Whole-genome sequencing uncovers the genetic basis of chronic mountain sickness in Andean highlanders.
Am J Hum Genet
; 93(3): 452-62, 2013 Sep 05.
Article
em En
| MEDLINE
| ID: mdl-23954164
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Genoma Humano
/
Análise de Sequência de DNA
/
Doença da Altitude
Tipo de estudo:
Prognostic_studies
Limite:
Adult
/
Animals
/
Female
/
Humans
/
Male
País/Região como assunto:
America do sul
/
Peru
Idioma:
En
Revista:
Am J Hum Genet
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Estados Unidos