Inferring the Demographic History of the Ashkenazi Jewish population Shai Carmi Pe’er lab,...
-
Upload
clarissa-emmeline-morrison -
Category
Documents
-
view
216 -
download
0
description
Transcript of Inferring the Demographic History of the Ashkenazi Jewish population Shai Carmi Pe’er lab,...
![Page 1: Inferring the Demographic History of the Ashkenazi Jewish population Shai Carmi Pe’er lab, Columbia University Leicester, UK April 2014.](https://reader035.fdocuments.us/reader035/viewer/2022062523/5a4d1b0e7f8b9ab05998d79f/html5/thumbnails/1.jpg)
Inferring the Demographic History of the Ashkenazi
Jewish population
Shai CarmiPe’er lab, Columbia University
Leicester, UKApril 2014
![Page 2: Inferring the Demographic History of the Ashkenazi Jewish population Shai Carmi Pe’er lab, Columbia University Leicester, UK April 2014.](https://reader035.fdocuments.us/reader035/viewer/2022062523/5a4d1b0e7f8b9ab05998d79f/html5/thumbnails/2.jpg)
Outline
• Introduction• A Recent Bottleneck• Ancient History• Origin of Gene Flow• Summary
![Page 3: Inferring the Demographic History of the Ashkenazi Jewish population Shai Carmi Pe’er lab, Columbia University Leicester, UK April 2014.](https://reader035.fdocuments.us/reader035/viewer/2022062523/5a4d1b0e7f8b9ab05998d79f/html5/thumbnails/3.jpg)
The Documented History
• Ca. 1000: Small communities in Northern France, Rhineland• Migration east• Expansion• Migration to US and Israel
![Page 4: Inferring the Demographic History of the Ashkenazi Jewish population Shai Carmi Pe’er lab, Columbia University Leicester, UK April 2014.](https://reader035.fdocuments.us/reader035/viewer/2022062523/5a4d1b0e7f8b9ab05998d79f/html5/thumbnails/4.jpg)
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
![Page 5: Inferring the Demographic History of the Ashkenazi Jewish population Shai Carmi Pe’er lab, Columbia University Leicester, UK April 2014.](https://reader035.fdocuments.us/reader035/viewer/2022062523/5a4d1b0e7f8b9ab05998d79f/html5/thumbnails/5.jpg)
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)
![Page 6: Inferring the Demographic History of the Ashkenazi Jewish population Shai Carmi Pe’er lab, Columbia University Leicester, UK April 2014.](https://reader035.fdocuments.us/reader035/viewer/2022062523/5a4d1b0e7f8b9ab05998d79f/html5/thumbnails/6.jpg)
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
![Page 7: Inferring the Demographic History of the Ashkenazi Jewish population Shai Carmi Pe’er lab, Columbia University Leicester, UK April 2014.](https://reader035.fdocuments.us/reader035/viewer/2022062523/5a4d1b0e7f8b9ab05998d79f/html5/thumbnails/7.jpg)
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)
![Page 8: Inferring the Demographic History of the Ashkenazi Jewish population Shai Carmi Pe’er lab, Columbia University Leicester, UK April 2014.](https://reader035.fdocuments.us/reader035/viewer/2022062523/5a4d1b0e7f8b9ab05998d79f/html5/thumbnails/8.jpg)
Allele Frequency Spectrum
Comparison panel:Flemish from Belgium, matched for platform (n=26)
![Page 9: Inferring the Demographic History of the Ashkenazi Jewish population Shai Carmi Pe’er lab, Columbia University Leicester, UK April 2014.](https://reader035.fdocuments.us/reader035/viewer/2022062523/5a4d1b0e7f8b9ab05998d79f/html5/thumbnails/9.jpg)
Joint Allele Frequency Spectrum
• Fit a model to the AFSo ∂a∂i (Gutenkunst et al.,
2009)
• Fix recent bottleneck
• Use “low” mutation rate
![Page 10: Inferring the Demographic History of the Ashkenazi Jewish population Shai Carmi Pe’er lab, Columbia University Leicester, UK April 2014.](https://reader035.fdocuments.us/reader035/viewer/2022062523/5a4d1b0e7f8b9ab05998d79f/html5/thumbnails/10.jpg)
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
?
