Sequencing an Ashkenazi reference panel supports population-targeted personal genomics and illuminates Jewish and European origins

Shai Carmi¹, Ken Y Hui², Ethan Kochav¹, Xinmin Liu³, James Xue¹, Fillan Grady¹, Saurav Guha⁴, Kinnari Upadhyay⁵, Dan Ben-Avraham⁶, Semanti Mukherjee⁷, B Monica Bowen², Tinu Thomas⁸, Joseph Vijai⁸, Marc Cruts⁹, Guy Froyen¹⁰, Diether Lambrechts¹¹, Stéphane Plaisance¹², Christine Van Broeckhoven⁹, Philip Van Damme¹³, Herwig Van Marck¹², Nir Barzilai⁶, Ariel Darvasi¹⁴, Kenneth Offit⁸, Susan Bressman¹⁵, Laurie J Ozelius¹⁶, Inga Peter¹⁶, Judy H Cho², Harry Ostrer¹⁷, Gil Atzmon⁶, Lorraine N Clark¹⁸, Todd Lencz¹⁹, Itsik Pe'er²⁰

Affiliations

¹ Department of Computer Science, Columbia University, 500 W 120th Street, New York, New York 10027, USA.
² Department of Internal Medicine, Genetics &Pediatrics, Yale School of Medicine, 300 Cedar Street, New Haven, Connecticut 06519, USA.
³ Department of Pathology and Cell Biology, Columbia University Medical Center, 1150 St Nicholas Avenue, New York, New York 10032, USA.
⁴ 1] Center for Psychiatric Neuroscience, The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York 11030, USA [2] Department of Psychiatry, Division of Research, The Zucker Hillside Hospital Division of the North Shore-Long Island Jewish Health System, Glen Oaks, New York 11004, USA [3] Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York 10029, USA.
⁵ Department of Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
⁶ 1] Department of Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA [2] Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
⁷ 1] Center for Psychiatric Neuroscience, The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York 11030, USA [2] Department of Psychiatry, Division of Research, The Zucker Hillside Hospital Division of the North Shore-Long Island Jewish Health System, Glen Oaks, New York 11004, USA.
⁸ 1] Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA [2] Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA.
⁹ VIB Department of Molecular Genetics, University of Antwerp, Universiteitsplein 1, 2610 Antwerpen, Belgium.
¹⁰ VIB Center for the Biology of Disease, KU Leuven, Herestraat 49, bus 602, 3000 Leuven, Belgium.
¹¹ VIB Vesalius Research Center, KU Leuven, Herestraat 49, bus 912, 3000 Leuven, Belgium.
¹² VIB BioInformatics Training and Services facility, Rijvisschestraat 120, 9052 Gent, Belgium.
¹³ 1] VIB Vesalius Research Center, KU Leuven, Herestraat 49, bus 912, 3000 Leuven, Belgium [2] Neurology Department, University Hospital Leuven, 3000 Leuven, Belgium.
¹⁴ Department of Genetics, The Institute of Life Sciences, The Hebrew University of Jerusalem, Givat Ram, Jerusalem 91904, Israel.
¹⁵ Department of Neurology, Beth Israel Medical Center, New York, New York 10003, USA.
¹⁶ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York 10029, USA.
¹⁷ 1] Department of Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA [2] Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
¹⁸ 1] Department of Pathology and Cell Biology, Columbia University Medical Center, 1150 St Nicholas Avenue, New York, New York 10032, USA [2] Taub Institute for Research of Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, 1150 St Nicholas Avenue, New York, New York 10032, USA.
¹⁹ 1] Center for Psychiatric Neuroscience, The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York 11030, USA [2] Department of Psychiatry, Division of Research, The Zucker Hillside Hospital Division of the North Shore-Long Island Jewish Health System, Glen Oaks, New York 11004, USA [3] Departments of Psychiatry and Molecular Medicine, Hofstra University School of Medicine, Hempstead, New York 11550, USA.
²⁰ 1] Department of Computer Science, Columbia University, 500 W 120th Street, New York, New York 10027, USA [2] Center for Computational Biology and Bioinformatics, Columbia University, 1130 St Nicholas Avenue, New York, New York 10032, USA.

