New Insights into the Genetic Basis of Monge’s Disease and Adaptation to High-Altitude

Abstract

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 nonCMS 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 noncarriers and accordingly, prioritize genes associated with the CMS or nonCMS phenotype. Haplotypes in eleven candidate regions, with SNPs mostly in nonexonic regions, were significantly different between CMS and nonCMS 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, nonHIF 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 nonexonic (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.

Novel insight into the genetic basis of high-altitude pulmonary hypertension in Kyrgyz highlanders

“…As this is a study of only 33 subjects, a question could be asked about a potential bias because the sample size is relatively small. Although largescale association studies of urban populations could potentially provide means for determining genetic architecture of common complex traits, studying of locally adapted ethnic populations can be used to increase statistical power and target less common phenotypes [5,7,21,[26][27][28]. This paradigm reduces the number of loci for association from millions to tens or thousands of genetic loci.…”

“…As hypoxia is involved in the pathophysiology of many diseases including PH, it also provides a unique opportunity to identify the genes involved in hypoxia regulation, which can be explored for therapeutic purposes. With this insight, numerous studies, including some from our group, were conducted to study human adaptation/mal-adaptation to HA in Ethiopians, Tibetans and Andeans, the three major highland populations [5][6][7][8][9]. Using whole-genome sequencing, we were able to identify and functionally validate novel genes involved in altitude adaptation in these populations [5-7, 10, 11].…”

Mitochondrial dysfunction in iPSC-derived neurons of subjects with chronic mountain sickness

“…And 3) are the changes observed in CMS cells as a result of hypoxia, inherent properties of the cells, or other types of stresses of high altitude? To address such questions, we should highlight the context and background of the research that we have undertaken for the past several years (2,3,18,29,32,36,37,42,48,50,51). In particular, we have done a large number of whole genome sequencing on high-altitude dwellers to investigate genetic differences between CMS and non-CMS (32,51).…”

Genetic variation in PTPN1 contributes to metabolic adaptation to high-altitude hypoxia in Tibetan migratory locusts

“…Adaptation to high-altitude hypoxia requires multiple systems, pathways, and molecular mechanisms 55 , 56 . Herein we also identified other PSGs in multiple pathways, such as tracheal growth and wing and muscle development.…”