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A substantial prehistoric European ancestry amongst Ashkenazi maternal lineages

A substantial prehistoric European ancestry amongst Ashkenazi maternal lineages
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  ARTICLE Received 11 Jul 2013 | Accepted 4 Sep 2013 | Published 8 Oct 2013 A substantial prehistoric European ancestryamongst Ashkenazi maternal lineages Marta D. Costa 1,2, *, Joana B. Pereira 1,2, *, Maria Pala 3 , Vero´nica Fernandes 1,2 , Anna Olivieri 4 , Alessandro Achilli 5 ,Ugo A. Perego 4,6 , Sergei Rychkov 7 , Oksana Naumova 7 , Jirˇi Hatina 8 , Scott R. Woodward 6,9 , Ken Khong Eng 1,10 ,Vincent Macaulay 11 , Martin Carr 3 , Pedro Soares 2 , Luı´sa Pereira 2,12 & Martin B. Richards 1,3 The srcins of Ashkenazi Jews remain highly controversial. Like Judaism, mitochondrial DNAis passed along the maternal line. Its variation in the Ashkenazim is highlydistinctive, with four major and numerous minor founders. However, due to their rarity in thegeneral population, these founders have been difficult to trace to a source. Here we show thatall four major founders, B 40% of Ashkenazi mtDNA variation, have ancestry in prehistoricEurope, rather than the Near East or Caucasus. Furthermore, most of the remaining minorfounders share a similar deep European ancestry. Thus the great majority of Ashkenazimaternal lineages were not brought from the Levant, as commonly supposed, nor recruited inthe Caucasus, as sometimes suggested, but assimilated within Europe. These results point toa significant role for the conversion of women in the formation of Ashkenazi communities,and provide the foundation for a detailed reconstruction of Ashkenazi genealogical history. DOI: 10.1038/ncomms3543  OPEN 1 Institute of Integrative and Comparative Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.  2 IPATIMUP (Instituto de Patologia eImunologia Molecular da Universidade do Porto), Porto 4200-465, Portugal.  3 School of Applied Sciences, University of Huddersfield, Queensgate,Huddersfield HD1 3DH, UK.  4 Dipartimento di Biologia e Biotecnologie, Universita` di Pavia, Pavia 27100, Italy.  5 Dipartimento di Chimica, Biologia eBiotecnologie, Universita` di Perugia, Perugia 06123, Italy.  6 Sorenson Molecular Genealogy Foundation, Salt Lake City, Utah 84115, USA.  7 Vavilov Institute ofGeneral Genetics, Moscow 119991, Russia.  8 Charles University, Medical Faculty in Pilsen, Institute of Biology, CZ-301 66 Pilsen, Czech Republic.  9 Ancestry,Provo, Utah 84604, USA.  10 Centre for Global Archaeological Research, Universiti Sains Malaysia, 11800 USM Penang, Malaysia.  11 School of Mathematicsand Statistics, University of Glasgow, Glasgow G12 8QQ, UK.  12 Faculdade de Medicina da Universidade do Porto, Porto 4200-319, Portugal. *These authorscontributed equally to this work. Correspondence and requests for materials should be addressed to M.B.R. (email: NATURE COMMUNICATIONS|4:2543|DOI: 10.1038/ncomms3543|  1 &  2013  Macmillan Publishers Limited. All rights reserved.  T he origins of Ashkenazi Jews—the great majority of living Jews—remain highly contested and enigmatic tothis day  1–11 . The Ashkenazim are Jews with a recentancestry in central and Eastern Europe, in contrast to Sephardim(with an ancestry in Iberia, followed by exile after 1492),Mizrahim (who have always resided in the Near East) andNorth African Jews (comprising both Sephardim and Mizrahim).There is consensus that all Jewish Diaspora groups, including the Ashkenazim, trace their ancestry, at least in part, to theLevant,  B 2,000–3,000 years ago 5,12–14 . There were Diasporacommunities throughout Mediterranean Europe and the NearEast for several centuries prior to the destruction