PMID: 25203624
PMCID: PMC4164776
DOI: 10.1038/ncomms5835

Sequencing an Ashkenazi reference panel supports population-targeted personal genomics and illuminates Jewish and European origins

Shai Carmi et al. Nat Commun. 2014.

. 2014 Sep 9:5:4835.

doi: 10.1038/ncomms5835.

Authors

Affiliations

¹ Department of Computer Science, Columbia University, 500 W 120th Street, New York, New York 10027, USA.
² Department of Internal Medicine, Genetics &Pediatrics, Yale School of Medicine, 300 Cedar Street, New Haven, Connecticut 06519, USA.
³ Department of Pathology and Cell Biology, Columbia University Medical Center, 1150 St Nicholas Avenue, New York, New York 10032, USA.
⁴ 1] Center for Psychiatric Neuroscience, The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York 11030, USA [2] Department of Psychiatry, Division of Research, The Zucker Hillside Hospital Division of the North Shore-Long Island Jewish Health System, Glen Oaks, New York 11004, USA [3] Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York 10029, USA.
⁵ Department of Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
⁶ 1] Department of Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA [2] Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
⁷ 1] Center for Psychiatric Neuroscience, The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York 11030, USA [2] Department of Psychiatry, Division of Research, The Zucker Hillside Hospital Division of the North Shore-Long Island Jewish Health System, Glen Oaks, New York 11004, USA.
⁸ 1] Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA [2] Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA.
⁹ VIB Department of Molecular Genetics, University of Antwerp, Universiteitsplein 1, 2610 Antwerpen, Belgium.
¹⁰ VIB Center for the Biology of Disease, KU Leuven, Herestraat 49, bus 602, 3000 Leuven, Belgium.
¹¹ VIB Vesalius Research Center, KU Leuven, Herestraat 49, bus 912, 3000 Leuven, Belgium.
¹² VIB BioInformatics Training and Services facility, Rijvisschestraat 120, 9052 Gent, Belgium.
¹³ 1] VIB Vesalius Research Center, KU Leuven, Herestraat 49, bus 912, 3000 Leuven, Belgium [2] Neurology Department, University Hospital Leuven, 3000 Leuven, Belgium.
¹⁴ Department of Genetics, The Institute of Life Sciences, The Hebrew University of Jerusalem, Givat Ram, Jerusalem 91904, Israel.
¹⁵ Department of Neurology, Beth Israel Medical Center, New York, New York 10003, USA.
¹⁶ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, New York 10029, USA.
¹⁷ 1] Department of Genetics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA [2] Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.
¹⁸ 1] Department of Pathology and Cell Biology, Columbia University Medical Center, 1150 St Nicholas Avenue, New York, New York 10032, USA [2] Taub Institute for Research of Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, 1150 St Nicholas Avenue, New York, New York 10032, USA.
¹⁹ 1] Center for Psychiatric Neuroscience, The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, New York 11030, USA [2] Department of Psychiatry, Division of Research, The Zucker Hillside Hospital Division of the North Shore-Long Island Jewish Health System, Glen Oaks, New York 11004, USA [3] Departments of Psychiatry and Molecular Medicine, Hofstra University School of Medicine, Hempstead, New York 11550, USA.
²⁰ 1] Department of Computer Science, Columbia University, 500 W 120th Street, New York, New York 10027, USA [2] Center for Computational Biology and Bioinformatics, Columbia University, 1130 St Nicholas Avenue, New York, New York 10032, USA.

PMID: 25203624
PMCID: PMC4164776
DOI: 10.1038/ncomms5835

Abstract

The Ashkenazi Jewish (AJ) population is a genetic isolate close to European and Middle Eastern groups, with genetic diversity patterns conducive to disease mapping. Here we report high-depth sequencing of 128 complete genomes of AJ controls. Compared with European samples, our AJ panel has 47% more novel variants per genome and is eightfold more effective at filtering benign variants out of AJ clinical genomes. Our panel improves imputation accuracy for AJ SNP arrays by 28%, and covers at least one haplotype in ≈ 67% of any AJ genome with long, identical-by-descent segments. Reconstruction of recent AJ history from such segments confirms a recent bottleneck of merely ≈ 350 individuals. Modelling of ancient histories for AJ and European populations using their joint allele frequency spectrum determines AJ to be an even admixture of European and likely Middle Eastern origins. We date the split between the two ancestral populations to ≈ 12-25 Kyr, suggesting a predominantly Near Eastern source for the repopulation of Europe after the Last Glacial Maximum.

