Transcript pptx - UC San Diego

Genetics of Chronic Mountain
Sickness in Andean Highlanders
Nov. 2, 2013
Roy Ronen
University of California, San Diego
Salt plains (Salar de Uyuni), Bolivia, 3800m
Me, circa 2006
Days
Years
Acute Mountain Sickness
Chronic Mountain Sickness
•
headaches
•
Polycythemia
•
fatigue, weakness
•
Palpitations
•
dizziness
•
Tinnitus
•
insomnia
•
>> pulmonary hypertension
•
…
•
>> stroke
•
>> poor birth outcome
•
…
2
Positive Darwinian Selection
a ‘recent’ example
Himalaya Mountains, Tibet
56% sea level O2
Andean Mountains, Peru
58% sea level O2
-
Beall et al. 2010
Bigham et al. 2010
Simonson et al. 2010
Yi et al. 2010
-
Scheinfeldt et al. 2012
Alkorta-Aranburu et al. 2012
Huerta-Sanchez et al. 2013
Bale Mountains, Ethiopia
61% sea level O2
3
High Altitude Adaptation
Time
Andean Mountains, Peru
58% see level O2migration to high altitude
Now
High alt. population
High Altitude Adaptation
MRCA
Time
migration to high altitude
Now
Out-group population
Low alt. population
High alt. population
Setup
WGS (~30x) of 10 CMS, 10 non-CMS
ADMIXTURE, k=4
Outgroup: 67 LWK
(Luhya, Kenya)
1000G, low pass WGS
Control: 66 MXL
(Mexican, LA)
1000G, low pass WGS
Setup
Selection Scan
few sites
(accurate freq.)
Arrays
‘all’ sites
(approx. freq.)
WGS
-
Beall et al. 2010
Bigham et al. 2010
Simonson et al. 2010
Yi et al. 2010
-
Scheinfeldt et al. 2012
Alkorta-Aranburu et al. 2012
Huerta-Sanchez et al. 2013
Whole Genome Sequencing
Chromosome 19, Sπ
SNP Frequency Profile (chr19)
Chromosome 19, Sπ
SNP Frequency Profile (chr19)
Genotyping
Array (Affy 6.0)
Whole Genome
Sequencing
8
Genome Wide Scan for Selection
MRCA
Time
migration to high altitude
Sπ , Sf , FST , PBS
Out-group population
Low alt. population
Sπ , Sf , FST , PBS
High alt. population
Chr12, q13.11
Known Functions
• SENP1
– Regulates GATA1 and HIF1α (!!!)
– Senp-/- mice show erythropoiesis defect
• PFKM
– pfkm deficient mice show hyper vascularization,
muscle hypoxia, and exercise intolerance
• ANP32D
– Oncogene…
Experimental Results (1)
Fibroblast cell lines derived
from CMS & nonCMS
Hypoxia
1.5% O2
Measure Expression
Normoxia controls
Experimental Results (2)
RNAi knock down of Drosophila orthologs
SENP1
ortholog
ANP32D ortholog
Condition
% Survival
Normal (21 % O2)
Hypoxia (5 %
O 2)
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.
Whole Genome Sequencing Uncovers the Genetic Basis of
Chronic Mountain Sickness in Andean Highlanders
American Journal of Human Genetics, Sept. 2013
14
Acknowledgments
UC San Diego
• Vineet Bafna Lab
– Nitin Udpa
• Gabriel Haddad Lab
– Dan Zhou
– Tsering Stobdan
– Huiwen Zhao
New Mexico HEMC
• Otto Appenzeller
Vanderbilt Med. Center
• Jorge L. Gamboa
Universidad Peruana Cayetano
Heredia
• Francisco Villafuerte
• David Callacondo
BGI
•
•
•
•
•
•
•
Junbin Liang
Yingrui Li
Yi Yin
Yuanping Du
Lixia Guo
Rui Cao
Yu Wang
•
•
•
•
•
•
Xin Jin
Chen Huang
Wenlong Jia
Dandan Cao
Guangwu Guo
Siqi Liu