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

Zhou D, Udpa N, Ronen R, Stobdan T, Liang J, Appenzeller O, Zhao HW, Yin Y, Du Y, Guo L, Cao R, Wang Y, Jin X, Huang C, Jia W, Cao D, Guo G, Gamboa JL, Villafuerte F, Callacondo D, Xue J, Liu S, Frazer KA, Li Y, Bafna V, Haddad GG
Am J Hum Genet. 2013 93 (3): 452-62

PMID: 23954164 · PMCID: PMC3769925 · DOI:10.1016/j.ajhg.2013.07.011

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.

Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

MeSH Terms (19)

Adult Altitude Sickness Animals Chronic Disease Down-Regulation Drosophila melanogaster Female Genetic Association Studies Genetics, Population Genome, Human Genomics Genomics Humans Hypoxia Male Peru Reproducibility of Results Sequence Analysis, DNA Survival Analysis

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