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 genetics

o 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 ConsortiumNY 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