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Figures

**Figure 1. Novel variants discovered in Ashkenazi Jewish and Flemish genomes.**
(a) Variant counts (all and heterozygous; left) and fraction novel (right) per genome in the Ashkenazi Jewish (AJ) and Flemish (FL) cohorts (corresponding to about ≈80% of the raw variants remaining after QC and cohort merging; Supplementary Note 2; error bars represent s.d.). (b) Efficiency of filtering all novel variants detected in an AJ personal genome, measured by counting those that remain new after filtering such a genome against either FL or AJ panels of a matched size (n=26) or our complete AJ panel (n=127). Left: all novel variants; right: non-synonymous novel variants. Error bars represent s.d. (c) The number of newly discovered segregating sites in AJ and FL versus the number of already sequenced individuals in each cohort (markers). Dashed and solid lines are expectations based on either a constant size or a bottleneck and growth model (bn/growth), respectively, fitted to each population separately (Supplementary Note 3). The inset magnifies the region (0, 10).

**Figure 2. Utility of the AJ reference panel in IBD-based and traditional imputation.**
(a) The distribution, over all pairs of individuals, of the fraction of the genome shared IBD (segment lengths >3 cM) either within AJ, within FL or between AJ and FL. (b) The average fraction of a genome (in AJ and CEU) where at least one haplotype is covered by segments shared with a population-matched panel. Data points (markers) were fit to (lines), where c is the average coverage and n is the number of individuals in the panel (Supplementary Note 4). (c) The aggregate r² (over the AJ study genomes) between the true and the imputed dosages versus the minor allele frequency, when imputing an AJ genome using a reference panel consisting of either AJ or CEU genomes.

formula image — **Figure 2. Utility of the AJ reference panel in IBD-based and traditional imputation.**
(a) The distribution, over all pairs of individuals, of the fraction of the genome shared IBD (segment lengths >3 cM) either within AJ, within FL or between AJ and FL. (b) The average fraction of a genome (in AJ and CEU) where at least one haplotype is covered by segments shared with a population-matched panel. Data points (markers) were fit to (lines), where c is the average coverage and n is the number of individuals in the panel (Supplementary Note 4). (c) The aggregate r² (over the AJ study genomes) between the true and the imputed dosages versus the minor allele frequency, when imputing an AJ genome using a reference panel consisting of either AJ or CEU genomes.

**Figure 3. The AFS and the lengths of shared segments.**
(a) The (normalized) minor allele frequency spectrum in AJ and FL, shown as counts in subsets of n=25 genomes in each cohort. The green line corresponds to the expectation in a constant-size population (Wright–Fisher), and bars represent deviations in AJ and FL. The inset shows the spectra of alleles private to each population. (b) A heat map of the joint (minor) allele frequency spectrum of AJ and FL (lower left triangle) compared with the expected joint AFS, had population labels been random (upper right triangle). (c) The average fraction of the genome found in shared segments versus the segment length (AJ only; circles), along with the best fit to a recent bottleneck and growth model (solid blue line; Fig. 4) and the expectation in a constant-size population with the same total sharing (dashed green line).

**Figure 4. A reconstruction of the AJ and FL demographic history.**
The upper part of the diagram shows the reconstruction of the ancient history by fitting the joint AFS (Fig. 3b) using *∂a∂i* and using a mutation rate of 1.44 × 10⁻⁸ per generation per bp. The lower diagram shows the recent AJ history, reconstructed by fitting the IBD length decay pattern (Fig. 3c). The wide arrow represents an admixture event; all effective population sizes (horizontal arrows) are in number of diploid individuals; all times were computed assuming 25 years per generation. Confidence intervals are provided in Supplementary Tables 6 and 7.

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References

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1. Ostrer H. & Skorecki K. The population genetics of the Jewish people. Hum. Genet. 132, 119–127 (2013). - PMC - PubMed
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Sequencing an Ashkenazi reference panel supports population-targeted personal genomics and illuminates Jewish and European origins

Affiliations

Sequencing an Ashkenazi reference panel supports population-targeted personal genomics and illuminates Jewish and European origins

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Molecular Biology Databases