of the SecondTemple in Jerusalem in 70 CE (Common Era), and some scholarssuggest that their scale implies proselytism and wide-scaleconversion, although this view is very controversial 9,15 .The Ashkenazim are thought to have emerged from dispersalsnorth into the Rhineland of Mediterranean Jews in the early Middle Ages, although there is little evidence before the twelfthcentury  5,15 . After expulsions from Western Europe between thethirteenth and fifteenth centuries, the communities are thought tohave expanded eastwards, especially in Poland, Lithuania andthen Russia. The implied scale of this expansion has led some toargue, again very controversially, for mass conversions in theKhazar kingdom, in the North Caucasus region to the north andeast of the Black Sea, following the Khazar leadership’s adoptionof Judaism between the ninth and tenth centuries CE 8,9 .We are then faced with several competing models forAshkenazi srcins: a Levantine ancestry; a Mediterranean/westEuropean ancestry; a North Caucasian ancestry; or, of course, ablend of these. This seems an ideal problem to tackle with geneticanalysis, but after decades of intensive study a definitive answerremains elusive. Although we might imagine that such anapparently straightforward admixture question might be readily addressed using genome-wide autosomal markers, recent studieshave proposed contradictory conclusions. Several suggest aprimarily Levantine ancestry with south/west European admix-ture 3,4 , but another concludes that the ancestry is largely Caucasian 16 , implying a major source from converts in theKhazar kingdom 17 . An important reason for disagreement is thatthe Ashkenazim have undergone severe founder effects during their history, drastically altering the frequencies of geneticmarkers and distorting the relationship with their ancestralpopulations.This problem can be resolved by reconstructing the relation-ships genealogically, rather than relying on allele frequencies,using the non-recombining marker systems: the paternally inherited male-specific part of the Y chromosome (MSY) andthe maternally inherited mitochondrial DNA (mtDNA). Thiskind of analysis can be very powerful, because nesting of particular lineages within clusters from a particular geographicalregion allows us to pinpoint the source for those lineages, by applying the parsimony principle. This has indeed beenattempted, with the MSY results interpreted plausibly to suggestan overwhelming majority of Near Eastern ancestry on theAshkenazi male line of descent 11,18–21 , albeit with much higherlevels ( 4 50%) of European (potentially east European) lineagesin Ashkenazi Levites 22 , suggesting a possible Khazar source inthat particular case.The maternal line has also been studied, and indeed AshkenazimtDNAs are highly distinctive, but they have proved difficult toassign to a source population 1,2,11 . Some progress has been madeby targeting whole-mtDNA genomes or mitogenomes, whichprovide much higher genealogical (and therefore geographical)and chronological resolution than the control-region sequencesused previously—although the far larger control-region databaseremains an invaluable guide to their geographic distribution.Using this approach, Behar  et al. 2 identified four major founderclusters, three within haplogroup K—amounting to 32% of sampled Ashkenazi lineages—and one within haplogroup N1b,amounting to another 9%. These lineages are extremely infrequent across the Near East and Europe, making theidentification of potential source populations very challenging.Nevertheless, they concluded that all four most likely arose in theNear East and were markers of a migration to Europe of peopleancestral to the Ashkenazim only   B 2,000 years ago 