Analysis of Ashkenazi Jewish genomes (Bray et al. 2010)

The paper hasn't gone live at the PNAS site as of this writing, but here is part of the press release. The abstract and my comments on the paper will be posted here (after I get through the zillion other interesting papers that the last week of August seems to have brought us):

Investigators in the laboratory of Stephen Warren, PhD, chairman of human genetics at Emory University School of Medicine, used DNA microarray technology to read variant sites across the entire genomes of 471 Ashkenazi Jews. The work comes from a collaboration between Warren and Ann Pulver, ScD, associate professor of psychiatry and behavioral sciences at Johns Hopkins University School of Medicine, who recruited the participants for a study of schizophrenia genetics.

Researchers looked for close to one million single nucleotide polymorphisms (SNPs): common alternative spellings in the genome, analogous to American and British spellings of words such as organize/organise. One measure of genetic diversity in a population is heterozygosity, or how many of the SNPs inherited from the mother and father are different; a more inbred population has less heterozygosity.

"We were surprised to find evidence that Ashkenazi Jews have higher heterozygosity than Europeans, contradicting the widely-held presumption that they have been a largely isolated group," says first author Steven Bray, PhD, a postdoctoral fellow in Warren's laboratory.

...

High linkage disequilibrium can come either from an isolated population (for example, an island whose residents are all descendents of shipwreck survivors) or the relatively recent mixture of separate populations. Bray and his colleagues did find evidence of elevated linkage disequilibrium in the Ashkenazi Jewish population, but were able to show that this matches signs of interbreeding or "admixture" between Middle Eastern and European populations.

The researchers were able to estimate that between 35 and 55 percent of the modern Ashkenazi genome comes from European descent.

"Our study represents the largest cohort of Ashkenazi Jews examined to date with such a high density of genetic markers, and our estimate of admixture is considerably higher than previous estimates that used the Y chromosome to calculate European admixture at between five and 23 percent," Bray says.

...

"Only six of the 21 disease genes that we examined showed evidence of selection," Bray says. "This supports the argument that most of the Ashkenazi-prevalent diseases are not generally being selected for, but instead are likely a result of a genetic bottleneck effect, followed by random drift."

The new paper comes in the heels of two other papers by Behar et al. and Atzmon et al. which considered Jews in general, discovering additional clusters of Jews that were distinct from Ashkenazi Jews. As I have argued in my review of these papers, the different clusters are not the result of isolation, as the different groups of Jews do not only deviate from each other, but also in the direction of their host populations. It would be worthwhile to perform similar admixture analyses on non-AJ populations to determine what their influence from host populations is. With a little effort it would be possible to reconstruct the ancestral Jewish population, by identifying what is common in the different Jewish populations.

UPDATE: The paper is now online and is open access.

From the paper:

The fixation index, FST, calculated concurrently to the PCA, confirms that there is a closer relationship between the AJ and several European populations (Tuscans, Italians, and French) than between the AJ and Middle Eastern populations (Fig. S2B). This finding can be visualized with a phylogenetic tree built using the FST data (Fig. S2C), showing that the AJ population branches with the Europeans and not Middle Easterners. Two recent studies performing PCA and population clustering with high-density SNP genotyping from many Jewish Diaspora populations, both showed that of the Jewish populations, the Ashkenazi consistently cluster closest to Europeans (13, 25). Genetic distances calculated by both groups also show that the Ashkenazi are more closely related to some host Europeans than to the ancestral Levant (13, 25). Although the proximity of the AJ and Italian populations could be explained by their admixture prior to the Ashkenazi settlement in Central Europe (13), it should be noted that different demographic models may potentially yield similar principal component projections (33); thus, it is also consistent that the projection of the AJ populations is primarily the outcome of admixture with Central and Eastern European hosts that coincidentally shift them closer to Italians along principle component axes relative to Middle Easterners. Taken as a whole, our results, along with those from previous studies, support the model of a Middle Eastern origin of the AJ population followed by subsequent admixture with host Europeans or populations more similar to Europeans. Our data further imply that modern Ashkenazi Jews are perhaps even more similar with Europeans than Middle Easterners.

The bolded part reminds me of what I wrote in my review of Atzmon et al. regarding the choice of parental populations and how they affect admixture estimates. The "Middle Eastern" component estimate will increase if central and eastern Europeans are used as representative of the European admixture, while the "European" estimate will increase if Italians are used. But, the same applies to the other end of the continuum: if ancestral Jews were indeed like current Middle Easterners such as the Druze or Palestinians, but the latter may have moved (in genetic space) away from ancient Levantines due to subsequent admixture (Arabs, and in the case of Palestinians even Africans): this would reduce the inferred Middle Eastern component.

Estimating admixture percentages in the absence of clear knowledge about parental populations is no easy thing, but the intermediate-leaning-on-Europe status of AJ relative to living Europeans and living Middle Easterners seems to be a pretty secure conclusion.

PNAS doi: 10.1073/pnas.1004381107

Signatures of founder effects, admixture, and selection in the Ashkenazi Jewish population

Steven M. Bray et al.

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.

Link