genetics of chronic mountain sickness in andean highlanders nov. 2, 2013 roy ronen university of...
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Genetics of Chronic Mountain Sickness in Andean Highlanders
Nov. 2, 2013
Roy RonenUniversity of California, San Diego
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Acute Mountain Sickness• headaches• fatigue, weakness• dizziness• insomnia• …
Chronic Mountain Sickness• Polycythemia• Palpitations• Tinnitus• >> pulmonary hypertension• >> stroke• >> poor birth outcome• …
Me, circa 2006
YearsDays
Salt plains (Salar de Uyuni), Bolivia, 3800m
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a ‘recent’ exampleAndean Mountains, Peru Himalaya Mountains, Tibet
Bale Mountains, Ethiopia
58% sea level O2
61% sea level O2
56% sea level O2
Positive Darwinian Selection
3
- Scheinfeldt et al. 2012- Alkorta-Aranburu et al. 2012- Huerta-Sanchez et al. 2013
- Beall et al. 2010- Bigham et al. 2010- Simonson et al. 2010- Yi et al. 2010
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High Altitude Adaptation
migration to high altitude
High alt. population
Andean Mountains, Peru58% see level O2
Time
Now
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Low alt. population
Time
MRCA
Out-group population
migration to high altitude
High alt. population
High Altitude Adaptation
Now
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WGS (~30x) of 10 CMS, 10 non-CMS
Setup
ADMIXTURE, k=4
Control: 66 MXL (Mexican, LA)1000G, low pass WGS
Outgroup: 67 LWK (Luhya, Kenya)1000G, low pass WGS
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Setup
‘all’ sites(approx. freq.)
few sites(accurate freq.)
Selection Scan
WGS
Arrays
- Scheinfeldt et al. 2012- Alkorta-Aranburu et al. 2012- Huerta-Sanchez et al. 2013
- Beall et al. 2010- Bigham et al. 2010- Simonson et al. 2010- Yi et al. 2010
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Whole Genome Sequencing
Whole Genome Sequencing
Chromosome 19, Sπ SNP Frequency Profile (chr19)
Genotyping Array (Affy 6.0)
SNP Frequency Profile (chr19)Chromosome 19, Sπ
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Low alt. population
Time
MRCA
Out-group population
migration to high altitude
High alt. population
Genome Wide Scan for Selection
Sπ , Sf , FST , PBS Sπ , Sf , FST , PBS
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Chr12, q13.11
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• SENP1– Regulates GATA1 and HIF1α (!!!)– Senp-/- mice show erythropoiesis defect
• PFKM– pfkm deficient mice show hyper vascularization,
muscle hypoxia, and exercise intolerance
• ANP32D – Oncogene…
Known Functions
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Measure Expression
Experimental Results (1)
Normoxia controls
Fibroblast cell lines derived from CMS & nonCMS
Hypoxia 1.5% O2
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Experimental Results (2)RNAi knock down of Drosophila orthologs
Normal (21 % O2)
Hypoxia (5 % O2)
% S
urvi
val
SENP1 ortholog
ANP32D ortholog Condition
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Summary
1. WGS important for identifying signature of selection.
2. New (experimentally validated!) hypoxia-tolerance genes:
• Selection of ANP32D, SENP1 in non-CMS (vs. CMS/MXL).
• Transcripts highly expressed in CMS vs. non-CMS.
• Knock downs remarkably more tolerant to hypoxia.
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Whole Genome Sequencing Uncovers the Genetic Basis of Chronic Mountain Sickness in Andean Highlanders
American Journal of Human Genetics, Sept. 2013
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UC San Diego• Vineet Bafna Lab
– Nitin Udpa
• Gabriel Haddad Lab– Dan Zhou– Tsering Stobdan– Huiwen Zhao
Acknowledgments
BGI• Junbin Liang• Yingrui Li• Yi Yin• Yuanping Du• Lixia Guo• Rui Cao• Yu Wang
New Mexico HEMC• Otto Appenzeller
Universidad Peruana Cayetano Heredia• Francisco Villafuerte• David Callacondo
• Xin Jin• Chen Huang• Wenlong Jia• Dandan Cao• Guangwu Guo• Siqi LiuVanderbilt Med. Center
• Jorge L. Gamboa