Inferring the Demographic History of the Ashkenazi Jewish population
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Transcript of Inferring the Demographic History of the Ashkenazi Jewish population
Inferring the Demographic History of the Ashkenazi
Jewish population
Shai CarmiPe’er lab, Columbia University
Leicester, UKApril 2014
Outline
• Introduction• A Recent Bottleneck• Ancient History• Origin of Gene Flow• Summary
The Documented History
• Ca. 1000: Small communities in Northern France, Rhineland• Migration east• Expansion• Migration to US and Israel
Ashkenazi Jewish (AJ) Genetics
Behar et al., Nature, 2010Bray et al., PNAS, 2010Guha et al., Genome Biol, 2012Behar et al., Hum. Biol., 2014
Price et al., PLoS Genet., 2008Olshen et al., BMC Genet, 2008Need et al., Genome Biol, 2009Kopelman et al., BMC Genet, 2009
AJJewish, non-AJ
Middle-East
Europe
Atzmon et al., AJHG, 2010
AJ Genetics: Significance
• Medical genetics:o Large founder population:
Useful in medical geneticso Mendelian disorders and
risk factors
• Population genetics:o Abundance of IBD sharingo Insight on European and
Middle-Eastern pastGusev et al., MBE, 2012
Ashkenazi JewsEU-Americans (non-Jewish)
The Ashkenazi Genome Consortium
NY area labs interested in specific diseases
Quantify utility in medical genetics
Learn about population
history
Phase I: 128 whole genomes (CG; completed)Phase II: ≈300 whole genomes (NYGC; under way)
Large genotyped cohorts
S. C. et al., submitted
A Recent Bottleneck: IBD analysis
• Assume a population of historical size diploids• Fraction of the genome in segments of length :
Palamara et al., AJHG, 2012
• Detect IBD segments in sample Infer history
Time (ya)
Allele Frequency Spectrum
Comparison panel:Flemish from Belgium, matched for platform (n=26)
Joint Allele Frequency Spectrum
• Fit a model to the AFSo ∂a∂i (Gutenkunst et al.,
2009)
• Fix recent bottleneck
• Use “low” mutation rate
A Model for Ancient History
Time(years ago)
Present
13,900
390090k
3700
170,000
21k
FLAJ
49%1k
Middle-East
Out-of-Africa
Formation of AJ
23,800
?
The Neolithic Transition
• Were hunter-gatherers replaced by ME farmers?
o Modern genomes: Battalglia et al., EJHG, 2009; Balaresque et al., PLoS Biol., 2010; Busby et al., PRSB, 2012; Patterson et al., Genetics, 2012; Wei et al., Genome Res., 2013
o Ancient genomes: Haak et al., PLoS Biol., 2009; Bramanti et al, Science; 2009; Lacan et al, PNAS, 2011; Skoglund et al., Science, 2012; Fu et al., PLoS One, 2012; Hervella, PLoS One, 2012; Lazaridis et al., 2013; Brandt et al., Science, 2013; Rasteiro and Chikhi, PLoS One, 2013
• No study with ME whole-genomes
Time (kya)
First modern humans in EU
051015202530354045
Farming in EUInferred EU-ME splitFarming in ME
The Neolithic Transition: Initial Thoughts
“High” mutation rate
The Neolithic Transition
• LGM hypothesiso Pala et al, AJHG, 2012;
Olivieri et al., PLoS One, 2013
• Interpretation is very sensitive to the mutation rate
Time (kya)
First modern humans in EU
05
1015202530354045
Farming
Inferred EU-ME split
Last Glacial Maximum
Farming in ME
Origin of AJ
• What is the source of AJ European ancestry?o Western Europeo Eastern Europeo Southern Europeo The Caucasus
• Middle-Eastern ancestry?
Problem
PCA
Build EU/ME panels
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EU ME
AJ
Solution
Local ancestry inference
(RFMix)
Ancestry-specific PCA
(PCAMask)
Build EU/ME panels
Admixture LD
(ALDER)
Johnson et al., PLoS Genetics, 2011; Moreno-Estrada, PLoS Genetics, 2013
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EU ME
Loh et al., Genetics, 2013
Preliminary Results
Time (generations)
38 3942*** ***
ALDER
East
West South
Middle-East Europe
AJ
Summary
• AJ: A medically important founder populationo Lots of datao Interesting history
• IBD sharing quantifies bottleneck
• Allele frequency spectrum hints on ancient history
• Exciting challengeso Sub-continental ancestry
Acknowledgements
Funding:Human Frontiers Science program
Itsik Pe’er’s lab:James Xue, Ethan Kochav
TAGC consortium members:Todd Lencz (LIJMC)Lorraine Clark, Xinmin Liu (CUMC)Gil Atzmon, Harry Ostrer, Danny Ben-Avraham (AECOM)Inga Peter, Judy Cho (MSSM) Joseph Vijai (MSKCC)Ken Hui (Yale)
Thank you for your attention!