Chosen genes of the Chosen People

By Razib Khan | August 27, 2010 1:48 am

ashjewheadshotLast spring two very thorough papers came out which surveyed the genetic landscape of the Jewish people (my posts, Genetics & the Jews it’s still complicated, Genetics & the Jews). The novelty of the results was due to the fact that the research groups actually looked across the very diverse populations of the Diaspora, from Morocco, Eastern Europe, Ethiopia, to Iran. They constructed a broader framework in which we can understand how these populations came to be, and how they relate to each other. Additionally, they allow us to have more perspective as to the generalizability of medical genetics findings in the area of “Jewish diseases,” which for various reasons usually are actually findings for Ashkenazi Jews (the overwhelming majority of Jews outside of Israel, but only about half of Israeli Jews).

Just as the two aforementioned papers were deep explorations of the genetic history of the Jewish people, and allowed for a systematic understanding of their current relationships, a new paper in PNAS takes a slightly different tack. First, it zooms in on Ashkenazi Jews. The Jews whose ancestors are from the broad swath of Central Europe, and later expanded into Poland-Lithuania and Russia. The descendants of Litvaks, Galicians, and the assimilated Jewish minorities such as the Germans Jews. Second, though constrained to a narrower population set, the researchers put more of an emphasis on the evolutionary parameter of natural selection. Like any population Jews have been impacted by drift, selection, migration (and its variant admixture), and mutation. Teasing apart these disparate parameters may aid in understanding the origin of Jewish diseases.

ResearchBlogging.orgThe paper is open access, so you don’t have to take my interpretation as the last word. Signatures of founder effects, admixture, and selection in the Ashkenazi Jewish population:

The Ashkenazi Jewish (AJ) population has long been viewed as a genetic isolate, yet it is still unclear how population bottlenecks, admixture, or positive selection contribute to its genetic structure. Here we analyzed a large AJ cohort and found higher linkage disequilibrium (LD) and identity-by-descent relative to Europeans, as expected for an isolate. However, paradoxically we also found higher genetic diversity, a sign of an older or more admixed population but not of a long-term isolate. Recent reports have reaffirmed that the AJ population has a common Middle Eastern origin with other Jewish Diaspora populations, but also suggest that the AJ population, compared with other Jews, has had the most European admixture. Our analysis indeed revealed higher European admixture than predicted from previous Y-chromosome analyses. Moreover, we also show that admixture directly correlates with high LD, suggesting that admixture has increased both genetic diversity and LD in the AJ population. Additionally, we applied extended haplotype tests to determine whether positive selection can account for the level of AJ-prevalent diseases. We identified genomic regions under selection that account for lactose and alcohol tolerance, and although we found evidence for positive selection at some AJ-prevalent disease loci, the higher incidence of the majority of these diseases is likely the result of genetic drift following a bottleneck. Thus, the AJ population shows evidence of past founding events; however, admixture and selection have also strongly influenced its current genetic makeup.

The sample size of Ashkenazi Jews was ~400, and they looked at ~700,000 SNPs. As I said, how Jews relate to other populations really isn’t at the core of this paper as it was in the earlier ones from the spring, but there were the PCA plots (sorry Mike), a frappe bar plot, and a phylogenetic tree derived from Fst statistic. Again, remember that PCA is showing you the largest independent components of genetic variation within the data. The bar plot has a set of ancestral populations of which individuals are composites of. And finally, Fst measures between population component of genetic variation. The larger the Fst across two populations the bigger the genetic distance.

