Report The Matrilineal Ancestry of Ashkenazi Jewry: Portrait of a ...

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Table 1Control-Region Sequences and Hg Affiliation ofAshkenazi mtDNAsThe table is available in its entirety in the onlineedition of The American Journal of Human Genetics.alleles during the rapid population expansion that followedthe founding event (Diamond 1994; Risch et al.1995; Ostrer 2001). The published genetic data addressingthe question of a founding event in the maternalhistory of Ashkenazi Jews (Torroni et al. 1996; Thomaset al. 2002; Behar et al. 2004) are partially discordant,with some studies detecting a strong founder event (Torroniet al. 1996; Behar et al. 2004) and others reachingthe conclusion that there is little evidence for such anevent (Thomas et al. 2002). In particular, our recentanalysis of HVS-I sequences (Behar et al. 2004), extendedherein to a larger fraction of the control-region(16024–00300) variation in Ashkenazi Jews, has yieldeda broad range of Hgs well known to be prevalent andshared between Europe and the Near East and, therefore,not informative in determining the geographic origin ofthe population ancestral to contemporary AshkenaziJews (tables 1 and 2). Despite the presence of the entirerange of west Eurasian Hgs in the Ashkenazi mtDNApool, Hg frequencies clearly deviated from those reportedelsewhere for west Eurasian populations. Thisdeviation was due to a striking overrepresentation ofHgs K and N1b. However, since common Hgs coverlarge geographic areas and comprise numerous lineagesthat usually coalesced tens of thousands of years ago,monitoring their general frequencies does not effectivelyallow determination of the real number of ancestral maternallineages that gave rise to the present-day diversityin a population. Therefore, although in previous studiesthe elevated frequencies of mtDNA Hgs K and N1b inAshkenazi Jews suggested a maternal founding event(Torroni et al. 1996; Behar et al. 2004), the number oflineages within these Hgs, their putative origin, and theirlevel of restriction to Ashkenazi Jews remain to be resolved.To this end, in the current study, using completemtDNA sequence analysis, we identified the foundinglineages of Ashkenazi Hgs K and N1b and contrastedtheir variation against a global set of mtDNAs belongingto the same Hgs. On the basis of these data, we inferthe actual number, as well as the temporal and geographicorigin, of these maternal founders.We initially generated a maximum parsimony tree of121 complete mtDNA sequences belonging to Hg K. Thetree encompassed 28 novel and 93 previously reportedmtDNAs (fig. 1 and table 3). The sequencing procedureand phylogeny construction were performed as describedin appendix A. Of the 28 novel samples, 13 werefrom Ashkenazi Jews, and 15 were selected from non-Ashkenazi Jews and non-Jewish Near Eastern populations.Samples for complete mtDNA sequencing werechosen to include the widest possible range of Hg Kinternal variation, on the basis of sequence analysis ofthe mtDNA control region. Figure 1 shows that Hg Ksplits at its root into two primary branches, K1 and K2.All 789 Hg K mtDNAs reported herein (table 4) weredesignated as either “K1” or “K2” (89% and 11%, respectively),revealing no additional branching at the rootof K. Subhaplogroup (subHg) K2 is subdivided into twosubsequent major branches labeled “K2a” and “K2b,”whereas K1 splits into three branches—K1a, K1b, andK1c—that are defined by positions 497, 5913, and498del, respectively. All but one of the K1 mtDNAs reportedin this study belong to one of these threebranches. SubHg K1a encompassed most subbranchesand is also the dominant branch in our sample set, encompassing80% of all Hg K mtDNAs. The 13 Ashkenazicomplete mtDNAs clustered into three distinctbranches in the phylogeny: K1a1b1a, K1a9, and K2a2a(fig. 1).K1a1b1a is marked by two coding-region transitions,10978 and 12954, and includes 14 of the 121 completesequences. Seven of these are reported for the first timeherein and are from Ashkenazi subjects, whereas theother seven were reported elsewhere as forming a specificcluster termed “K1a” (Herrnstadt et al. 2002). The ethnicitiesor religious affiliations of these seven subjects arenot available, but they were all collected in the UnitedStates and shared the control-region mutations with theAshkenazi samples. Since the majority of contemporaryAshkenazi Jews reside in the United States, it is possiblethat this cluster represents a sample set of AshkenaziJews, though we have no way to confirm or refute this.K1a9 mtDNAs are marked only by the control-regiontransition 16524 but lack the diagnostic mutations ofthe other K1a2 through K1a8 subHgs (fig. 1). Six samplesbelong to this lineage—four of which, from AshkenaziJews, are reported herein for the first time. Theother two mtDNAs were reported elsewhere, and thesame considerations noted for subHg K1a1b1a, withrespect to the ethnic or religious affiliation, also apply(Herrnstadt et al. 2002). K2a2a mtDNAs are markedby three coding-region transitions: 9254, 11348, and11914. Three mtDNAs belong to this lineage, two ofwhich are from Ashkenazi individuals and are reportedherein for the first time. The third mtDNA was reportedTable 2Control-Region Haplotypes of Ashkenazi Hg KmtDNAsThe table is available in its entirety in the onlineedition of The American Journal of Human Genetics.488 The American Journal of Human Genetics Volume 78 March 2006 www.ajhg.org
