Abstract The Ashkenazi Jewish (AJ) population is important in medical genetics due to its high rate of Mendelian disorders and other unique genetic characteristics. Ashkenazi Jews have appeared in Europe in the 10 th century, and their ancestry is thought to involve an admixture of European (EU) and Middle-Eastern (ME) groups. However, both the time and place of admixture in Europe are obscure and subject to intense debate. Here, we attempt to characterize the Ashkenazi admixture history using a large Ashkenazi sample and careful application of new and existing methods. Our main approach is based on local ancestry inference, assigning each Ashkenazi genomic segment as EU or ME, and comparing allele frequencies across EU segments to those of different EU populations. The contribution of each EU source was also evaluated using GLOBETROTTER and analysis of IBD sharing. The time of admixture was inferred using multiple tools, relying on statistics such as the distributions of EU segment lengths and the total EU ancestry per chromosome and the correlation of ancestries along the chromosome. Our simulations demonstrated that distinguishing EU vs ME ancestry is subject to considerable noise at the single segment level, but nevertheless, conclusions could be drawn based on chromosome-wide statistics. The predominant source of EU ancestry in AJ was found to be Southern European (≈60-80%), with the rest being likely Eastern European. The inferred admixture time was ≈35 generations ago, but multiple lines of evidence suggests that it represents an average over two or more admixture events, pre-and post-dating the founder event experienced by AJ in late medieval times, with the prebottleneck admixture event bounded between 25-55 generations ago. Author Summary The Ashkenazi Jewish population has dwelt in Europe for much of its 1000-year existence. However, the ethnic and geographic origins of Ashkenazi Jews are controversial, due to the lack of reliable historical records. Previous genetic studies have exposed links to Middle-Eastern and European ancestries, but the history of admixture in Europe has not been studied in detail yet, partly due to technical difficulties in disentangling signals from multiple admixture events. Here, we address this challenge by presenting an in-depth analysis of the sources of European gene flow and the time of admixture events, using a wide spectrum of genetic methods, extensive simulations, and a number of new approaches. Specifically, to ensure minimal confounding by the Ashkenazi Middle-Eastern ancestry, we mask out genomic regions with Middle-Eastern ancestry, and investigate the lengths and geographic sources of the remaining regions. Our results suggest a model of at least two events of European admixture. One event slightly pre-dated a late medieval founder event and was likely from a Southern European source. Another event post-dated the founder event and was likely in Eastern Europe. These results, as well as the methods introduced, will be highly valuable for geneticists and other researchers interested in Ashkenazi Jewish origins and medical genetics.

The Time and Place of European Admixture in Ashkenazi Jewish History