Whole-Genome sequencing uncovers the genetic basis of chronic mountain sickness in andean highlanders

Zhao, Huiwen W.; Du, Yuanping; Bafna, Vineet; Li, Yingrui; Cao, Rui.; Appenzeller, Otto; Guo, Guangwu; Wang, Yu; Xue, Jin; Yin, Yi; Gamboa, Jorge L.; Frazer, Kelly A.; Liang, Junbin; Callacondo, David; Zhou, Dan; Guo, Lixia; Jin, Xin; Cao, Dandan; Haddad, Gabriel G.; Huang, Chen; Udpa, Nitin; Jia, Wenlong; Stobdan, Tsering; Liu, Siqi; Villafuerte, Francisco C.; Ronen, Roy

dc.contributor.author	Zhou, Dan
dc.contributor.author	Udpa, Nitin
dc.contributor.author	Ronen, Roy
dc.contributor.author	Stobdan, Tsering
dc.contributor.author	Liang, Junbin
dc.contributor.author	Appenzeller, Otto
dc.contributor.author	Zhao, Huiwen W.
dc.contributor.author	Yin, Yi
dc.contributor.author	Du, Yuanping
dc.contributor.author	Guo, Lixia
dc.contributor.author	Cao, Rui.
dc.contributor.author	Wang, Yu
dc.contributor.author	Jin, Xin
dc.contributor.author	Huang, Chen
dc.contributor.author	Jia, Wenlong
dc.contributor.author	Cao, Dandan
dc.contributor.author	Guo, Guangwu
dc.contributor.author	Gamboa, Jorge L.
dc.contributor.author	Villafuerte, Francisco C.
dc.contributor.author	Callacondo, David
dc.contributor.author	Xue, Jin
dc.contributor.author	Liu, Siqi
dc.contributor.author	Frazer, Kelly A.
dc.contributor.author	Li, Yingrui
dc.contributor.author	Bafna, Vineet
dc.contributor.author	Haddad, Gabriel G.
dc.date.accessioned	2022-01-04T20:29:53Z
dc.date.available	2022-01-04T20:29:53Z
dc.date.issued	2013
dc.identifier.uri	https://hdl.handle.net/20.500.12866/10359
dc.description.abstract	The hypoxic conditions at high altitudes present a challenge for survival, causing pressure for adaptation. Interestingly, many highaltitude 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.	en_US
dc.language.iso	eng
dc.publisher	Elsevier
dc.relation.ispartofseries	American Journal of Human Genetics
dc.rights	info:eu-repo/semantics/restrictedAccess
dc.subject	Animals	en_US
dc.subject	gene expression	en_US
dc.subject	haplotype	en_US
dc.subject	major clinical study	en_US
dc.subject	male	en_US
dc.subject	Peru	en_US
dc.subject	controlled study	en_US
dc.subject	priority journal	en_US
dc.subject	altitude disease	en_US
dc.subject	Altitude Sickness	en_US
dc.subject	Chronic Disease	en_US
dc.subject	human cell	en_US
dc.subject	Reproducibility of Results	en_US
dc.subject	gene sequence	en_US
dc.subject	hypoxemia	en_US
dc.subject	genotype	en_US
dc.subject	Anoxia	en_US
dc.subject	down regulation	en_US
dc.subject	Down-Regulation	en_US
dc.subject	Genetics, Population	en_US
dc.subject	article	en_US
dc.subject	human tissue	en_US
dc.subject	hypoxia	en_US
dc.subject	clinical article	en_US
dc.subject	animal cell	en_US
dc.subject	gene	en_US
dc.subject	Genomics	en_US
dc.subject	genome	en_US
dc.subject	Sequence Analysis, DNA	en_US
dc.subject	Genome, Human	en_US
dc.subject	adaptation	en_US
dc.subject	Survival Analysis	en_US
dc.subject	Genetic Association Studies	en_US
dc.subject	survival rate	en_US
dc.subject	ANP32D gene	en_US
dc.subject	Drosophila melanogaster	en_US
dc.subject	exome	en_US
dc.subject	genetic transcription	en_US
dc.subject	haplotype map	en_US
dc.subject	SENP1 gene	en_US
dc.title	Whole-Genome sequencing uncovers the genetic basis of chronic mountain sickness in andean highlanders	en_US
dc.type	info:eu-repo/semantics/article
dc.identifier.doi	https://doi.org/10.1016/j.ajhg.2013.07.011
dc.subject.ocde	https://purl.org/pe-repo/ocde/ford#1.06.07
dc.relation.issn	1537-6605