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
o
o
o
o
A severe founder event; isolation
Large current size
Many genetic risk factors discovered
Sequencing panel missing
Palamara et al., 2012
Why Study Ashkenazi Jewish Genetics?
 Unique demography conducive to medical genetics
 Population genetics
o Insight on both European and Middle-Eastern past
AJ
Europeans
Jewish,
non-AJ
MiddleEastern
Atzmon et al., 2010
Price et al., 2008
Olshen et al., 2008
Need et al., 2009
Kopelman et al., 2009
Behar et al., 2010
Bray et al., 2010
Guha et al., 2012
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 FL
o 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 panel
o 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 panel
o 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
>3cM
Theory predicts the average coverage:
1 − 1 − 𝑐max 1 − 𝑒 −𝑛
𝑛0
2
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 Model
Time
(years ago)
Present
AJ
FL
Time
(years ago)
The Inferred Model
6500
52k
Out-of-Africa
2300
Middle-East
1800
10.8k
1.7k
Present
55% Jewish diaspora
AJ
Method: Gutenkunst et al., 2009
FL
Summary
• Data: 128 high coverage AJ genomes
• Medical genetics:
Useful for genome screening and imputation
• Population genetics:
o Recent severe bottleneck and
rapid expansion
o Over 50% European ancestry in AJ
o Europeans diverged from ME only ≈10-20 kya
Thank you!
TAGC consortium members:
Columbia University Computer Science:
Itsik Pe’er
Fillan Grady, Ethan Kochav, James Xue
Shlomo Hershkop
Long-Island Jewish Medical Center:
Todd Lencz, Semanti Mukherjee, Saurav Guha
Columbia University Medical Center:
Lorraine Clark, Xinmin Liu
Albert Einstein College of Medicine:
Gil Atzmon, Harry Ostrer, Nir Barzilai,
Kinnari Upadhyay, 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, Stephane Plaisance
Complete Genomics
Omicia
Funding:
Human Frontiers Science program