The origin of Eastern European Jews revealed by autosomal, sex chromosomal and mtDNA polymorphisms

Biparental versus uniparental markers

At first sight it seems that there is more than one explanation for the differing results produced by the analysis of the NRY haplogroups. It thus seems possible that EEJ founder population in Rome was composed of exiled Israelite males and local Roman females. In its simple form this clearly contradicts the facts, because both the autosomal and X-chromosomal polymorphisms demonstrate that EEJ do not occupy an intermediate position between European and Middle Eastern populations, but rather a strict European one. From table 1 it is clear that Italians are as close or closer to the other Jewish populations and Palestinians as EEJ. It is possible that once the founder population was established no other males but many females joined it, thus creating a population that is almost entirely European in all genetic aspects apart from its Y chromosomes. Such phenomenon was described for the population of Antioquia, Columbia, where the autosomes point to 79% of European ancestry and only 16% of Amerindian ancestry, whereas according to mtDNA the ancestry is 90% Amerindian and only 2% European (there is also a small African component). Historical records demonstrate that local Amerindian females joined the population only at its beginning, whereas European males joined it also in later periods [26]. The suggestion that the proselyte ancestors of EEJ were almost entirely females does not however accord with what we know about conversion to Judaism [10, 12, 27–29].

The inference that the NRY points to a Middle Eastern origin of EEJ is erroneous not only because the Y chromosomal analysis contradicts the analyses based on the other chromosomes, and because the NRY is a single uniparental marker that does not represent the whole history of the population, but also because its smaller effective population size makes it much more vulnerable to severe genetic drift caused by demographic bottlenecks. The demographic histories of three Jewish populations exemplify how different demographic patterns make the uniparental markers more reliable for Iraqi (Babylonian) Jews and Yemenite Jews and less reliable for EEJ. Both Yemenite Jews and Iraqi Jews resemble populations from their regions of origin according to autosomal markers [1, 3, 30–32]. Yemenite Jews, who are usually considered a small isolate, were numerous enough to have an independent kingdom in the first centuries AD [33]. They numbered a few hundred thousand in the 12th century AD, and gradually declined; reaching only about 30-40,000 in the beginning of the 20th century [34]. Babylonian Jews numbered more than a million in the first century AD [35], and constituted the majority of the population in the area between the Euphrates and the Tigris in the 2^nd-3^rd centuries AD [36]. Gilbert [37] estimates that by 600 AD there were 806,000 Jews in Mesopotamia, and according to Sassoon [38] it was inhabited by about a million Jews in the 7^th century. In the 14^th century the estimates for Baghdad alone range from 70,000 to hundreds thousands [38]. By 1939, 11 years before their emigration, there were 91,000 Jews in Iraq [35]. In contrast, the Jewish population of the Polish-Lithuanian Kingdom (EEJ) went through the opposite process. Their history is one of founder effects, migrations, demographic bottlenecks and finally a rapid expansion. We know nothing about their number in the first millennium, but after their emigration from Italy to Western Europe it is estimated that they numbered 4,000 in 1000 and 20,000 a hundred years later [8]. In 1500 already in Eastern Europe they numbered 10,000-30,000, in 1648 230,000-450,000 and in 1764 750,000 [39–41]. In the 19^th century because of the partitions of the Polish-Lithuanian Kingdom and the immigrations of Jews to Central and Western Europe and America, the estimation of the number of EEJ becomes more difficult, but there is no doubt that the increase in numbers was impressive, as the number of EEJ under Russian rule alone was 5,200,000 in 1897 [41].

The existence of severe demographic bottlenecks in the history of EEJ has also been suggested by genetic studies of disease-causing-mutations and mtDNA [42–46]. The comparison based on this second uniparental marker, mtDNA, may help to resolve from within genetics itself the problem of the Y chromosome reliability for inferring the origin of the male ancestors of EEJ. If the European and Middle Eastern contributions to the gene pool of EEJ were female and male respectively, then comparisons based on mtDNA must place EEJ among other European populations, distant from Middle Eastern populations. The mtDNA analysis presented in this study does not place EEJ among other European populations rather their position is more intermediate and marginal, as can be seen in figure 5 and in figure 6, where autosomal distances are correlated with mtDNA distances. This lends further support to the notion that because of the unique demographic history of EEJ, their uniparental markers were subjected to stronger genetic drift than the biparental markers and thus should not be used to trace their origin.

