4 years ago

New insights into the genetic basis of Monge's disease and adaptation to high-altitude.

Bafna, Poulsen, Zhou, Haddad, Appenzeller, Azad, Akbari, Wong, Kirkness, Saini, Telenti, Gonzales, Stobdan, Venter
Human high-altitude (HA) adaptation or mal-adaptation is explored to understand the physiology, pathophysiology and molecular mechanisms that underlie long-term exposure to hypoxia. Here we report the results of an analysis of the largest whole-genome-sequencing of Chronic Mountain Sickness (CMS) and non-CMS individuals, identified candidate genes and functionally validated these candidates in a genetic model system (Drosophila). We used PreCIOSS algorithm that uses Haplotype Allele Frequency score to separate haplotypes carrying the favored allele from the non-carriers and accordingly prioritize genes associated with the CMS or non-CMS phenotype. Haplotypes in eleven candidate regions, with SNPs mostly in non-exonic regions, were significantly different between CMS and non-CMS subjects. Closer examination of individual genes in these regions revealed the involvement of previously identified candidates (e.g., SENP1) and also unreported ones SGK3, COPS5, PRDM1 and IFT122 in CMS. Remarkably, in addition to genes like SENP1, SGK3 and COPS5 which are HIF-dependent, our study reveals for the first time HIF-independent gene PRDM1, indicating an involvement of wider, non-HIF pathways in HA adaptation. Finally, we observed that down-regulating orthologs of these genes in Drosophila significantly enhanced their hypoxia tolerance. Taken together, the PreCIOSS algorithm, applied on a large number of genomes, identifies the involvement of both new and previously reported genes in selection sweeps, highlighting the involvement of multiple hypoxia response systems. Since the overwhelming majority of SNPs are in non-exonic (and possibly regulatory) regions, we speculate that adaptation to HA necessitates greater genetic flexibility allowing for transcript variability in response to graded levels of hypoxia.

Publisher URL: http://doi.org/10.1093/molbev/msx239

DOI: 10.1093/molbev/msx239

You might also like
Discover & Discuss Important Research

Keeping up-to-date with research can feel impossible, with papers being published faster than you'll ever be able to read them. That's where Researcher comes in: we're simplifying discovery and making important discussions happen. With over 19,000 sources, including peer-reviewed journals, preprints, blogs, universities, podcasts and Live events across 10 research areas, you'll never miss what's important to you. It's like social media, but better. Oh, and we should mention - it's free.

  • Download from Google Play
  • Download from App Store
  • Download from AppInChina

Researcher displays publicly available abstracts and doesn’t host any full article content. If the content is open access, we will direct clicks from the abstracts to the publisher website and display the PDF copy on our platform. Clicks to view the full text will be directed to the publisher website, where only users with subscriptions or access through their institution are able to view the full article.