1,2 . Theremaining   B 60% of mtDNA lineages in the Ashkenazimremained unassigned to any source, with the exception of theminor haplogroup U5 and V lineages ( B 6% in total), whichimplied European ancestry  1,23 .Here we focus on both major and minor founders, with a muchlarger database from potential source populations. We firstanalyse 956 (72 newly generated) mitogenomes from haplogroupU8 (including 909 from haplogroup K, U8’s major subclade): 477of these are from Europe and 106 from the Near East/Caucasus.We show that European and Near Eastern lineages largely fallinto discrete, ancient clusters, with minor episodes of gene flow,suggesting that haplogroup K diversified separately in Europeand the Near East during the last glacial period. Of the threeAshkenazi founders, K1a1b1a and K1a9 were most likely assimilated in west (perhaps Mediterranean) Europe andK2a2a1 in west/central Europe. Most surprisingly, by analysing two new N1b2 sequences selected from a database of 278 N1bHVS-I sequences, in the context of 44 published N1b sequences 24 ,we show that the highly distinctive N1b2 subclade, making upanother 9% of Ashkenazi lineages, was likely assimilated inMediterranean Europe, rather than in the Near East as previously proposed 2 . Moreover, from a survey of another 4 2,500 completemtDNA genomes and  4 28,000 control-region sequences fromEurope, the Near East and the Caucasus, in comparison with theavailable database of 836 Ashkenazi control-region sequences anda handful of published mitogenomes, we also evaluate the minorfounders. Overall, we estimate that most ( 4 80%) AshkenazimtDNAs were assimilated within Europe. Few derive from a NearEastern source, and despite the recent revival of the ‘Khazarhypothesis’ 16 , virtually none are likely to have ancestry in theNorth Caucasus. Therefore, whereas on the male side there may have been a significant Near Eastern (and possibly east European/Caucasian) component in Ashkenazi ancestry, the maternallineages mainly trace back to prehistoric Western Europe. Theseresults emphasize the importance of recruitment of local womenand conversion in the formation of Ashkenazi communities, andrepresent a significant step in the detailed reconstruction of Ashkenazi genealogical history. Results Four major founder lineages within haplogroup K and N1b .Haplogroup K arose within haplogroup U8 B 36ka, in Europe orthe Near East, with the minor subclades K1b, K1c and K2 all mostlikely arising in Europe, between the last glacial period and theNeolithic (Fig. 1; Supplementary Note 1; Supplementary Data 1–3;Supplementary Figs S1–S3; Supplementary Tables S1–S3). K1aexpanded from  B 20ka onwards, both in the Near East andEurope, with its major subclade, K1a1b1 (Fig. 2), mainly restrictedto Europe (with a few instances in North Africa), arriving fromthe Near East by   B 11.5ka, the beginning of the Holocene(Supplementary Note 1).Almost half of mtDNAs in west/central European AshkenaziJews belong to haplogroup K, declining to  B 15% in eastEuropean Jews 1,11 , with almost all falling into three subclades:K1a1b1a, K1a9 and K2a2a1 2,25 (Figs 1–4; Supplementary Fig. S4).These three founder clusters show a strong expansion signal ARTICLE  NATURE COMMUNICATIONS | DOI: 10.1038/ncomms3543 2  NATURE COMMUNICATIONS|4:2543|DOI: 10.1038/ncomms3543| &  2013  Macmillan Publishers Limited. All rights reserved.  