The data on the Y chromosome itself also support the unreliability of the uniparental markers for discovering the origin of EEJ. Nebel et al. [47] studied haplogroup R-M17, whose frequency is ~12% in Ashkenazi Jews. By comparing the structure of the STRs network among the various Ashkenazi populations and among the various European non-Jewish populations they reached the conclusion that a single male founder introduced this haplogroup into Ashkenazi Jews in the first millennium. Behar et al. [48] write "It is striking that whereas Ashkenazi populations are genetically more diverse at both the SNP and STR level compared with their European non-Jewish counterparts, they have greatly reduced within-haplogroup STR variability ... This contrasting pattern of diversity in Ashkenazi populations is evidence for a reduction in male effective population size, possibly resulting from a series of founder events and high rates of endogamy within Europe. This reduced effective population size may explain the high incidence of founder disease mutations despite overall high levels of NRY diversity". It is unlikely that EEJ are the descendants of a single population. Admixture coupled with small effective population size and bottlenecks can create the puzzling situation we encounter in the uniparental markers. Thus smaller contributions from several populations, including possibly the original Middle Eastern Jewish population, and a major contribution from Italy combined with the unique demography of EEJ can create the current genetic picture without the need to invoke a major contribution from the Middle East, which contradicts the autosomal and X-chromosomal data.

Comments on previous studies

Some previous studies based on classical autosomal markers concluded that EEJ are a Middle Eastern population with genetic affinities to other Jewish populations. The problems with these studies have been previously discussed in detail [1]. These studies used fewer markers (mostly the less reliable antigenic markers) and failed to include European Mediterranean populations, apart from the discriminant analysis of Carmelli and Cavalli-Sforza [49], which used only four markers and contradicts the results of the later more elaborate discriminant analysis [1], and the genetic distance analysis of Livshits et al. [32], which includes a single European Mediterranean population, Spain. Despite this when a genetic distance analysis was performed, the greater similarity of EEJ to Russians and to a lesser extent to Germans more than to Non-European Jews was evident [32]. In fact Russians were more similar to EEJ than to any Non-Jewish European population in that analysis.

Recently, Cochran et al. [50] used 251 autosomal loci to calculate genetic distances and concluded that "from the perspective of a large collection of largely neutral genetic variation Ashkenazim are essentially European, not Middle Eastern". More recently, thousands of SNPs were used by Need et al. [51] to infer the relationships between Ashkenazi Jews and non-Jewish Europeans and Middle Easterners. They concluded that Ashkenazi Jews lie approximately midway between Europeans and the Middle Easterners, implying that Ashkenazi Jews may contain mixed ancestry from these two regions, and that they are close to the Adygei population from the Caucasus. However these conclusions are ill-founded, because, they used a highly selected set of SNPs, which were selected specifically for the purpose of distinguishing between Ashkenazi Jews and other populations and they inferred the origin of Ashkenazi Jews from principal components analysis (PCA), but as Tian et al. [52] show "PCA results are highly dependent on which population groups are included in the analysis. Thus, there should be some caution in interpreting these results and other results from similar analytic methods with respect to ascribing origins of particular ethnic groups'" Tian et al. [52] also published a table of paired Fst distances based on 10,500 random SNPs, which demonstrates that Ashkenazi Jews are not at all close to the Adygei population, and similarly to what is seen in table 1, their smallest distance is to Italians and then to Greeks. Unlike the assertion of Need et al. [51] on the midway position, and again similarly to what is seen in table 1, Italians and Greeks are closer to the Middle Eastern populations than Ashkenazi Jews.

The same phenomenon is seen in the table of Fst distances of Atzmon et al. [53]. North Italians (Bergamo and Tuscany) are a little closer to the Jewish and Middle Eastern populations than Ashkenazi Jews. The Italians from Tuscany (surprisingly the sample from Bergamo was not used) in Behar et al. [54] are also closer to the Jewish and Middle Eastern populations than Ashkenazi Jews. The Italians from Tuscany are in fact the closest population to Ashkenazi Jews in Behar et al. [54]. There is one sample that is apparently a little closer, what they call Sephardic Jews. Unfortunately this sample is composed of two populations, Turkish Jews and Bulgarian Jews, which should have been studied separately like all other Jewish populations. Bulgarian Jews have been shown in the past based on autosomal classical markers to be closer to EEJ than to populations with Sephardic ancestry and considering their history it was concluded that the Ashkenazi component in their gene pool is at least as large or even larger that the Sephardic component [1]. From both The current study and those of Atzmon et al. [53] and Behar et al. [54] it can be seen that the only Jewish populations that are as close to Ashkenazi Jews as non-Jewish Europeans are those with a significant Sephardic (The descendants of the Jews who were expelled from the Iberian peninsula at the end of the 15^th century) component in their gene pool. It is not possible at this stage to say what is the source of this resemblance, since we don't know what is the origin of Sephardic Jews, but considering all the genetic affinities of both groups it likely stems from Sephardic Jews being the descendants of converts in the Mediterranean basin rather than from a common Jewish origin in the Land of Israel. When one compares the autosomal distances of EEJ (current study) or Ashkenazi Jews (in Atzmon et al. [53] and Behar et al. [54]) from the Jewish populations that were investigated in the current study, Iraqi, Iranian, Moroccan, Yemenite and Ethiopian Jews, one finds perfect agreement. EEJ or Ashkenazi Jews are much closer to non-Jewish Europeans than to these Jewish populations in all three studies.

