title: Whole-genome sequencing uncovers the genetic basis of chronic mountain sickness in Andean highlanders.
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.
authors: Division of Respiratory Medicine, Department of Pediatrics, University of California-San Diego, La Jolla, CA 92093, USA.
authors: Dan
authors: D
authors: Zhou
authors: Nitin
authors: N
authors: Udpa
authors: Roy
authors: R
authors: Ronen
authors: Tsering
authors: T
authors: Stobdan
authors: Junbin
authors: J
authors: Liang
authors: Otto
authors: O
authors: Appenzeller
authors: Huiwen W
authors: HW
authors: Zhao
authors: Yi
authors: Y
authors: Yin
authors: Yuanping
authors: Y
authors: Du
authors: Lixia
authors: L
authors: Guo
authors: Rui
authors: R
authors: Cao
authors: Yu
authors: Y
authors: Wang
authors: Xin
authors: X
authors: Jin
authors: Chen
authors: C
authors: Huang
authors: Wenlong
authors: W
authors: Jia
authors: Dandan
authors: D
authors: Cao
authors: Guangwu
authors: G
authors: Guo
authors: Jorge L
authors: JL
authors: Gamboa
authors: Francisco
authors: F
authors: Villafuerte
authors: David
authors: D
authors: Callacondo
authors: Jin
authors: J
authors: Xue
authors: Siqi
authors: S
authors: Liu
authors: Kelly A
authors: KA
authors: Frazer
authors: Yingrui
authors: Y
authors: Li
authors: Vineet
authors: V
authors: Bafna
authors: Gabriel G
authors: GG
authors: Haddad
mesh_terms: D000328:Adult; D000532:Altitude Sickness / Q000235:genetics*; D000818:Animals; D002908:Chronic Disease; D015536:Down-Regulation / Q000235:genetics; D004331:Drosophila melanogaster / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D005828:Genetics, Population; D015894:Genome, Human / Q000235:genetics*; D023281:Genomics; D006801:Humans; D000860:Hypoxia / Q000235:genetics; D008297:Male; D010568:Peru; D015203:Reproducibility of Results; D017422:Sequence Analysis, DNA; D016019:Survival Analysis
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