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
Jewish, non-AJ
Middle-Eastern
Europeans
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
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
Quantify utility in medical genetics
Learn about population history

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:
1− 1− 𝑐 max 1− 𝑒 − 𝑛 𝑛

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. A Model
Time
(years ago)
Present AJ FL

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