Table 3Source and Ethnic Origin of the 121 CompletemtDNA SequencesSample a Source PopulationD5939 Present article Algerian JewD1123 Present article Ashkenazi JewD1139 Present article Ashkenazi JewD1282 Present article Ashkenazi JewD1369 Present article Ashkenazi JewD1606 Present article Ashkenazi JewD1829 Present article Ashkenazi JewD4207 Present article Ashkenazi JewD4232 Present article Ashkenazi JewD4262 Present article Ashkenazi JewD4481 Present article Ashkenazi JewD4777 Present article Ashkenazi JewD5551 Present article Ashkenazi JewD5677 Present article Ashkenazi JewD5077 Present article CherkesD1311 Present article DruzeD1320 Present article DruzeD1626 Present article DruzeD1701 Present article DruzeD1520 Present article Moroccan JewD5908 Present article Moroccan JewD5257 Present article PalestinianD1435 Present article Yemenite JewD1656 Present article Yemenite JewD4757 Present article Yemenite JewE1089 Present article LebaneseE1221 Present article SaudiE1365 Present article SyrianA Achilli et al. 2005 ItalianH Herrnstadt et al. 2002 UnknownF Finnila et al. 2001 FinnishK Coble et al. 2004 UnknownMa Maca-Meyer et al. 2001 IberianMi Mishmar et al. 2003 UnknownP Palanichamy et al. 2004 IndianaSerial numbers of mtDNAs from the literaturewere not changed.elsewhere in the same U.S. data set (Herrnstadt et al.2002).After the delineation of the Hg K topology and in asearch for clues regarding the possible origin of the Ashkenazilineages, 789 Hg K mtDNAs of a global set of13,359 samples (tables 5 and 6) were hierarchicallyscreened for polymorphisms relevant to include or excludethe samples from the three Ashkenazi K subbranches—K1a1b1a,K1a9, and K2a2a. The position ofthe three dominant Ashkenazi founding sequenceswithin the phylogenetic tree of 789 Hg K genomes isillustrated in figure 2. Of the 182 Ashkenazi Hg KmtDNAs, 179 could be readily assigned to K1a1b1a,K1a9, or K2a2a (table 6), demonstrating that virtuallyall Hg K genomes present in the Ashkenazi Jews belongto these three distinct monophyletic clades and, in turn,comprise 30% of all Ashkenazi maternal lineages. Of123 K1a1b1a mtDNAs (fig. 2 and table 6), 122 werefrom Jews—113 of Ashkenazi and 9 of Spanish-exileancestry (6 Bulgarian, 2 Italian, and 1 Turkish). The onlynon-Jewish K1a1b1a mtDNA that shared the HVS-Ihaplotype 16223-16224-16234-16311 with the AshkenaziJews was found in a subject from Hmelnitski, aUkrainian town with a major Jewish settlement until theSecond World War. As for K1a9, 48 of the 789 KmtDNAs were members of this subHg (fig. 2 and table6), and 47 were from Jews—41 Ashkenazi, 4 Spanishexile (2 Bulgarian, 1 former Yugoslavian, and 1 fromTurkey), 1 from Iraq, and 1 from Syria. A subHg K1a9mtDNA was found in one Hungarian of unidentifiedethnic or religious affiliation. Finally, 28 (25 AshkenaziJews, 1 Bulgarian Jew, 1 Georgian Jew, and 1 AzerbaijaniJew) of the 789 K samples belonged to subHg K2a2a(fig. 2 and table 6). This subHg and its parental Hg werenot found in any of 11,452 non-Jewish samples.The same principles were followed to investigate thehigh incidence of Hg N1b in Ashkenazi Jews. Hg N1bis virtually absent in Europeans but appears at frequenciesof ∼3% or higher in those from Levant, Arabia, andEgypt (Richards et al. 2003; Kivisild et al. 2004; unpublishedresults of Tartu and Haifa groups). This Hgis defined by the transversion C16176G, relative to therevised Cambridge Reference Sequence (rCRS) (Andrewset al. 1999), and is reported in all non-Jewish Near EasternN1b mtDNAs. However, all but one of the AshkenaziN1b mtDNAs were found to harbor a CrA transversionat nucleotide position 16176. To assess whetherthis was another Ashkenazi founding lineage, we followedthe same approach applied to Hg K. We randomlychose two mtDNAs for complete sequencing and identifiedseveral shared mutations that were absent in apreviously reported N1b complete sequence (Maca-Meyer et al. 2001) (fig. 3). We then examined nucleotidepositions 11928 and 12092—sites of two of the privatemutations—in 82 N1b mtDNAs that were available tous (table 7). Fifty-six of the 57 Ashkenazi Jews, the Spanish-exileJews, and the Moroccan Jew, who shared16176A, could be assigned to this same lineage. Thesingle Ashkenazi and all other mtDNAs with 16176Gdid not harbor the mutations at 11928 and 12092. Curiously,the 16176A transversion probably occurredtwice in the phylogeny of N1b. Indeed, we have foundlineages with 16176A in Slavic-speaking populationsboth in the Balkans and in Ukraine, but these possessedHVS-I mutations different from those present among theJews, and they did not harbor the mutations at 11928and 12092; thus, they are clearly phylogenetically distinctfrom N1b genomes of the Ashkenazi Jews.In total, we have identified four Ashkenazi foundinglineages, three within Hg K and one in Hg N1b, derivingfrom only four ancestral women and accounting for fully40% of the mtDNAs of the current Ashkenazi popu-www.ajhg.org Behar et al.: Portrait of a Founder Event 489
Page 1: ReportThe Matrilineal Ancestry of A
Page 6 and 7: Table 6SubHg Affiliation of the 789
Page 8 and 9: Table 8Coalescence Ages of the Four
Page 10 and 11: Web ResourcesAccession numbers and

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