beginning  B 2.3ka, with the overall effective population size forthese lineages increasing 13-fold by 275 years ago (Fig.1).K1a1b1a (slightly re-defined, due to the improved resolution of the new tree) (Fig. 2) accounts for 63% of Ashkenazi K lineages(or B 20% of total Ashkenazi lineages) and dates to B 4.4ka withmaximum likelihood (ML); however, all of the samples within it,except for one, nest within a further subclade, K1a1b1a1, dating to B 2.3ka (Supplementary Data 2). K1a1b1a1 is also present innon-Ashkenazi samples, mostly from central/east Europe. As they are nested by Ashkenazi lineages, these are likely due to gene flow from Ashkenazi communities into the wider population. Thepattern of gene flow out into the neighbouring communities isseen in the other two major K founders, and also in haplogroupsH and J; it is especially clear when the nesting and nestedpopulations are more distinct, for example in the case of haplogroup HV1b, which has a deep ancestry in the Near East(Fig. 5; Supplementary Table S4).The K1a1b1 lineages within which the K1a1b1a sequences nest(including 19 lineages of known ancestry) are solely European,pointing to an ancient European ancestry. The closest nesting  Likely near eastern srcinUndetermined srcinLikely European srcinEuropeans and Ashkenazim 55 U8U8b1U8bU8aK1a1bK1a1K1a1aK1a2K1a9 ′ 10 ′ 15 ′ 26 ′ 30K1a1b1K1a1b1aK1a1b1a1K1a9K1a28K1a3aK1a4a1K1aK1a3K1a4K1a8K1a12K1K1cK1d ′ e ′ fK1bK1b1K1b1aK1b2K1b1cK2a2a1K1c2K1c1K1a13 ′ 16 ′ 31K2aK2bK2KK2c 50454035302520151050 1,000,000    E   f   f  e  c   t   i  v  e  p  o  p  u   l  a   t   i  o  n  s   i  z  e   (   N  e   f   ) 100,00010,0001,000100100510101520Time (ka) Figure 1 | Inferred ancestry of the main subclades within haplogroup U8.  The timescale (ka) is based on ML estimations for mitogenomes. Inset:Bayesian skyline plot of 34 Ashkenazi haplogroup K lineages, showing growth in effective population size ( N ef  ) over time.   1142001,717G16,09216,184A14,3884,8236,5288,842C14,5693,79613,05016,09311,765A8276,28410,60916,09216,223K1a1b1dK1a1b1fK1a1b1aK1a1b1a1K1a1b1K1a1b1eK1a1b1cK1a1b1b10,97816,23412,95411,0051528,7879,92114,2498,02314,1181953,316114!114!8,46211,0201,39318915,35516,3551525,46016,0931,70916,22351316,2787238,047 14 , 203C 14,517 16 , 234! 6,366477 9 , 21416 , 288 8,5217,9279,86112,1891149,9321463,70516,0938,29115,04711,2041955,58312,0071891145,87616,36239014,279 0 5,58516,2227895932,4835,74611,62011413,85116,0932,62813,44316,093 5 , 74215 , 07416 , 224!16 , 278 9,644 Ashkenazi JewUSAEuropeUnknown36912 Figure 2 | Phylogenetic tree of haplogroup K1a1b1.  Time scale (ka) based on ML estimations for mitogenome sequences.NATURE COMMUNICATIONS | DOI: 10.1038/ncomms3543  ARTICLE NATURE COMMUNICATIONS|4:2543|DOI: 10.1038/ncomms3543|  3 &  2013  Macmillan Publishers Limited. All rights reserved.  lineages are from Italy, Germany and the British Isles, with othersubclades of K1a1b1 including lineages from west and Mediter-ranean Europe and one Hutterite (Hutterites trace their ancestry to sixteenth-century Tyrol) 26 . Typing/HVS-I results have alsoindicated several from Northwest Africa, matching EuropeanHVS-I types 2 , likely the result of gene flow from Mediter-ranean Europe. K1a1b1a is also present at low frequencies inSpanish-exile Sephardic Jews, but absent from non-EuropeanJews, including a database of 289 North African Jews 2,25 . Notably,it is not seen in Libyan Jews 25 , who are known to have a distinctNear Eastern ancestry, with no known influx from Spanish-exileimmigrants (although Djerban Jews, with a similar history, havenot been tested to date for mtDNA, they closely resemble LibyanJews in autosomal analyses 27 ). Thus the Ashkenazi subclade of K1a1b1 most likely had a west European source.K1a9 (Fig. 3; Supplementary Fig. S4), accounting for another20% of Ashkenazi K lineages (or 6% of total Ashkenazi lineages)and also dating to  B 2.3ka with ML (Supplementary Data 2)again includes both Ashkenazi and non-Ashkenazi lineages solely from east Europeans (again suggesting gene flow out into thewider communities). Like K1a1b1a, it is also found, at