Ashkenazi Jewish gene pool derives from "recent severe bottleneck" of 300-400 individuals ca. 800 years ago

Some AJ-related ASHG 2013 abstracts.

(1) "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. [. . .] 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. [. . .] the fraction of European ancestry in AJ to be ≈55±2%."

(2) "For the AJ, we estimated mean ancestral proportions of 0.380, 0.305, 0.113, 0.041 and 0.148 for Middle Eastern, Italian, French, Russian and Caucasus ancestry, respectively."

(3) "Employing a variety of standard techniques for the analysis of population structure, we find that Ashkenazi Jewish samples share the greatest genetic ancestry with other Jewish populations, and among non-Jewish populations, with groups from Mediterranean Europe and the Middle East"

Full abstracts below:

The Ashkenazi Jewish Genome. S. Carmi¹, E. Kochav¹, K. Hui², X. Liu³, J. Xue¹, F. Grady¹, S. Guha^4,5, K. Upadhyay⁶, S. Mukherjee^4,5, B. M. Bowen², V. Joseph⁷, A. Darvasi⁸, K. Offit⁷, L. Ozelius⁹, I. Peter⁹, J. Cho², H. Ostrer⁶, G. Atzmon⁶, L. Clark³, T. Lencz^4,5, I. Pe'er^1,10 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 ≈52,000±4000ya, and the fraction of European ancestry in AJ to be ≈55±2%. We also inferred the split between the ancestral Middle-Eastern population and contemporary Europeans to be as recent as ≈11,000±500ya, 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.


Admixture Estimation in a Founder Population. Y. Banda¹, M. Kvale¹, T. Hoffmann¹, S. Hesselson¹, H. Tang³, D. Ranatunga², L. Walter², C. Schaefer², P. Kwok¹, N. Risch¹ 1) Institute Human Genetics, University California San Francisco, San Francisco, CA; 2) Kaiser Permanente Northern California, Division of Research, Oakland, CA; 3) Department of Genetics, Stanford University, Stanford, CA.

   Admixture between previously diverged populations yields patterns of genetic variation that can aid in understanding migrations and natural selection. An understanding of individual admixture (IA) is also important when conducting association studies in admixed populations. However, genetic drift, in combination with shallow allele frequency differences between ancestral populations, can make admixture estimation by the usual methods challenging. We have, therefore, developed a simple but robust method for ancestry estimation using a linear model to estimate allele frequencies in the admixed individual or sample as a function of ancestral allele frequencies. The model works well because it allows for random fluctuation in the observed allele frequencies from the expected frequencies based on the admixture estimation. We present results involving 3,366 Ashkenazi Jews (AJ) who are part of the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort and genotyped at 674,000 SNPs, and compare them to the results of identical analyses for 2,768 GERA African Americans (AA). For the analysis of the AJ, we included surrogate Middle Eastern, Italian, French, Russian, and Caucasus subgroups to represent the ancestral populations. For the African Americans, we used surrogate Africans and Northern Europeans as ancestors. For the AJ, we estimated mean ancestral proportions of 0.380, 0.305, 0.113, 0.041 and 0.148 for Middle Eastern, Italian, French, Russian and Caucasus ancestry, respectively. For the African Americans, we obtained estimated means of 0.745 and 0.248 for African and European ancestry, respectively. We also noted considerably less variation in the individual admixture proportions for the AJ (s.d. = .02 to .05) compared to the AA (s.d.= .15), consistent with an older age of admixture for the former. From the linear model regression analysis on the entire population, we also obtain estimates of goodness of fit by r2. For the analysis of AJ, the r2 was 0.977; for the analysis of the AA, the r2 was 0.994, suggesting that genetic drift has played a more prominent role in determining the AJ allele frequencies. This was confirmed by examination of the distribution of differences for the observed versus predicted allele frequencies. As compared to the African Americans, the AJ differences were significantly larger, and presented some outliers which may have been the target of selection (e.g. in the HLA region on chromosome 6p).


No indication of Khazar genetic ancestry among Ashkenazi Jews. M. Metspalu^1,13,14, D. M. Behar^2,1,14, Y. Baran³, S. Rosset⁴, N. Kopelman⁵, B. Yunusbayev^1,6, A. Gladstein⁷, M. F. Hammer⁷, S. Tzur², E. Halperin^3,8,9, K. Skorecki^2,10, R. Villems^1,11, N. A. Rosenberg¹² 1) Evolutionary Biology, Estonian Biocentre & Tartu Univ, Tartu, Estonia; 2) Molecular Medicine Laboratory, Rambam Health Care Campus, Haifa 31096, Israel; 3) The Blavatnik School of Computer Science, Tel Aviv University, Tel-Aviv 69978, Israel; 4) Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; 5) Porter School of Environmental Studies, Department of Zoology, Tel Aviv University, Tel Aviv 69978, Israel; 6) Institute of Biochemistry and Genetics, Ufa Research Center, Russian Academy of Sciences, Ufa 450054, Russia; 7) ARL Division of Biotechnology, University of Arizona, Tucson, Arizona 85721, USA; 8) Department of Molecular Microbiology and Biotechnology, George Wise Faculty of Life Science, Tel-Aviv University, Tel-Aviv 69978, Israel; 9) International Computer Science Institute, Berkeley, California 94704, USA; 10) Ruth and Bruce Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa 31096, Israel; 11) Estonian Academy of Sciences, Tallinn 10130, Estonia; 12) Department of Biology, Stanford University, Stanford, California 94305, USA; 13) Department of Integrative Biology, University of California Berkeley, 94720, USA; 14) these authors contributed equally.