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Using the Druze & Palestinians as the ancestral Middle Eastern reference the authors estimated that the European admixture into Ashkenazi Jews is on the order of 30-55%. This is in the same ballpark as the previous studies, so no great surprise. As I stated in earlier posts the authors can spin the same results in very different ways. From what I can tell these authors are inclined to emphasize the strong possibility that in terms of genetic distance Ashkenazi Jews are somewhat closer to Europeans than they are to Levantine Arabs. Of course these sorts of assertions need to be handled with care. The genetic distance between Ashkenazi Jews and Tuscans is less than half that between Ashenazi Jews and Russians, while the Jewish-Russian value is about 50% larger than the Jewish-Palestinian one. Remember that there’s a fair amount of circumstantial evidence that Tuscans may themselves be a relatively recent hybrid population between indigenous residents of the Italian peninsula and Near Easterners.

ashjtab1One thing that this paper does do is rebut any strong assertion that Ashkenazi Jews are a genetically homogeneous population which went through a powerful bottleneck. Basically, the idea that Jewish diseases are just an outcome of the operational inbreeding that occurs when genetic variation is expunged from a population through low effective population size. The clincher seems to be comparison of heterozygosity of Ashkenazi Jews and gentile Europeans. The former are actually somewhat more heterozygous than the latter. There’s been a bit of evidence from previous research that the long term effective population size of Ashkenazi Jews was not necessarily very small, so this isn’t a total surprise. Remember that heterozygosity simply means the fraction of individuals heterozygous at a locus.

One way you can become heterozygous is naturally admixture. Remember that populations differ across many genes. As an example, there’s a pigmentation gene, SLC24A5, where all Europeans are at one state, and all West Africans in another. Naturally African Americans exhibit much more heterozygosity on this locus than the ancestral populations. The Ashkenazi Jewish case is less extreme because the two parental populations are genetically closer, but the principle still holds.

A consequence of recent admixture between genetically different populations are high levels of linkage disequilibrium, non-random associations of alleles at different loci across the genome. Why? There are many genes where two populations may be very different. Offspring inherit half their genome from one parent, and half from the other, and the parents pass along to their offspring particular associations of alleles. There may be a set of European distinctive alleles on a chromosome, and an African distinctive set of alleles, so that in a hybrid individual the alleles are strongly correlated across loci. These associations are broken down over time by recombination. The regularity of this process can serve as a clock with which to measure the period since admixture. African Americans were used to calibrate the time since admixture for the Uyghur people of western China, who are mixed from West and East Eurasian populations. The authors did not do this in this paper, I assume because the ancestral populations were genetically rather close in comparison to the two above examples, so there’d be less linkage disequilibrium to break down in the first place.

In the Ashkenazi Jewish population they found more linkage disequilibrium than in Europeans as well as longer haplotypes. This could be the result of a population bottleneck where drift could drive up the frequency of blocks of the genome, but as they note in the paper that should probably reduce heterozygosity. The natural inference then is that admixture between distinct populations can explain both data points.

ashslselectBut let’s cut to the chase. What genes exhibit signatures of natural selection in Ashkenazi Jews? More precisely, what distinctive regions of the genome exhibit signatures of natural selection? They used the standard haplotype type based methods. Basically you’re looking for regions of the genome where there are long blocks of correlated alleles, signs of a selective sweep due to a favored variant which dragged along flanking genomic regions as it rose rapidly in frequency, more rapidly than recombination could break apart the associations. Because recombination does breaks up associations over time, you need the selective sweeps to be relatively recent to detect them with these methods. Since the Jewish people, and Ashkenazi Jews more particularly, are relatively recent historically timing shouldn’t be an issue for Jewish specific sweeps. But another factor is that the two primary tests they used, EHH and iHS, are not good at picking up sweeps which are just starting. EHH is geared toward sweeps which are almost complete, so the frequency of the selected allele is near 100%. iHS is better are mid-range values. Using a combination of these two techniques they found that six genes which are implicated in diseases characteristic of Ashkenazi Jews have the hallmarks of natural selection. Natural selection is self-evident, so what seems to have been going here is that the disease was simply a side effect or byproduct of adaptation.