muchlower frequencies, in Sephardim. Here the ancestral branching relationships are less clear (Supplementary Note 1 andSupplementary Fig. S4), but K1a9 is most plausibly nested withinthe putative clade K1a9 0 10 0 15 0 26 0 30, dating to  B 9.8ka, whichotherwise includes solely west European (and one Tunisian)lineages, again pointing to a west European source.K2a2 (Fig. 4) accounts for another 16% of AshkenaziK lineages (or  B 5% of total Ashkenazi lineages) and dates to B 8.4ka (Supplementary Data 2). Ashkenazi lineages are oncemore found in a shallow subclade, K2a2a1, dating to  B 1.5ka,that otherwise again includes only east Europeans, suggesting gene flow from the Ashkenazim. Conversely, the nesting clades,K2a2 and K2a2a, although poorly sampled, include only Frenchand German lineages. K2a2a is not found in non-EuropeanJews 25 .Haplogroup K is rarer in the North Caucasus than in Europe orthe Near East ( o 4% (ref. 23)) and the three Ashkenazi founderclades have not been found there (Supplementary Note 2). Wetested all eight K lineages out of 208 samples from the NorthCaucasus, and all belonged to the Near Eastern subclades K1a3,K1a4 and K1a12. Haplogroup K is more common in Chuvashia,but those sampled belong to K1a4, K1a5 and pre-K2a8.The fourth major Ashkenazi founder mtDNA falls withinhaplogroup N1b (ref. 2). The distribution of N1b is much morefocused on the Near East than that of haplogroup K (ref. 24),and the distinctive Ashkenazi N1b2 subclade has accordingly being assigned to a Levantine source 2 . N1b2 has until now been 14,947K1a30K1a2613,65116,19267,25A4,1138,4008,52116,214A16,3541521464,7395,5635,96411,98912,71115,75816,12431012,06314,44016,52711,45311,2872,2583,3386,51516,093!14,83115,75815216,524K1a9K1a9 ′ 10 ′ 15 ′ 26 ′ 30K1a10K1a10a14,1601955,24012,69615,22616,04816,2913168,76416,04716,093!15,43116,2015,3009,4779,698!9,95116,093!230T16,0513381,9585,6556,22715,2045,054 Ashkenazi JewUSANorth AfricaEuropeUnknown 16,2232,4834,45216,2498,155 86420 9,62912,40314,5649316,093!K1a15 Figure 3 | Phylogenetic tree of haplogroup K1a9 in the context of the putative clade K1a9 0 10 0 15 0 26 0 30.  Time scale (ka) based on ML estimations formitogenome sequences. Europe8,697K2a2K2a2aK2a2a111,3481959,263T16,3906415,5208,697!63512C9,25411,91411,719!9,4614,3259,21415314,599UnknownAshkenazi JewUSA107.552.50 Figure 4 | Phylogenetic tree of haplogroup K2a2.  Time scale (ka) basedon ML estimations for mitogenome sequences. ARTICLE  NATURE COMMUNICATIONS | DOI: 10.1038/ncomms3543 4  NATURE COMMUNICATIONS|4:2543|DOI: 10.1038/ncomms3543| &  2013  Macmillan Publishers Limited. All rights reserved.  found exclusively in Ashkenazim, and although it dates to only  B 2.3ka, it diverged from other N1b lineages  B 20ka (ref. 24)(Supplementary Table S5). N1b2 can be recognized in the HVS-Idatabase by the variant 16176A, but Behar  et al. 2 tested 14 NearEastern samples (and some east Europeans) with this motif andidentified it as a parallel mutation. Therefore, despite the long branch leading to N1b2, no Near Eastern samples are known tobelong to it.In our unpublished database of 6991 HVS-I sequences,however, we identified two Italian samples with the 16176Amarker, which we completely sequenced. We confirmed that they belong to N1b2 but diverge before the Ashkenazi lineages B 5ka,nesting the Ashkenazi cluster (Fig. 6; Supplementary Table S5).This striking result suggests that the Italian lineages may be relictsof a dispersal from the Near East into Europe before 5ka, and thatN1b2 was assimilated into the ancestral Ashkenazi population onthe north Mediterranean  B 2ka. Although we found only twosamples suggesting an Italian ancestry for N1b2, the control-region database available for inspection is