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 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., PLoS Genet., 2008 Olshen et al., BMC Genet, 2008 Need et al., Genome Biol, 2009 Kopelman et al., BMC Genet, 2009 AJ Jewish, non-AJ Middle- East Europ e Atzmon et al., AJHG, 2010

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

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

7. A Recent Bottleneck: IBD analysis Palamara et al., AJHG, 2012 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 o ∂a∂i (Gutenkunst et al., 2009) Fix recent bottleneck Use “low” mutation rate

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

11. The Neolithic Transition Were hunter-gatherers replaced by ME farmers? o Modern genomes: Battalglia et 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 o 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. Time (kya) First modern humans in EU 0 5 10 15 20 25 30 35 40 45 Farming in EU Inferred EU-ME split Farming in ME The Neolithic Transition: Initial Thoughts “High” mutation rate

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

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

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

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

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

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

19. Acknowledgements Funding: Human Frontiers Science program Itsik Pe’er’s lab: James Xue, Ethan Kochav 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) Thank you for your attention!