An international team, consisting of scientists from the University of California San Diego, BGI and other institutes, has investigated the entire DNA code of Andean individuals with chronic mountain sickness (CMS), or Monge’s disease to unravel the puzzle of genetic mutations associated with CMS from whole-genome level. The study published online in American Journal of Human Genetics, provides evidence to support whole-genome sequencing as an ultimate approach to advance the understanding of the genetic basis of CMS and its treatment.
More than 140 million humans have permanently settled on high altitude regions in various locations around the world, such as the Ethiopian plateau in East Africa, the Tibetan plateau in Asia and the Andes Mountains in South America. These native or long-time residents are likely to be affected by CMS, especially those living over 3000 meters and many of them are desperate to be cured from the symptoms. The team decoded the genomes of some local residents to unravel the genetic mechanism and develop safer treatments for CMS.
In this study, a total of 20 Andean individuals were sequenced, including ten individuals with CMS and ten not with CMS as control. Researchers surveyed the entire spectrum of variations with high efficiency, and found 11 regions that showed significant differences in haplotype frequencies consistent with selective sweeps. In these regions, two genes, ANP32D and SENP1, were found to have significantly increased expression in the CMS individuals compared to the non-CMS ones, and played an essential role in hypoxia tolerance.
The genomic data also enabled researchers to better understand the mechanisms of human adaptation to hypoxia. They speculated that the increased expression of SENP1 may play a role in the basic pathogenesis of polycythemia in CMS individuals. ANP32D acts as an oncogene, which may alter cellular metabolism in a fashion that is similar to that of cancer cells, especially given that such cells can flourish in low oxygen conditions.
“Whole-genome sequencing serves as an ultimate approach to advance the understanding of the genetic basis of CMS,” said, Xin Jin, project manager of BGI, “Our study provides an unbiased framework to identify and validate the genetic basis of adaptation to high altitudes, and highlight the potentially targetable mechanisms for CMS treatment.”
Dr. Dan Zhou and Dr. Gabriel Haddad, the leading scientists of this project from University of California San Diego, said, “Hypoxia is a common pathogenic factor in many human diseases. Understanding the mechanisms underlying hypoxia tolerance is essential to develop novel therapeutic strategies to treat these clinical conditions. Current studies combine the power of whole genome sequencing, in vitro human cell model and in vivo. Drosophila model allowed us not only to identify candidate genes that are associated to hypoxia adaptation but also to functionally evaluate their contributions to the trait. This unique unbiased framework has the potential to be applied to identify causal mutations in human diseases.
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