   The origin and history of the Ashkenazi Jewish population have long been of great interest. Most studies have concluded that the population derives its genetic ancestry from both Europe and the Middle East, and that it retains high genetic similarity to other Jewish groups such as the Sephardi Jews in Europe and Jewish communities in Northern Africa. It has recently been claimed, however, that a large part of the ancestry of the Ashkenazi population originates with the Khazars, a conglomerate of multi-ethnic, mostly Turkic-speaking tribes who consolidated into a powerful state just north of the Caucasus mountains between ca. 1,400 to 1,000 years ago. It has been difficult to explicitly test for Khazar contributions into Ashkenazi Jews, because it is not clear which extant populations can be used to represent modern descendants of the Khazars, and because the proximity of the southern Caucasus region to the Middle East makes it difficult to attribute any potential signal of Caucasus ancestry to Khazars rather than Middle Eastern populations. Here, we assemble the largest sample set available to date for assessment of Ashkenazi Jewish genetic origins, containing genome-wide single-nucleotide polymorphism data in 1,774 samples from 107 Jewish and non-Jewish populations that span the possible regions of potential Ashkenazi Jewish ancestry: Europe, the Middle East, and 15 populations from the region historically associated with the Khazar kingdom at its peak. Employing a variety of standard techniques for the analysis of population structure, we find that Ashkenazi Jewish samples share the greatest genetic ancestry with other Jewish populations, and among non-Jewish populations, with groups from Mediterranean Europe and the Middle East, and that they have no particular signal of genetic sharing with populations from the Caucasus. Thus, analysis of the most comprehensive set of Jewish and other Middle Eastern and European populations together with a large sample from the region of the Khazar kingdom does not support the hypothesis of a significant contribution of the elusive Khazars into the gene pool of the Ashkenazi Jews.


Population Structure and Genetic Diversity in a Population of 15,000 Patients from East Harlem, NY. G. Belbin¹, D. Ruderfer^2,3,4, E. A. Stahl^2,3,5,6, J. Jeff⁵, Y. Lu⁵, R. J. F. Loos^5,7, O. Gottesman⁵, S. Purcell^2,3,4,5, E. Bottinger⁵, E. E. Kenny^1,4,5,6 1) Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY; 2) Broad Institute, Cambridge, MA; 3) Division of Psychiatric Genomics, Icahn School of Medicine at Mt Sinai, New York, NY; 4) Center for Statistical Genetics, Icahn School of Medicine at Mt Sinai, New York, NY; 5) Institute for Personalized Medicine, Icahn School of Medicine at Mt Sinai, New York NY; 6) Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mt Sinai, New York, NY; 7) The Mindich Child Health and Development Institute, Icahn School of Medicine at Mt Sinai, New York, NY.

   New York City has historically been a significant point of entry for immigration into the United States and as a consequence is today peopled by a highly structured and ethnically diverse population. Census ethnic labeling reveals some of this diversity, but does not fully capture the variety of cultural groups, with complex and diverse demographic origins, foods and traditions, living in New York. Using genome-wide data, it is possible to detect such population structure which can both inform population history inference and result in better outcomes for medical genetics studies. We present a diversity of approaches for the analysis of fine-scale population structure in a population of 29,093 patients enrolled in the Icahn School of Medicine BioMe Biobank Cohort (BioMe), of which ~13,500 have available Illumnia Omni Express and Exome Chip data (~900K SNPs). BioMe comprises 34%, 47% and 19% participants with self-reported African-American (AA), Hispanic-Latino (HL) and European-American (EA), respectively, and is representative of the population of Northern Manhattan. We combined these data with both data generated from the 1000 genomes project and an additional unique database of genomic variation in over 4,000 individuals from diverse European, Middle Eastern, East Asian, African and Native American populations. Population genetic analysis using standard Principle Component Analysis (PCA) and ADMIXTURE, and a novel ancestry-specific PCA method using Native American, European and African local ancestry haplotypes from AA and HL genomes, reveals diverse sub-continental structure in the BioMe cohort. In particular, we detect a large proportion of Ashkenazi Jewish and Eastern European ancestry in the BioMe EAs. We also performed identity-by-descent (IBD) analysis and detect elevated cryptic relatedness in the AAs and HLs, which results in increased genetic tract sharing compared to EAs. For example, analysis of IBD haplotype sharing between any two less-than-fourth-degree relatives in our cohort indicates a larger percent of their genome is shared (~0.4% and 3.72%, for AA and HL, respectively), compared with the same analysis in EA (~0.12%).