The relative roles of natural selection and accentuated genetic drift as explanations for the high frequency of more than 20 Ashkenazi Jewish disease alleles remain controversial. To test for the effects of a maternal bottleneck on the Ashkenazi Jewish population, we performed an extensive analysis of mitochondrial DNA (mtDNA) hypervariable segment 1 (HVS-1) sequence and restriction site polymorphisms in 565 Ashkenazi Jews from different parts of Europe. These patterns of variation were compared with those of five Near Eastern (n = 327) and 10 host European (n=849) non-Jewish populations. Only four mtDNA haplogroups (Hgs) (defined on the basis of diagnostic coding region RFLPs and HVS-1 sequence variants) account for ∼70% of Ashkenazi mtDNA variation. While several Ashkenazi Jewish mtDNA Hgs appear to derive from the Near East, there is also evidence for a low level of introgression from host European non-Jewish populations. HVS-1 sequence analysis revealed increased frequencies of Ashkenazi Jewish haplotypes that are rare or absent in other populations, and a reduced number of singletons in the Ashkenazi Jewish sample. These diversity patterns provide evidence for a prolonged period of low effective size in the history of the Ashkenazi population. The data best fit a model of an early bottleneck (∼ 100 generations ago), perhaps corresponding to initial migrations of ancestral Ashkenazim in the Near East or to Europe. A genetic bottleneck followed by the recent phenomenon of rapid population growth are likely to have produced the conditions that led to the high frequency of many genetic disease alleles in the Ashkenazi population.
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We thank Laurent Excoffier for valuable comments, Dr Marc-Alain Levy for help in collecting samples from the French Rhine Valley, the National Laboratory for the Genetics of Israeli Populations for contributing samples to this study and David Goldstein for providing non-Ashkenazi Jewish mtDNA data. This work was supported by a grant from the National Institute of General Medical Sciences (GM53566-06) to MH and an award grant from the Israeli Science Foundation to KS, as well as a kind donation from the Milin Charitable Foundation.