The strongest signal they found was in ALDH2. The strongest signal in Europeans, LCT, was not found in Ashkenazi Jews. But is LCT a strong signal in Europeans? Many Southern European populations have low frequencies of the derived LCT allele, indicating that they haven’t been subject to strong selection for lactase persistence. These are the same populations genetically close to the Ashkenazi Jews. The authors suggest that the Jewish-European admixture occurred before the sweep of the derived LCT allele, but it seems more plausible that the Ashkenazim simply admixed with a European population, such as Italians, which do not exhibit much lactase persistence. As for ALDH2, the association between genetic variation on this locus and alcoholism is well known, and has been used to explain the low Jewish rates of the disease. In this case, the authors posit that protection from alcoholism is a positive side effect of natural selection:

The mechanism driving selection of the ALDH2 locus is unknown, but a plausible target of selection also within this selected region is the TRAFD1/FLN29 gene, which is a negative regulator of the innate immune system, important for controlling the response to bacterial and viral infection (49). TRAFD1/FLN29 may have conferred a selective advantage in the immune response to a pathogen, perhaps near the time that the Jews returned to Israel from their Babylonian captivity. Despite the unclear selective mechanism, this remains a remarkable example of a putatively selected region accounting for a known population phenotype.

Many of the other loci naturally did not show signatures of natural selection. But this sort of work is exploratory, and there are limits to the power of their techniques. As it is, it seems that we’re very far along on understanding the phylogenetic tree of the Jewish people, and we’re finally getting a grip on the exogenous parameters which might prune the branches.

Citation: Steven M. Bray, Jennifer G. Mulle, Anne F. Dodd, Ann E. Pulver, Stephen Wooding, & Stephen T. Warren (2010). Signatures of founder effects, admixture, and selection in the Ashkenazi Jewish population PNAS : 10.1073/pnas.1004381107

Related: John Hawks, New data on Ashkenazi population history.

Image Credit: Wikimedia

CATEGORIZED UNDER: Anthroplogy, Genetics
  • Pingback: Anonymous

  • dan

    i maintained focus until i got to Natalie Portman….

  • http://www.uyghuramerican.org Yolvas Tiger

    I am a Uyghur. I am pleasantly surprised to find out that Uyghurs are an admixture of West and East Eurasians. I was just wondering how you came to this conclusion. I would really appreciate your scientific answer. I’d love to translate that into Uyghur.

    Thanks.

    Yolvas

  • omar

    It seems like there are a lot of population genetics studies on Ashkenazi Jews (no surprise perhaps, since there are so many Ashkhenazi Jews doing the studying), but I just wanted to ask Razib: what other groups have been studied in this kind of detail and is there some finding that leapt out at you in those studies? I may have exposed my total ignorance here, but all I know about this field is from cursory readings of your blog and I am just trying to take a shortcut.

  • http://blogs.discovermagazine.com/gnxp Razib Khan
  • http://blogs.discovermagazine.com/gnxp Razib Khan

    omar, no other groups in such detail. the etruscan genetics, and reich et al.’s study of indians, and the neandertal paper jump out at me.

  • Y ddraig werdd

    The Jewish genome is one of the most, if not the most, studied genomes. A lot of studies have even reached the mainstream press. But still we get things like the German banker (Thilo Sarrazin ) accused of racism for saying that Jews share genes. I mean “ Stephan Kramer of the Central Council of Jews in Germany told German news agency DAPD: “Whoever tries to identify Jews by their genetic makeup succumbs to racism.”” Even there one traditions state that you are Jewish if you have a Jewish mother.
    Is it simply “German says Jews are a race = Nazi” or the “elite” really lives in some kind of time warp?

  • Leah

    Thanks for a fascinating series on this topic.

    I think the racial issue is complex, because while Jews may have been a race at some point, after two thousands years of scattering across the world, there have been (and continue to be) many converts, as well as coerced mixing, and more recently, a huge jump in interracial (if we’re defining Jewish as a race) marriages.
    The difference between this gene-pool and the Kohen haplotype is that Kohens are restricted in marriage in ways that other Jews are not. Still, if a gentile woman converted to Judaism, her daughter could potentially marry a Kohen and transmit “gentile” mitochondrial DNA to her Kohen grandkids. How would geneticists interpret this?
    I think the hesitation around a racial definition has more to do with its historic abuses, and current political wars about land rights in the Middle East.

