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    ARTICLE MtDNA and Y chromosome polymorphisms inHungary: inferences from the palaeolithic, neolithicand Uralic influences on the modern Hungarian genepool Ornella Semino 1 , Giuseppe Passarino 1,2 , Llu´ıs Quintana-Murci 1 , Aiping Liu 1 , Judit B´eres 3 ,Andreas Czeizel 3 and A Silvana Santachiara-Benerecetti 1 1 Dipartimento di Genetica e Microbiologia ‘A Buzzati Traverso’, Universit`a di Pavia;  2 Dipartimento di BiologiaCellulare, Universit`a della Calabria, Arcavacata di Rende, Italy;  3 Department of Human Genetics and Teratology,National Institute of Hygiene, Budapest, Hungary  Magyars imposed their language on Hungarians but seem not to have affected their genetic structure. Tobetter investigate this point, we analysed some mtDNA and Y chromosome polymorphisms in a sample of the Hungarian Pal´oc who, for historical reasons, could have retained genetic traces of Magyars more thanother groups. In addition, we examined a mixed sample from Budapest. About 100individuals were testedfor the markers defining all the European and Asian mtDNA haplogroups and about 50individuals forsome Y chromosome markers, namely the 12f2 and 49a,f/TaqI RFLPs, the YAP insertion, the microsatellitesYCAIIa, YCAIIb, DYS19 and the Asian 50f2/C deletion. In the mtDNA analysis only two subjects belongedto the Asian B and M haplogroups. The Y chromosome analyses showed that the Pal´oc differed from theBudapest sample by the absence of YAP + allele and by the DYS19 allele distribution; that theproto-European 49a,f Ht15 and the neolithic 12f2–8Kb were rather uncommon in both groups; that thereis a high prevalence of the 49a,f Ht11 and the YCAII a5–b1; and that the Asian 50f2/C deletion is absent.These results suggest that the influence of Magyars on the Hungarian gene pool has been very lowthrough both females and males and the Hungarian language could be an example of cultural dominance.Alternative explanations are discussed. An expansion centred on YAP – ; 49a,f Ht11 is revealed by themedian network based on compound haplotypes. 49a,f Ht11 could represent either a paleolithic marker of eastern Europe which underwent expansion after the last glacial period, or a marker of the more recentspread of the Yamnaia culture from southern Ukraine. European Journal of Human Genetics (2000) 8 , 339–346. Keywords: Hungary; Pal´oc; mtDNA variations; Y chromosome polymorphisms Introduction Linguistic relationships among populations generally corre-late with their genetic affinities. 1,2 In Europe, the onlypopulations of non-Indo-European language are the Basquesand the Finno-Ugric speakers (Saami, Finns, Estonians andHungarians). The Finno-Ugric languages were brought fromthe Urals to eastern-Europe by migratory tribes. In Hungary,the Finno-Ugric language arrived with the Magyars whosettled in the Carpathian Basin in 895 AD where otherpopulations such as Slavs, Avars, and Bulgarians were presentand subsequently assimilated. After the Magyar conquest,Hungary experienced other invasions, the most important of which was the Turkish, and also admixtures with neighbour-ing populations. 3 It is a matter of debate as to what extent theFinno-Ugric invaders affected the genetic structure of thelocal pre-existing inhabitants. Correspondence: Professor A Silvana Santachiara-Benerecetti,Dipartimento di Genetica e Microbiologia ‘A Buzzati Traverso’,Universit`a di Pavia, Via Abbiategrasso, 207, 27100Pavia, Italy. Tel:+390382505542/43; Fax: +390382528496; E-mail:santa@ipvgen.unipv.itReceived 23 April 1999; revised 5 January 2000; accepted 7 January2000 European Journal of Human Genetics (2000) 8, 339–346 ©2000 Macmillan Publishers LtdAll rights reserved 1018–4813/00 $15.00  y        www.nature.com/ejhg  Analyses of classical markers showed that, as for the Finns,only about 10% of Hungarian genes could be of non-European srcin. 