SMBE 2014: Whole genome sequencing of an Ashkenazi Jewish reference panel supports population-targeted personal genomics and illuminates Jewish and European origins

Whole genome sequencing of an Ashkenazi Jewish reference panel supports population-targeted personal genomics and illuminates Jewish and European origins
Shai Carmi 1, Ken Hui2, Ethan Kochav1, Xinmin Liu1, James Xue1, Fillan Grady1, Saurav Guha3 ,5, Kinnari Upadhyay6, Danny Ben-Avraham6, Semanti Mukherjee3 ,4, B. Monica Bowen2, Tinu Thomas7, Joseph Vijai7, Nir Barzilai6, Ariel Darvasi8, Kenneth Offit7, Susan Bressman9, Laurie Ozelius5, Inga Peter5, Judy Cho2, Harry Ostrer6, Gil Atzmon6, Lorraine Clark1, Todd Lencz3 ,4, Itsik Pe'er1
1Columbia University, New York, NY, USA, 2Yale University, New Haven, CT, USA, 3The Feinstein Institute, Manhasset, NY, USA, 4The Zucker Hillside Hospital, Glen Oaks, NY, USA, 5Icahn School of Medicine at Mount Sinai, New York, NY, USA, 6Albert Einstein College of Medicine, New York, NY, USA, 7Memorial Sloan Kettering Cancer Center, New York, NY, USA, 8The Hebrew University of Jerusalem, Jerusalem, Israel, 9Beth Israel Medical Center, New York, NY, USA
The Ashkenazi Jewish (AJ) population is a genetic isolate, close to European and Middle-Eastern populations. AJ experienced a severe medieval bottleneck followed by rapid expansion, leading to genetic diversity patterns conducive to powerful disease mapping. Here, we report the high-depth sequencing of 128 complete genomes of AJ controls. Compared to a European reference panel, our AJ panel is 47% richer in novel variants and 8-fold more effective at filtering benign variants, a necessary step for interpreting AJ clinical genomes. Our panel improves the accuracy of imputation of AJ SNP arrays by 28%, and covers with long, identical-by-descent segments at least one haplotype in ≈67% of the genome of any other AJ individual. Reconstruction of recent AJ history from such segments confirms and quantifies a recent bottleneck of merely ≈350 individuals. Further modeling of ancient histories for AJ and European populations using their joint allele frequency spectrum determines AJ to be an admixture of European (50% of ancestry) and likely Middle-Eastern (50%) origins. This composition facilitates inferring that the split between the two ancestral populations occurred as recently as ≈21 kya, suggesting a predominantly near-Eastern source for the repopulation of Europe at the end of the Last Glacial Maximum.

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