Whole-genome sequencing uncovers the genetic basis of chronic mountain sickness in Andean highlanders

Zhou, Dan, Udpa, Nitin, Ronen, Roy, Stobdan, Tsering, Liang, Junbin, Appenzeller, Otto, Zhao, Huiwen W., Yin, Yi, Du, Yuanping, Guo, Lixia, Cao, Rui, Wang, Yu, Jin, Xin, Huang, Chen, Jia, Wenlong, Cao, Dandan, Guo, Guangwu, Gamboa, Jorge L., Villafuerte, Francisco, Callacondo, David, Xue, Jin, Liu, Siqi, Frazer, Kelly A., Li, Yingrui, Bafna, Vineet and Haddad, Gabriel G. (2013) Whole-genome sequencing uncovers the genetic basis of chronic mountain sickness in Andean highlanders. American Journal of Human Genetics, 93 3: 452-462. doi:10.1016/j.ajhg.2013.07.011

Author Zhou, Dan
Udpa, Nitin
Ronen, Roy
Stobdan, Tsering
Liang, Junbin
Appenzeller, Otto
Zhao, Huiwen W.
Yin, Yi
Du, Yuanping
Guo, Lixia
Cao, Rui
Wang, Yu
Jin, Xin
Huang, Chen
Jia, Wenlong
Cao, Dandan
Guo, Guangwu
Gamboa, Jorge L.
Villafuerte, Francisco
Callacondo, David
Xue, Jin
Liu, Siqi
Frazer, Kelly A.
Li, Yingrui
Bafna, Vineet
Haddad, Gabriel G.
Title Whole-genome sequencing uncovers the genetic basis of chronic mountain sickness in Andean highlanders
Journal name American Journal of Human Genetics   Check publisher's open access policy
ISSN 0002-9297
Publication date 2013-09-05
Year available 2013
Sub-type Article (original research)
DOI 10.1016/j.ajhg.2013.07.011
Open Access Status Not yet assessed
Volume 93
Issue 3
Start page 452
End page 462
Total pages 11
Place of publication Cambridge, MA, United States
Publisher Cell Press
Language eng
Formatted abstract
The hypoxic conditions at high altitudes present a challenge for survival, causing pressure for adaptation. Interestingly, many high-altitude denizens (particularly in the Andes) are maladapted, with a condition known as chronic mountain sickness (CMS) or Monge disease. To decode the genetic basis of this disease, we sequenced and compared the whole genomes of 20 Andean subjects (10 with CMS and 10 without). We discovered 11 regions genome-wide with significant differences in haplotype frequencies consistent with selective sweeps. In these regions, two genes (an erythropoiesis regulator, SENP1, and an oncogene, ANP32D) had a higher transcriptional response to hypoxia in individuals with CMS relative to those without. We further found that downregulating the orthologs of these genes in flies dramatically enhanced survival rates under hypoxia, demonstrating that suppression of SENP1 and ANP32D plays an essential role in hypoxia tolerance. Our study provides an unbiased framework to identify and validate the genetic basis of adaptation to high altitudes and identifies potentially targetable mechanisms for CMS treatment.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Chemistry and Molecular Biosciences
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