4 Subsequently, mtDNA and Y chromosomemarkers, which make it possible to identify separately maleand female components in the genetic structure of apopulation, have been very helpful in revealing that theUralic speakers, Finns and Saami, show almost exclusivelymtDNA lineages of European ancestry 5–8 but a considerable Y-specific lineage which can be traced back to Siberian andCentral Asian peoples. 9–11 An important Uralic male compo-nent has also been identified in Estonians. 10  These findingsare in agreement with the notion that Y chromosomefeatures parallel linguistic data more than do mtDNA andnuclear genes. 12–14 By contrast, this Uralic Y-specific lineagewas not observed in a sample of Cs´ang´o of Hungary 15 and inmixed samples from Budapest. 10–15  To increase our knowledge of the genetic structure of theHungarian population, we analysed another ethnic group thePal´oc, for some mtDNA and Y chromosome polymorphisms,as well as a control sample from Budapest. Through thesestudies, not only could we investigate the Magyar contribu-tion to the Hungarian genetic structure and verify if it wasmainly male mediated, but we could also search for pale-olithic and neolithic components in this eastern Europeanpopulation. The mtDNA markers we used were the haplotypes definedby the six classic enzymes, 16 and the restriction sites whichidentify all European and Asian specific haplogroups. 7,17–19 As to Y chromosome variations, the two Hungarian sampleswere analysed for the 50f2/C deletion, which has beenconsidered to be a very valuable marker of the Uralicmigrations; 9 for the 49a, f and 12f2/TaqI RFLPs 20,21 whichallowed some paleolithic and neolithic European malelineages to be highlighted. 22 In addition, the Y Alu polymor-phism (YAP) which, as the 12f2 system, is a monophyleticbi-allelic marker, 23 and the DYS19 and YCAIIa and bmicrosatellites 24,25 were examined. Compound haplotypes(c-Hts) were obtained by combining the single system ‘alleles’for each individual, and were used to construct phylogeneticnetworks. Materials and methods The Pal´oc  The Pal´oc live in a border region of the northern Carpathianbasin (Matra, Figure1) neighbouring the Slavs in the highermountains and speaking a specific Hungarian dialect. Theirsrcin is yet unclear. The Pal´oc land, first inhabited bywestern Slavs, was occupied by Magyars in the second half of the 10th century. Subsequent invasions from south-easternand central Europe experienced by Hungary from the 14thcentury onward did not seem to have influenced the Pal´oc. They are believed therefore to be direct descendants of theHungarians of the 10th–13th centuries. 3 The sample  The sample consisted of 102unrelated healthy subjects whogave their informed consent. Twenty-two were ‘mixed Hun-garians’ from Budapest, and 80 were Pal´oc.Blood specimens were collected in EDTA and buffy coatswere separated and frozen within 24hours. DNA wasextracted according to standard methods. mtDNA analyses  Six classical enzymes  This analysis was performed accord-ing to Passarino et al . 26 Haplogroup analyses With the exception of the Asianhaplogroup (Hg) F (– Hpa I/ Hinc  II 12406site), G (+ Hae II4830site) and T (+ Bam HI13366 /–  Ava II13367 and –  Msp I15925sites) which were detectable by the six classic enzymeanalyses, the Caucasoid and the remaining Asianhaplogroups were identified by PCR amplification of therelevant fragments 26 and digestion with the appropriateenzymes. 7,18,27 Y chromosome analyses  50f2/C deletion (DYS7C), and YAP insertion (DYS- 287)  These polymorphisms were determined as describedby Jobling et al 9 and Hammer and Horai, 23 respectively. TaqI 12f2 and 49a,f polymorphisms (DYS11, DYS1)  Theconditions of these analyses are detailed in Passarino et al 13  STRs analyses DYS19 and YCAII STRs were analysedaccording to Roewer et al 24 and Mathias et al , 25 respectively. Phylogenetic analyses A median network, 28 has been drawn with the Network1.6program. 