The Ashkenazi Jewish Genome. S. Carmi1, E. Kochav1, K. Hui2, X. Liu3, J. Xue1, F. Grady1, S. Guha4,5, K. Upadhyay6, S. Mukherjee4,5, B. M. Bowen2, V. Joseph7, A. Darvasi8, K. Offit7, L. Ozelius9, I. Peter9, J. Cho2, H. Ostrer6, G. Atzmon6, L. Clark3, T. Lencz4,5, I. Pe'er1,10 1) Department of Computer Science, Columbia University, New York, NY; 2) Department of Internal Medicine, Yale School of Medicine, New Haven, CT; 3) Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY; 4) Center for Psychiatric Neuroscience, The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, NY; 5) Department of Psychiatry, Division of Research, The Zucker Hillside Hospital Division of the North Shore-Long Island Jewish Health System, Glen Oaks, NY; 6) Department of Genetics, Albert Einstein College of Medicine, Bronx, NY; 7) Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY; 8) Department of Genetics, The Institute of Life Sciences, The Hebrew University of Jerusalem, Givat Ram, Jerusalem, Israel; 9) Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY; 10) Center for Computational Biology and Bioinformatics, Columbia University, New York, New York.

   Ashkenazi Jews (AJ) number 10 million individuals worldwide, mostly in the US and Israel. In accordance with historical records, recent studies showed that AJ are genetically homogeneous with mixed European and Middle-Eastern ancestry and that the AJ population had undergone a severe bottleneck around 800ya followed by an extremely rapid expansion. These characteristics make the AJ population highly attractive for genetic studies. Here, we report the sequencing of 128 complete genomes of healthy AJ individuals. Sequencing was carried out by Complete Genomics to coverage >50x, and achieved 97% call rate, Ti/Tv=2.14, and 99.7% concordance with SNP arrays. Additional cleaning further reduced the number of false positives to just 5000, as determined by examining runs-of-homozygosity. We show that our AJ sequencing panel is 3- fold more effective in filtering out benign variants in clinical AJ genomes than a European, non-Jewish panel. Similarly, our AJ panel reduced the inaccuracy of AJ array imputation, for both rare and common alleles, by 10-20%. Inspection of specific genes related to AJ genetic disorders identified known disease mutations as well as dozens of additional risk alleles. Population-genetic comparison of the AJ genomes to 26 Flemish genomes sequenced using the same technology revealed increased heterozygosity and less allele sharing in AJ, in accordance with the AJ admixed nature and partial Middle-Eastern origin. On the other hand, AJ showed more population-specific allele sharing, higher load of deleterious alleles, and a smaller overall projected number of variants, potentially due to the recent bottleneck. Analysis of identical-by-descent segments, which are abundant in AJ and highly informative on recent history, confirmed a recent severe bottleneck of merely 300-400 individuals. Using the allele frequency spectrum, which is informative on ancient history, we inferred the time of the Out-of-Africa founder event to be 52,0004000ya, and the fraction of European ancestry in AJ to be 552%. We also inferred the split between the ancestral Middle-Eastern population and contemporary Europeans to be as recent as 11,000500ya, suggesting the genetic origin of modern-day Europeans is predominantly Neolithic, and much later than the first dated Homo sapiens migration into Europe. This result, made possible by our pioneering sequencing of individuals with Middle-Eastern ancestry, resolves a long-standing debate over European origins.

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