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 Guha^{3 ,5}, Kinnari Upadhyay⁶, Danny Ben-Avraham⁶, Semanti Mukherjee^{3 ,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 Lencz^{3 ,4}, Itsik Pe'er^1
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.