29 In this phylogeny the YAP + and 12f2–8Kballeles were considered as separate lineages, and differencesamong microsatellites were considered according to thestepwise model, 30 by weighting each single step as 1;similarly, each band acquisition and loss in the 49a,f system Figure1 Map of Hungary showing the Matra region, wherethe Pal´oc sample was collected. mtDNA and Y chromosome markers in Hungary  y        O Semino et al 340 European Journal of Human Genetics  was considered as a single step, by weighting the mostvariable A band as 1 31 and the other polymorphic fragmentsas 2. Results MtDNA analyses  The distribution of the mtDNA types defined by the ‘sixclassic enzymes’, together with that of the Caucasoid and theobserved Asian specific haplogroups are reported in Table1. The ‘six classic enzymes’ analysis shows the profile of theCaucasoid populations, although with a lower frequency of types6 and 18, and a particularly high frequency of type1. Type1 is the most represented type in Caucasoids, but it isvery frequently also in Orientals. 16,32 In this analysis, how-ever, typical Oriental features, as those characterised by Hpa Imorph1 (site loss at np12406) or by Hae II Morph5 (site lossat np4830), which define the Asian lineages F and the Msubgroup G, respectively, 33 were not observed. The frequencydistribution of the continental specific haplogroups showsthat 93.9% of the Hungarian mtDNAs were Caucasoid, 4.1%of unidentified srcin, and only two subjects belonged to theAsian haplogroups M (Budapest) and B (Pal´oc). As to theEuropean mtDNA lineages, the two Hungarian groups sig-nificantly differ from each other for the H lineage (50.6% inthe Pal´oc vs 33.3% in the Budapest sample, P approximately0.02). In both samples, this lineage, as in the other Europeanpopulations, is the most frequent, followed by the U (17.3%).Haplogroups T, K and V occur at low frequencies (2.0%, 2.0%and 1.0%, respectively) and X and I are absent. Haplogroup J,which is considered a neolithic arrival, 19 has a frequency(12.2%) in the range of the other European populations.Since all the four subjects of unidentified srcin did not showany of the Asian haplogroup markers (also including the  Alu Isite loss at np5176 which is an indicator of the Asian Dde I 10394 –  Alu I 10397 [––] sub-haplogroup D 19 ), these analysesindicated that at least 94% of the Hungarian mtDNAs haveEuropean characteristics. In agreement with other data (PLahermo 1998, personal communication) these results sug-gest, therefore, that the female contribution of the Uralics tothe Hungarian gene pool has been very low. Y chromosome analyses Data on Y chromosome single polymorphisms are reportedin Figure2 and Tables2–4; the frequencies of the compoundhaplotypes (c-Hts) are given in Table5.As shown in Figure2A, the 50f2/C deletion was notobserved in the Hungarian sample, whereas it is quitecommon in Mongolians and especially in Siberians, Finnsand Saami. 9,11  Thus, in keeping with the finding of Zerjal et al 10 and Lahermo et al , 15 a genetic male contribution of Uralics into the Hungarian genetic structure has not beendetected in this analysis. Table 1 Assocatons etween te mtDNA contnent-specc apogroups an cassc enzymes types n Hungarans. Percentfrequencies of haplogroups are compared with those of some relevant populations Haplogroups pre-HV H V U W X T J K I M B Others b n.t. Total  Types a 1.2 (2.1.1.1.1.2)737115101144801.3 (2.1.1.1.1.3)116.2 (2.1.2.1.1.2)2215.2 (2.1.1.1.8.2)2218.2 (2.3.1.4.9.2)1121.2 (2.1.1.1.2.2)3321.9 (2.1.1.1.2.9)1147.2 (2.1.1.1.3.2)1157.2 (2.3.1.4.13.2)1159.2 (2.1.1.1.20.2)1172.2 (2.1.1.1.12.2)11n.t.15118 Total8461174–2122–1144102 Hungarians ( n =98)8.246.9 c 1.017.34.1–2.012.22.0–1.01.04.1 Italians 58 ( n =99)n.t.33.35.122.22.03.09.17.18.14.0––6.1Swedes 7 ( n =36)n.t.40.55.416.2––21.62.713.5––––Finns 7 ( n =49)n.t.40.84.116.34.14.16.114.34.12.02.0–2.0Siberians 27 ( n =153)n.t.–n.t.n.t.––––––61.4–38.6n.t.