  • nebbish

    Y ddraig werdd,

    I don’t disagree with your point that there is a genetic component to Jewishness, but it’s a bit of a stretch to consider the Jews a race in the sense of the continental scale macro-races like Caucasoids, Mongoloids, etc. Almost all self-labeled Jewish populations are clearly Caucasoid. Ashkenazim appear to be for the most part a mixture of Middle Eastern Caucasoids and South European Caucasoids, and this places them not particularly far from other European Caucasoids in a global genetic context. If you would describe the English, Russians, Chinese, etc. as races, then I suppose using the term to describe Jews would not be inconsistent.

  • Y ddraig werdd

    I don’t thing they are a race either and the German banker didn’t say anything like that. He just said that they have distinctive genes in common, just as the Basques. This is all that he said about this. The rest of the interview was about Turkish immigration. My problem was that the reactions (especially in the US, see Huffington Post for example) was along the lines of Jew have genes in common => Jews are a race => Nazi. I mean the state of Israel does exactly what Stephan Kramer of the Central Council of Jews in Germany condemns as racist. I was thinking that with the popularity of sites like 23andme and the like, the fact that ancestry can be, in most cases, pinpointed using genes was finally accepted. But it appears that you don’t even have to say something still controversial and tabu like genetic differences in intelligence and still you can be attacked as racist.
    Regarding the adoptions and the conversions I think this is a very recent and limited phenomenon to have a big effect. Do you really think that a Jewish couple could adopt a non-Jewish child anywhere in the world until 50-60 years ago? What do you think would have been the reactions of locals?
    My opinion is that starting from about 500-600 AD due to political / religious reasons there wasn’t any big gene flow from gentiles to Jews. (the reverse was definitely true, a lot of Jews being converted by force or converted themselves).Because of this Jews are a very big extend family and a Ashkenazi Jew f has more genes in common with Sephardi Jew then each of them has with the neighboring populations. (not sure about the Yemeni Jews) Evidence for this can be found on the many posts on this blog about Jewish genetics.
    I also think is dangerous for Jews themselves to insist on the converting, adoption thing because this is basically what a lot of anti-Semites and Palestinians say. ( the whole theory of “If they are just a bunch of converted Khazars and whatnot then what are they doing in Israel?”)

  • onur

    There are three genetic bodies among Caucasoid Jews (today all Jews except Sub-Saharan and South Asian Jews), each of which is genetically separated from each other: There is an uninterrupted genetic continuity between Ashkenazi, Sephardic (note that Greek, Turkish, Moroccan and Syrian Jewish communities are composed of more Sephardic immigrants than the native Jews of those countries) and Italian Jews, so they form one genetic body. The native Jews of the Middle East except Yemen, of the Caucasus and of Central Asia also have an uninterrupted genetic continuity and they form another genetic body. Yemenite Jews form yet another genetic body.

    Here is a PCA plot showing all the three genetic bodies of Caucasoid Jews in a West Eurasian context:

    http://1.bp.blogspot.com/_Ish7688voT0/TBDgV2r3hxI/AAAAAAAACck/sYi1shNB8bc/s1600/westeurasianpca.jpg

    And here is a PCA plot showing all the three genetic bodies of Caucasoid Jews except the Yemenite one (note that the populations designated with three capital letters are all Jewish populations) again in a West Eurasian context:

    http://3.bp.blogspot.com/_Ish7688voT0/TAimWIpgDAI/AAAAAAAACao/0uuOXPXvqcQ/s1600/pc-jews.jpg

    Which of the three Caucasoid Jewish genetic bodies is the genetically closest to the original Jews of the Iron Age is at least for now an open-ended question, but clearly each of the three genetic bodies shows some genetic closeness to some of its respective gentile (non-Jewish) host populations.

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About Razib Khan

I have degrees in biology and biochemistry, a passion for genetics, history, and philosophy, and shrimp is my favorite food. In relation to nationality I'm a American Northwesterner, in politics I'm a reactionary, and as for religion I have none (I'm an atheist). If you want to know more, see the links at http://www.razib.com

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