very large (28,418HVS-I sequences from Europe, the Near East and the Caucasus,of which 278, or B 1%, were N1b). Moreover, the conclusion issupported by our previous founder analysis of N1b HVS-Isequences, which dated the dispersal into Europe to the latePleistocene/early Holocene 24 . Minor Ashkenazi mtDNA lineages . There is now a largenumber of mitogenomes from Europe, the Caucasus and theNear East ( B 3,500, with  4 70 Ashkenazim), and a substantialAshkenazi mtDNA control-region database of 836 samples 1,2,11 (Supplementary Table S6). We therefore endeavoured to cross-reference the two in order to pinpoint most of the control-regiondata within the mitogenome phylogeny.Besides the four haplogroup K and N1b founders, the majorhaplogroup in Ashkenazi Jews is haplogroup H, at 23% of Ashkenazi lineages, which is also the major haplogroup inEuropeans (40–50% in Europe, B 25% in the North Caucasus and B 19% in the Near East) 28 . There are 29 Ashkenazi Hmitogenomes available (Supplementary Table S7), 26 (90%) of which nest comfortably within European subclades dating to theearly Holocene (Supplementary Note 3, Figs 7 and 8;Supplementary Figs S5–S10; Supplementary Table S8). Most, infact, nest more specifically within west/central Europeansubclades, with closely matching sequences in east Europe, aswith the pattern for the K founder clades. The Ashkenazimitogenomes from haplogroup H include 39% belonging to H1or H3, which are most frequent in west Europe and rare outsideEurope. The nesting relationships in some cases point (albeittentatively) to a central European source, but in many casescomparison with the HVS-I database indicates matches in westEurope. The phylogeographic conclusions based on the nesting relationships are strongly supported for haplogroup H by evidence from the study of prehistoric remains, showing inalmost all cases that the lineages concerned were present inEurope since at least the early Bronze Age,  B 3.5ka(Supplementary Table S7) 29 . There is no suggestion of assimilation from the North Caucasus, where most H lineagesdiffer from those of Europe 23 (Supplementary Note 2).Haplogroup J comprises 7% of the Ashkenazi control-regiondatabase. Around 72% of these can be assigned to J1c, now thought to have arisen within Late Glacial Europe 30 , and 19%belong to J1b1a1, also restricted to Europe. Thus 4 90% of theAshkenazi J lineages have a European srcin, with B 7% (J1b andJ2b) less clearly associated. Many have a probable west/centralEuropean source, despite (like H) being most frequent in easternAshkenazim. The four Ashkenazi J mitogenomes, in J1c5, J1c7a1aand J1c7d, once again show a striking pattern of Mediterranean,west and central European lineages enclosing Ashkenazi/eastEuropean ones (Fig. 9).Haplogroups U5, U4 and HV0 (6.3% between them overall)arose within Europe. Some of these lineages, which are againmore frequent in the eastern than western Ashkenazi, may have Europe12,696 HV1bHV1b3HV1b2HV1b1HV1b1bHV1b1a 1524,0471955,25014,30516,15816,2343,6875,65611,3142,7559,11713,7083,5917,9128,02715214,86196116,1585,46014,46416,1297094,8561503,2905,1346,2639,5852,626201510504,7397,59816,2748,0208,71510,29510,75012,87914,16116,3111511837,66415,17215,23615,51916,1789,43816,1291,6941315,03311,081T15,4633,5476,02316,1895,32713,43416,39910,09516,526Anatolia, South Caucasus and the Near EastUnknownAshkenazi JewEastern AfricaNorth Africa Figure 5 | Phylogenetic tree of haplogroup HV1b.  Time scale (ka) based on ML estimations for mitogenome sequences.NATURE COMMUNICATIONS | DOI: 10.1038/ncomms3543  ARTICLE NATURE COMMUNICATIONS|4:2543|DOI: 10.1038/ncomms3543|  5 &  2013  Macmillan Publishers Limited. All rights reserved.
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