Reviewer's report 1

Damian Labuda, Pediatrics Department, Montreal University Sainte-Justine Hospital Research Center, Montreal, PQ Canada (nominated by Jerzy Jurka, Genetic Information Research Institute, Mountain View, California USA).

The author compiled and reanalyzed the data on autosomal and sex chromosomes polymorphisms collected by different laboratories on different Jewish and West-Eurasiatic populations. His analysis indicates much greater European component of Eastern European Jews, EEJ (essentially Ashkenazim) than of other Jewish groups. Moreover the analysis points to Italians as the closest population to EEJ.

The question is how to interpret this evidence. Imperial Rome was a very cosmopolitan city culturally and genetically diverse. To what extent a sample of contemporary Italians preserves the genetic link to its population? It can simply reflect a mixture of historical influences from different centers around the Mediterranean Sea. We should thus keep in mind that the Italian connection may simply indicate Southern European and Mediterranean links with the latter including Middle Eastern roots.

Interestingly, this analysis that is based on a limited number of markers provided results that are very similar to a paper of Atzmon and colleagues, published five days ago in the American Journal of Human Genetics, and based on the microarray-based genotyping genome of wide distributed markers. I would like the author to comment on this paper in the context of his findings and his thoughts and reflections on the origin of Jewish Diasporas. Should we go back to the single locus analyses, as in the case of uniparentally transmitted markers, but targeting one by one different individual segments of the nuclear genome? Perhaps, in this way we could partition and identify genetic ancestries of different populations, which due to their history of relative isolation, are considered as genetically homogenous.

The author refers to Sangvi's G2 as the most appropriate distance metrics. Could you make it more clear when this metric was used and when that of Reynolds (only to produce a tree?).

Reviewer's report 2

Kateryna Makova, Department of Biology, Penn State University, Pennsylvania USA.

Reviewer's report 3

Qasim Ayub, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK (nominated by Dan Graur, Department of Biology and Biochemistry, University of Houston, Houston, USA).

The paper by Zoossmann-Diskin entitled 'The origin of Eastern European Jews revealed by autosomal and sex chromosomal polymorphisms' explores autosomal and sex chromosomal polymorphisms in six Jewish populations using previously published and additional unpublished data. The author concludes that the Jewish populations examined do not share a common origin and that Eastern European Jews are closer to the Italian population.

My major concern is the choice of markers and populations used in this study. The author has analyzed 17 autosomal loci, including 9 polymorphic protein electrophoretic variants in which the genotype was assumed. Although phenotypes often do correlate with genotypes assuming that they do can lead to erroneous results. Of the remaining 8 it is unclear whether the same samples were genotyped as the sample numbers for each locus vary widely (Supplementary Tables 2-4).

The author also uses Y hapologroup frequencies and shows a multidimensional scaling plot of Y chromosomal genetic distance matrix. However, the supplementary data (Supplementary Table 5) lists an outdated nomenclature for Y haplogroups as the M78 marker is no longer considered part of haplogroup E3b1. It would be more appropriate to list which markers are used to designate the haplogroups to ensure that they are comparable. In addition, the haplogroups that are selected for these analyses do not provide phylogenetic resolution to reliably detect male genetic sub-structure within the Middle East. The omission of recent mtDNA studies (Behar et al., 2008, PLoS One 3:e2062) is surprising as is the use of a single X chromosomal locus (DYS44) to make broad conclusions about genetic relatedness.

Current evidence, supported more recently by two major studies carried out on Jewish populations (Atzmon et al., Am J H Genetics 86:850-859; Behar et al., Nature doi:10.1038) using a much larger dataset clearly demonstrate a common genetic thread linking the diverse Mizrahi, Sephardic and Ashkenazi Jewish populations with the populations from the Levant and Middle East. The Ashkenazi show a European component but this is shared with many Eastern and Southern Europeans populations. These studies contradict the author's conclusion and demonstrate the power of using unbiased markers and host populations in corresponding geographic regions to address issues such as genetic relatedness among Jewish and non-Jewish populations