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Inferring the Demographic History of the Ashkenazi Jewish population. Shai Carmi Pe’er lab, Columbia University. Leicester, UK April 2014. Outline. Introduction A Recent Bottleneck Ancient History Origin of Gene Flow Summary. The Documented History.

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inferring the demographic history of the ashkenazi jewish population

Inferring the Demographic History of the Ashkenazi Jewish population

Shai Carmi

Pe’er lab, Columbia University

Leicester, UK

April 2014

outline
Outline
  • Introduction
  • A Recent Bottleneck
  • Ancient History
  • Origin of Gene Flow
  • Summary
the documented history
The Documented History
  • Ca. 1000: Small communities in Northern France, Rhineland
  • Migration east
  • Expansion
  • Migration to US and Israel
ashkenazi jewish aj genetics
Ashkenazi Jewish (AJ) Genetics

Atzmonet al., AJHG, 2010

AJ

Europe

Jewish, non-AJ

Behar et al., Nature, 2010

Bray et al., PNAS, 2010

Guha et al., Genome Biol, 2012

Behar et al., Hum. Biol., 2014

Price et al., PLoSGenet., 2008

Olshen et al., BMC Genet, 2008

Need et al., Genome Biol, 2009

Kopelman et al., BMC Genet, 2009

Middle-East

aj genetics significance
AJ Genetics: Significance

Ashkenazi Jews

  • Medical genetics:
    • Large founder population: Useful in medical genetics
    • Mendelian disorders and risk factors
  • Population genetics:
    • Abundance of IBD sharing
    • Insight on European and Middle-Eastern past

EU-Americans (non-Jewish)

Gusev et al., MBE, 2012

t he a shkenazi g enome c onsortium
The Ashkenazi Genome Consortium

NY area labs interested in specific diseases

Large genotyped cohorts

Phase I: 128 whole genomes (CG; completed)

Phase II: ≈300 whole genomes (NYGC; under way)

Learn about population history

Quantify utility in medical genetics

S. C. et al., submitted

a recent bottleneck ibd analysis
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
Allele Frequency Spectrum

Comparison panel:Flemish from Belgium, matched for platform (n=26)

joint allele frequency spectrum
Joint Allele Frequency Spectrum
  • Fit a model to the AFS
    • ∂a∂i(Gutenkunstet al., 2009)
  • Fix recent bottleneck
  • Use “low” mutation rate
a model for ancient history
A Model for Ancient History

Time

(years ago)

13,900

3900

Out-of-Africa

90k

Middle-East

3700

?

21k

49%

23,800

170,000

1k

Present

AJ

FL

Formation of AJ

the neolithic transition
The Neolithic Transition
  • Were hunter-gatherers replaced by ME farmers?
    • Modern genomes:Battalgliaet 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
    • 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
the neolithic transition initial thoughts
The Neolithic Transition: Initial Thoughts

Time (kya)

45

First modern humans in EU

40

35

30

25

20

15

Inferred EU-ME split

Farming in ME

10

Farming in EU

“High” mutation rate

5

0

the neolithic transition1
The Neolithic Transition

Time (kya)

  • LGM hypothesis
    • Pala et al, AJHG, 2012; Olivieri et al., PLoS One, 2013
  • Interpretation is very sensitive to the mutation rate

45

First modern humans in EU

40

35

30

25

Last Glacial Maximum

20

Inferred EU-ME split

15

Farming in ME

10

Farming

5

0

origin of aj
Origin of AJ
  • What is the source of AJ European ancestry?
    • Western Europe
    • Eastern Europe
    • Southern Europe
    • The Caucasus
  • Middle-Eastern ancestry?
problem
Problem

Build EU/ME panels

PCA

ME

x

x

x

EU

x

x

x

x

x

x

x

x

x

o

o

o

x

o

o

x

o

x

x

x

x

x

x

x

x

x

x

x

x

x

AJ

solution
Solution

Admixture LD(ALDER)

Build EU/ME panels

Loh et al., Genetics, 2013

ME

EU

Local ancestry inference(RFMix)

x

x

x

x

o

o

o

x

o

x

x

x

x

x

x

o

x

o

x

x

x

x

x

x

x

x

x

x

x

x

x

x

o

o

o

x

x

o

o

x

x

x

o

x

x

x

x

x

x

x

Ancestry-specific PCA(PCAMask)

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

x

Johnson et al., PLoS Genetics, 2011; Moreno-Estrada, PLoS Genetics, 2013

preliminary results
Preliminary Results

Europe

Middle-East

AJ

ALDER

Time (generations)

*

42

**

***

39

38

West

South

East

summary
Summary
  • AJ: A medically important founder population
    • Lots of data
    • Interesting history
  • IBD sharing quantifies bottleneck
  • Allele frequency spectrum hints on ancient history
  • Exciting challenges
    • Sub-continental ancestry
acknowledgements
Acknowledgements

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)

ItsikPe’er’s lab:

James Xue, Ethan Kochav

Funding:

Human Frontiers Science program

Thank you for your attention!

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