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Inferring the Demographic History of the Ashkenazi Jewish population

Inferring the Demographic History of the Ashkenazi Jewish population. Shai Carmi Pe’er lab, Columbia University. Leicester, UK April 2014. Outline. Introduction A Recent Bottleneck Ancient History Origin of Gene Flow Summary. The Documented History.

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Inferring the Demographic History of the Ashkenazi Jewish population

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  1. Inferring the Demographic History of the Ashkenazi Jewish population Shai Carmi Pe’er lab, Columbia University Leicester, UK April 2014

  2. Outline • Introduction • A Recent Bottleneck • Ancient History • Origin of Gene Flow • Summary

  3. The Documented History • Ca. 1000: Small communities in Northern France, Rhineland • Migration east • Expansion • Migration to US and Israel

  4. Ashkenazi Jewish (AJ) Genetics Atzmonet al., AJHG, 2010 AJ Europe Jewish, non-AJ Behar et al., Nature, 2010 Bray et al., PNAS, 2010 Guha et al., Genome Biol, 2012 Behar et al., Hum. Biol., 2014 Price et al., PLoSGenet., 2008 Olshen et al., BMC Genet, 2008 Need et al., Genome Biol, 2009 Kopelman et al., BMC Genet, 2009 Middle-East

  5. AJ Genetics: Significance Ashkenazi Jews • Medical genetics: • Large founder population: Useful in medical genetics • Mendelian disorders and risk factors • Population genetics: • Abundance of IBD sharing • Insight on European and Middle-Eastern past EU-Americans (non-Jewish) Gusev et al., MBE, 2012

  6. The Ashkenazi Genome Consortium NY area labs interested in specific diseases Large genotyped cohorts Phase I: 128 whole genomes (CG; completed) Phase II: ≈300 whole genomes (NYGC; under way) Learn about population history Quantify utility in medical genetics S. C. et al., submitted

  7. A Recent Bottleneck: IBD analysis • Assume a population of historical size diploids • Fraction of the genome in segments of length : Palamara et al., AJHG, 2012 • Detect IBD segments in sample Infer history Time (ya)

  8. Allele Frequency Spectrum Comparison panel:Flemish from Belgium, matched for platform (n=26)

  9. Joint Allele Frequency Spectrum • Fit a model to the AFS • ∂a∂i(Gutenkunstet al., 2009) • Fix recent bottleneck • Use “low” mutation rate

  10. A Model for Ancient History Time (years ago) 13,900 3900 Out-of-Africa 90k Middle-East 3700 ? 21k 49% 23,800 170,000 1k Present AJ FL Formation of AJ

  11. The Neolithic Transition • Were hunter-gatherers replaced by ME farmers? • Modern genomes:Battalgliaet al., EJHG, 2009; Balaresque et al., PLoS Biol., 2010; Busby et al., PRSB, 2012; Patterson et al., Genetics, 2012; Wei et al., Genome Res., 2013 • Ancient genomes:Haak et al., PLoS Biol., 2009; Bramanti et al, Science; 2009; Lacan et al, PNAS, 2011; Skoglund et al., Science, 2012; Fu et al., PLoS One, 2012; Hervella, PLoS One, 2012; Lazaridis et al., 2013; Brandt et al., Science, 2013; Rasteiro and Chikhi, PLoS One, 2013 • No study with ME whole-genomes

  12. The Neolithic Transition: Initial Thoughts Time (kya) 45 First modern humans in EU 40 35 30 25 20 15 Inferred EU-ME split Farming in ME 10 Farming in EU “High” mutation rate 5 0

  13. The Neolithic Transition Time (kya) • LGM hypothesis • Pala et al, AJHG, 2012; Olivieri et al., PLoS One, 2013 • Interpretation is very sensitive to the mutation rate 45 First modern humans in EU 40 35 30 25 Last Glacial Maximum 20 Inferred EU-ME split 15 Farming in ME 10 Farming 5 0

  14. Origin of AJ • What is the source of AJ European ancestry? • Western Europe • Eastern Europe • Southern Europe • The Caucasus • Middle-Eastern ancestry?

  15. Problem Build EU/ME panels PCA ME x x x EU x x x x x x x x x o o o x o o x o x x x x x x x x x x x x x AJ

  16. Solution Admixture LD(ALDER) Build EU/ME panels Loh et al., Genetics, 2013 ME EU Local ancestry inference(RFMix) x x x x o o o x o x x x x x x o x o x x x x x x x x x x x x x x o o o x x o o x x x o x x x x x x x Ancestry-specific PCA(PCAMask) x x x x x x x x x x x x x x x x Johnson et al., PLoS Genetics, 2011; Moreno-Estrada, PLoS Genetics, 2013

  17. Preliminary Results Europe Middle-East AJ ALDER Time (generations) * 42 ** *** 39 38 West South East

  18. Summary • AJ: A medically important founder population • Lots of data • Interesting history • IBD sharing quantifies bottleneck • Allele frequency spectrum hints on ancient history • Exciting challenges • Sub-continental ancestry

  19. Acknowledgements TAGC consortium members: Todd Lencz(LIJMC) Lorraine Clark, Xinmin Liu (CUMC) Gil Atzmon, Harry Ostrer, Danny Ben-Avraham (AECOM) Inga Peter, Judy Cho (MSSM) Joseph Vijai (MSKCC) Ken Hui (Yale) ItsikPe’er’s lab: James Xue, Ethan Kochav Funding: Human Frontiers Science program Thank you for your attention!

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