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The Ashkenazi Genome Project

The Ashkenazi Genome Project. Shai Carmi Pe’er lab, Columbia University and The Ashkenazi Genome Consortium (TAGC). ASHG 2013, Boston. Why Study Ashkenazi Jewish Genetics?. Unique demography conducive to medical genetics A severe founder event; isolation Large current size

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The Ashkenazi Genome Project

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  1. The Ashkenazi Genome Project Shai Carmi Pe’er lab, Columbia University and The Ashkenazi Genome Consortium (TAGC) ASHG 2013, Boston

  2. Why Study Ashkenazi Jewish Genetics? • Unique demography conducive to medical genetics • A severe founder event; isolation • Large current size • Many genetic risk factors discovered • Sequencing panel missing Palamara et al., 2012

  3. Why Study Ashkenazi Jewish Genetics? • Unique demography conducive to medical genetics • Population genetics • Insight on both European and Middle-Eastern past AJ Europeans Jewish, non-AJ Price et al., 2008 Olshen et al., 2008 Need et al., 2009 Kopelman et al., 2009Behar et al., 2010 Bray et al., 2010 Guha et al., 2012 Middle-Eastern Atzmon et al., 2010

  4. The Ashkenazi Genome Consortium NY area labs interested in specific diseases Study design: • 128 unrelated healthy controls • PCA-validated AJ ancestry • High-coverage whole-genome sequencing • Complete Genomics Learn about population history Quantify utility in medical genetics

  5. Variant Discovery & Screening • Comparison cohort: 26 Flemish individuals from Belgium • AJ have more novel variants than FL • Variant discovery in AJ predicted to decay faster Method: Gravel et al., 2011

  6. Variant Discovery & Screening • Comparison cohort: 26 Flemish individuals from Belgium • Most novel AJ variants do not appear in a FL panel

  7. Variant Discovery & Screening • Comparison cohort: 26 Flemish individuals from Belgium • Most novel AJ variants do not appear in a FL panel • Many novel AJ variants appear in an AJ panel

  8. Variant Discovery & Screening • Comparison cohort: 26 Flemish individuals from Belgium • Most novel AJ variants do not appear in a FL panel • Many novel AJ variants appear in an AJ panel

  9. Abundance of Genetic Sharing • Sharing common in AJ (but not in FL or between AJ-FL) • Long segments shared with the panel cover the majority of a typical AJ genome >3cM Theory predicts the average coverage:

  10. Recent AJ History Method: Palamara et al., 2012

  11. The Joint Allele Frequency Spectrum • Allele frequencies correlated, but populations distinct • Fit a historical model to the AFS.

  12. Time (years ago) A Model Present AJ FL

  13. Time (years ago) The Inferred Model 6500 Out-of-Africa 52k 2300 Middle-East 1800 Early Neolithic migrants 10.8k Jewish diaspora 1.7k 55% Present AJ FL Method: Gutenkunstet al., 2009

  14. Summary • Data: 128 high coverage AJ genomes • Medical genetics:Useful for genome screening and imputation • Population genetics: • Recent severe bottleneck and rapid expansion • Over 50% European ancestry in AJ • Europeans diverged from ME only ≈10-20 kya

  15. Thank you! TAGC consortium members: Columbia University Computer Science: Itsik Pe’erFillan Grady, Ethan Kochav, James XueShlomo Hershkop Long-Island Jewish Medical Center: Todd Lencz, Semanti Mukherjee, SauravGuha Columbia University Medical Center: Lorraine Clark, Xinmin Liu Albert Einstein College of Medicine: Gil Atzmon, Harry Ostrer, NirBarzilai, KinnariUpadhyay, Danny Ben-Avraham Mount Sinai School of Medicine: Inga Peter, Laurie Ozelius Memorial Sloan Kettering Cancer Center: Ken Offit, Joseph Vijai Yale School of Medicine: Judy Cho, Ken Hui, Monica Bowen The Hebrew University of Jerusalem: Ariel Darvasi Beth Israel Medical Center: Susan Bressman VIB, Gent, Belgium Herwig Van Marck, StephanePlaisance Complete GenomicsOmicia Funding: Human Frontiers Science program

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