![Page 11: Inferring the Demographic History of the Ashkenazi Jewish population Shai Carmi Pe’er lab, Columbia University Leicester, UK April 2014.](https://reader035.fdocuments.us/reader035/viewer/2022062523/5a4d1b0e7f8b9ab05998d79f/html5/thumbnails/11.jpg)
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
![Page 12: Inferring the Demographic History of the Ashkenazi Jewish population Shai Carmi Pe’er lab, Columbia University Leicester, UK April 2014.](https://reader035.fdocuments.us/reader035/viewer/2022062523/5a4d1b0e7f8b9ab05998d79f/html5/thumbnails/12.jpg)
Time (kya)
First modern humans in EU
051015202530354045
Farming in EUInferred EU-ME splitFarming in ME
The Neolithic Transition: Initial Thoughts
“High” mutation rate
![Page 13: Inferring the Demographic History of the Ashkenazi Jewish population Shai Carmi Pe’er lab, Columbia University Leicester, UK April 2014.](https://reader035.fdocuments.us/reader035/viewer/2022062523/5a4d1b0e7f8b9ab05998d79f/html5/thumbnails/13.jpg)
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
![Page 14: Inferring the Demographic History of the Ashkenazi Jewish population Shai Carmi Pe’er lab, Columbia University Leicester, UK April 2014.](https://reader035.fdocuments.us/reader035/viewer/2022062523/5a4d1b0e7f8b9ab05998d79f/html5/thumbnails/14.jpg)
Origin of AJ
• What is the source of AJ European ancestry?o Western Europeo Eastern Europeo Southern Europeo The Caucasus
• Middle-Eastern ancestry?
![Page 15: Inferring the Demographic History of the Ashkenazi Jewish population Shai Carmi Pe’er lab, Columbia University Leicester, UK April 2014.](https://reader035.fdocuments.us/reader035/viewer/2022062523/5a4d1b0e7f8b9ab05998d79f/html5/thumbnails/15.jpg)
Problem
PCA
Build EU/ME panels
xx xxxx
xxxxxxx x
x
ooooooxxxxxx
xxxxxx
EU ME
AJ
![Page 16: Inferring the Demographic History of the Ashkenazi Jewish population Shai Carmi Pe’er lab, Columbia University Leicester, UK April 2014.](https://reader035.fdocuments.us/reader035/viewer/2022062523/5a4d1b0e7f8b9ab05998d79f/html5/thumbnails/16.jpg)
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
xx xxxx
xxxxxxx x
x
ooooooxxxxxx
xxxxxx
xx xxxx
xxxxxxx x
x
oooooo xxxxxxxxxxx x
EU ME
Loh et al., Genetics, 2013
![Page 17: Inferring the Demographic History of the Ashkenazi Jewish population Shai Carmi Pe’er lab, Columbia University Leicester, UK April 2014.](https://reader035.fdocuments.us/reader035/viewer/2022062523/5a4d1b0e7f8b9ab05998d79f/html5/thumbnails/17.jpg)
Preliminary Results
Time (generations)
38 3942*** ***
ALDER
East
West South
Middle-East Europe
AJ
![Page 18: Inferring the Demographic History of the Ashkenazi Jewish population Shai Carmi Pe’er lab, Columbia University Leicester, UK April 2014.](https://reader035.fdocuments.us/reader035/viewer/2022062523/5a4d1b0e7f8b9ab05998d79f/html5/thumbnails/18.jpg)
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
![Page 19: Inferring the Demographic History of the Ashkenazi Jewish population Shai Carmi Pe’er lab, Columbia University Leicester, UK April 2014.](https://reader035.fdocuments.us/reader035/viewer/2022062523/5a4d1b0e7f8b9ab05998d79f/html5/thumbnails/19.jpg)
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!