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The Ashkenazi Genome Project
Shai CarmiPe’er lab, Columbia University
andThe Ashkenazi Genome Consortium (TAGC)
ASHG 2013, Boston
Why Study Ashkenazi Jewish Genetics?
Unique demography conducive to medical geneticso A severe founder event; isolationo Large current sizeo Many genetic risk factors discoveredo Sequencing panel missing
Palamara et al., 2012
Why Study Ashkenazi Jewish Genetics?
Unique demography conducive to medical genetics
Population geneticso Insight on both European and Middle-Eastern past
AJ
Jewish, non-AJ
Middle-Eastern
Europeans
Price et al., 2008Olshen et al., 2008Need et al., 2009Kopelman et al., 2009Behar et al., 2010Bray et al., 2010Guha et al., 2012
Atzmon et al., 2010
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
Quantify utility in medical genetics
Learn about population history
Variant Discovery & Screening• Comparison cohort: 26 Flemish individuals from Belgium
o AJ have more novel variants than FLo Variant discovery in AJ predicted to decay faster
Method: Gravel et al., 2011
Variant Discovery & Screening• Comparison cohort: 26 Flemish individuals from Belgium
o Most novel AJ variants do not appear in a FL panel
Variant Discovery & Screening• Comparison cohort: 26 Flemish individuals from Belgium
o Most novel AJ variants do not appear in a FL panelo Many novel AJ variants appear in an AJ panel
Variant Discovery & Screening• Comparison cohort: 26 Flemish individuals from Belgium
o Most novel AJ variants do not appear in a FL panelo Many novel AJ variants appear in an AJ panel
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
Theory predicts the average coverage:
>3cM
Recent AJ History
Method: Palamara et al., 2012
The Joint Allele Frequency Spectrum
• Allele frequencies correlated, but populations distinct
• Fit a historical model to the AFS.
A ModelTime(years ago)
PresentFLAJ
The Inferred ModelTime(years ago)
Present
6500
230052k
180010.8k
1.7k
FLAJ
55%
Middle-East
Early Neolithic migrants
Jewish diaspora
Method: Gutenkunst et al., 2009
Out-of-Africa
Summary
• Data: 128 high coverage AJ genomes
• Medical genetics:Useful for genome screening and imputation
• Population genetics:o Recent severe bottleneck and
rapid expansiono Over 50% European ancestry in AJo Europeans diverged from ME only ≈10-20 kya
Thank you!TAGC consortium members:Columbia University Computer Science:Itsik Pe’erFillan Grady, Ethan Kochav, James XueShlomo HershkopLong-Island Jewish Medical Center:Todd Lencz, Semanti Mukherjee, Saurav GuhaColumbia University Medical Center:Lorraine Clark, Xinmin LiuAlbert Einstein College of Medicine:Gil Atzmon, Harry Ostrer, Nir Barzilai, Kinnari Upadhyay, Danny Ben-AvrahamMount Sinai School of Medicine:Inga Peter, Laurie OzeliusMemorial Sloan Kettering Cancer Center:Ken Offit, Joseph Vijai Yale School of Medicine:Judy Cho, Ken Hui, Monica BowenThe Hebrew University of Jerusalem:Ariel DarvasiBeth Israel Medical Center:Susan Bressman
Funding:Human Frontiers Science program
VIB, Gent, BelgiumHerwig Van Marck, Stephane PlaisanceComplete GenomicsOmicia