smaller fraction of H (table 1). However, its highest frequencies are found among the Basques of Spain (13.9%), in Galicia (8.3%), and, again, in Sardinia (8.5%)—in other words, in the same areas where H1 is also most frequent. The frequency decline of both H1 and H3 from their peaks centered in southwestern Europe is not completely uniform, but a few intermediate local peaks are also observed. Both Austria and Estonia harbor peaks for haplogroup H1 (14.4% and 16.7%, respectively), whereas a local maximum of H3 is observed in Hungary (6.2%). Some intermediate peaks are indeed expected, as a result of random genetic drift. However, in some instances, these could also indicate a more direct genetic link of the populations living in these areas with those of southwestern Europe than with their current surrounding neighbors. Thus, although the frequency distribution of haplogroup H overall in Europe is rather uniform (fig. 2), those of H1 and H3 harbor clear-cut patterns, with peaks both centered in Iberia and surrounding areas. We noted with great interest that such frequency patterns are extremely similar to that previously described for haplogroup V, an autochthonous European haplogroup, which most likely originated in the northern Iberian Peninsula or southwestern France at about the time of the Younger Dryas (Torroni et al. Torroni et al., 1998Torroni A Bandelt H-J D’Urbano L Lahermo P Moral P Sellitto D Rengo C Forster P Savontaus M-L Bonné-Tamir B Scozzari R MtDNA analysis reveals a major late Palaeolithic population expansion from southwestern to northeastern Europe.Am J Hum Genet. 1998; 62: 1137-1152Abstract Full Text Full Text PDF PubMed Scopus (295) Google Scholar, Torroni et al., 2001aTorroni A Bandelt H-J Macaulay V Richards M Cruciani F Rengo C Martinez-Cabrera V et al.A signal, from human mtDNA, of postglacial recolonization in Europe.Am J Hum Genet. 2001a; 69: 844-852Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar; Richards Richards, 2003Richards M The Neolithic invasion of Europe.Annu Rev Anthropol. 2003; 32: 135-162Crossref Scopus (102) Google Scholar). The distribution of haplogroup V was attributed to a major Paleolithic/Mesolithic population expansion from southwestern Europe, which occurred 13–10 kya and eventually carried those mtDNAs into Central and Northern Europe following the postglacial improvement of the climate conditions. To determine if the distributions of H1 and H3 could be attributed to the same phenomenon, we estimated the coalescence ages of the two subhaplogroups from the sequence data reported in figure 1. To obtain the estimates, only the coding-region data were used, according to 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 (786) Google Scholar). When all 54 H sequences were included, the coalescence estimate for the entire haplogroup H was 18.4 ± 2.0 kya (table 2); a value that, taking into account that the large majority of the H mtDNAs we sequenced are from Western Europe, is in good agreement with those proposed in the past (Torroni et al. Torroni et al., 1998Torroni A Bandelt H-J D’Urbano L Lahermo P Moral P Sellitto D Rengo C Forster P Savontaus M-L Bonné-Tamir B Scozzari R MtDNA analysis reveals a major late Palaeolithic population expansion from southwestern to northeastern Europe.Am J Hum Genet. 1998; 62: 1137-1152Abstract Full Text Full Text PDF PubMed Scopus (295) Google Scholar; 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 (781) Google Scholar; Loogväli et al. Loogväli et al., in pressLoogväli EL, Roostalu U, Malyarchuk BA, Derenko MV, Kivisild T, Metspalu E, Tambets K, et al (2004) Disuniting uniformity: a pied cladistic canvas of mtDNA haplogroup H in Eurasia. Mol Biol Evol (in press)Google Scholar). As expected, when only mtDNAs belonging to H1 and H3 were included, younger coalescence times were obtained. They were 12.8 ± 2.4 kya for H1, and 10.3 ± 2.4 kya for H3. These coalescence ages are very similar, and they become even more similar (10.8 ± 1.1 kya and 11.0 ± 1.4 kya, respectively) when the estimates are obtained by inclusion of previously published H1 and H3 sequences (table 2). Furthermore, they overlap to the coalescence time (11.2 ± 2.7 kya) estimated for haplogroup V from control-region data (Torroni et al. Torroni et al., 2001aTorroni A Bandelt H-J Macaulay V Richards M Cruciani F Rengo C Martinez-Cabrera V et al.A signal, from human mtDNA, of postglacial recolonization in Europe.Am J Hum Genet. 2001a; 69: 844-852Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar) and the coalescence time (12.4 ± 2.5 kya) that can now be estimated from the pool of the 66 available coding-region sequences belonging to V (table 2). Then, the assumption of a common origin and spread for H1, H3, and V would give an averaged age of 11.3 ± 0.9 kya. This estimate would be consistent with an origin of these haplogroups, say, in the terminal Pleistocene (16–11.5 kya), with major expansion in the early Holocene (perhaps ∼10 kya, when vegetation stabilized) (Roberts Roberts, 1998Roberts N The Holocene—an environmental history. 2nd ed. Blackwell, Oxford1998Google Scholar).Table 2Age Estimates of Haplogroups H, H1, H3, and VHaplogroup and Source of DataNo. of mtDNAsρaThe average number of base substitutions in the mtDNA coding region (between nps 577 and 16023) from the ancestral sequence type.σbStandard error calculated from an estimate of the genealogy, in the manner of Saillard et al. (2000).T ± ΔT (kya)cEstimate of the time to the most recent common ancestor of each cluster, using an evolutionary rate estimate of 1.26±0.08×10−8 base substitutions per nucleotide per year in the coding region (Mishmar et al. 2003), corresponding to 5,140 years per substitution in the whole coding region.H: This study543.574.39518.4 ± 2.0H1: This study122.500.46412.8 ± 2.4 TotaldThe sequences from this study plus the coding-region sequences from the studies by Ingman et al. (2000), Finnilä et al. (2001), Herrnstadt et al. (2002, 2003), Mishmar et al. (2003), and Coble et al. (2004).1342.112.21910.8 ± 1.1H3: This study102.000.45810.3 ± 2.4 TotaldThe sequences from this study plus the coding-region sequences from the studies by Ingman et al. (2000), Finnilä et al. (2001), Herrnstadt et al. (2002, 2003), Mishmar et al. (2003), and Coble et al. (2004).502.140.27911.0 ± 1.4V: TotaldThe sequences from this study plus the coding-region sequences from the studies by Ingman et al. (2000), Finnilä et al. (2001), Herrnstadt et al. (2002, 2003), Mishmar et al. (2003), and Coble et al. (2004).662.409.49012.4 ± 2.5a The average number of base substitutions in the mtDNA coding region (between nps 577 and 16023) from the ancestral sequence type.b Standard error calculated from an estimate of the genealogy, in the manner of 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 (415) Google Scholar).c Estimate of the time to the most recent common ancestor of each cluster, using an evolutionary rate estimate of 1.26±0.08×10−8 base substitutions per nucleotide per year in the coding region (Mishmar et al. Mishmar et al., 2003Mishmar D Ruiz-
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