=not tested; a In parentheses are the morphs defined by the enzymes Hpa I, Bam HI, Hae II,  Msp I,  Ava II, Hinc  II; b  These subjects were all Dde I 10394 –  Alu I 10397 (– –) and negative in the analyses for the markers of the Asian Dde I 10394 –  Alu I 10397 (– –) haplogroups. They were also negative whentested for the  Alu I site loss at np 5176 which is an indicator of the Asian haplogroup D, also including the sub-haplogroup D reverted from Dde I 10394 –  Alu I 10397 (++) to Dde I 10394 –  Alu I 10397 (– –); 19c  This value refers to the whole Hungarian sample. However, the Palóc frequency (50.6%)significantly differs ( P about 0.02) from that (33.3%) of the Budapest sample. mtDNA and Y chromosome markers in Hungary O Semino et al  y        341 European Journal of Human Genetics  As reported in Figure2B, all the YAP + chromosomes wereobserved in the mixed population of Budapest, where theyaccount for 22.7% of the sample. This value is close to that(17.5%) found in Budapest by Lahermo et al . 15 Whereas inthe Pal´oc the YAP + allele was not observed, it reaches afrequency of 37.5% in the Cs´ang´o. 15 At the 12f2 and 49a,f RFLP analyses (Figure2C and Table2,respectively), Hungarians display the neolithic 12f2–8Kballele and the proto-European 49a,f haplotype15, both at lowfrequency. By contrast, they show an incidence of the 49a,f haplotype11 (42.5%) which is by far the highest yet observedin a European population. 34,35–38 Data relative to DYS19 are given in Table3. The Pal´oc donot display the DYS19 A allele and show one of the lowestfrequencies so far encountered of the DYS19 C allele (6.7%);the DYS19 B allele has a value (53.3%) close to central-northern Europeans, 14,39–41 whereas the DYS19 D allelereaches a frequency (26.7%) similar to those of easternEuropean populations (31% in Trieste and Bratislava) and of a group of Mongolians (30%). 39,41,42  The ‘mixed Hungarians’of Budapest significantly differ from the Pal´oc sample( P =0.027, Fisher exact test). They are more heterogeneousand show a high frequency (22.7%) of the DYS19 A allele (asRomanians, 22% 39,41 ), lower frequencies of alleles DYS19 Band DYS19 D (31.8% and 13.6%, respectively) and a higherfrequency of the DYS19 C allele (18.2%). Both Hungariansamples show a relative high incidence of the DYS19 E allele(13–14%).In the YCAII analysis the two Hungarian groups were verysimilar and were pooled (Table4). The most importantfeature is the very high incidence of the YCAII a5–b1haplotype (69.8%). This frequency is one of the highestobserved in Europe, 14,25,39,41,43,44 and is close to the value(78%) displayed by the Basques. 45,46 . Table5 shows the 22c-Hts observed in the 46Hungarianstyped for all the systems here analysed. Fourteen c-Hts weresingle observations. The two stable markers (YAP and 12f2)define three main Y chromosome lineages: the YAP – /12f2–10Kb, the YAP + /12f2–10Kb, and the YAP – / 12f2–8Kb,separately shown in the full median network (Figure3). Thefirst is the most important lineage where the most repre-sented haplotypes carry the 49a,f Ht11, YCAII a5–b1 andDYS19 B combination. The other two lineages account onlyfor 10.9% (c-Hts1–3) and 2.2% (c-Ht22) of the sample,respectively, and do not show the preferential associationsfound in the first lineage. The YAP + / 12f2–10Kb lineageshows preferential associations with 49a,f Ht5 and DYS19 Aallele, which is the most common north African combinationand is also frequent in Greeks and Turks (AS Santachiara-Benerecetti, personal communication); the YAP – /12f2–8Kblineage, here represented by only one c-haplotype, displaysthe association with 49a,f Ht7 and DYS19 B allele, which is a Figure2 Distribution of 50f2/Cdeletion ( A ), YAP + allele ( B ), and 12f2–8Kb allele ( C ) in Hungarians compared with some relevantpopulations. Populations of the present study are in bold with sample size in parentheses. mtDNA and Y chromosome markers in Hungary  y        O Semino et al 342 European Journal of Human Genetics
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