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.he Ashkenazi Jewish (AJ) population has long been viewed as a genetic isolate, kept separate from its European neighbors by religious and cultural practices of endogamy (1). Population isolates are frequently used in genetic research, as such groups are presumed to have reduced genetic diversity, along with increased frequencies of recessive disorders, identity-by-descent (IBD), and linkage disequilibrium (LD) as the result of founder events and population bottlenecks (2, 3). Accordingly, the AJ population is often the subject of Mendelian and complex disease studies, although evidence that the AJ population carries all of the hallmarks of a genetic isolate has not been fully established.The most compelling genetic evidence of founder events in the AJ population is the elevated frequency of at least 20 rare recessive diseases attributed to genetic drift following bottlenecks. Coalescence times ascribed to founder mutations for some of these diseases correspond well with historical migrations or episodes of extreme persecution, supporting the argument for genetic drift (1, 4, 5). Strong evidence of founder events also comes from studies of mitochondrial DNA (mtDNA), which show significantly less diversity of mtDNA haplotypes among the AJ population (6, 7). Ychromosome studies also indicate only a low amount of admixture with neighboring Europeans (8-10). Additionally, some reports have measured higher LD in the AJ genome compared with reference p...