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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xxxxxxx x

x

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xxxxxx

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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!