1. New Insights into the Genetic Basis of Monge's Disease and Adaptation to High-Altitude
- Author
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Shubham Saini, Amalio Telenti, Tsering Stobdan, J. Craig Venter, Priti Azad, Gustavo F. Gonzales, Dan Zhou, Ali Akbari, Ewen F. Kirkness, Gabriel G. Haddad, Otto Appenzeller, Emily H. M. Wong, Orit Poulsen, and Vineet Bafna
- Subjects
Male ,Acclimatization ,genetic analysis ,adaptation ,Altitude Sickness ,Altitude Sickness/genetics/metabolism/physiopathology ,Peru ,genetics ,Aetiology ,Hypoxia ,SENP1 gene ,pathophysiology ,IFT122 gene ,whole genome sequencing ,altitude disease ,Altitude ,allele ,Adaptation, Physiological/genetics ,Drosophila melanogaster ,down regulation ,Evolution ,phenotype ,Physiological ,1.1 Normal biological development and functioning ,Haplotypes/genetics ,Single-nucleotide polymorphism ,Chronic Mountain Sickness ,Article ,Evolution, Molecular ,03 medical and health sciences ,Genetics ,Humans ,human ,procedures ,Polymorphism ,Molecular Biology ,genome ,Ecology, Evolution, Behavior and Systematics ,Alleles ,molecular evolution ,Positive Regulatory Domain I-Binding Factor 1/genetics/metabolism ,animal model ,Haplotype ,genetic transcription ,Monge's disease ,Molecular ,scoring system ,Hypoxia/genetics/physiopathology ,major clinical study ,030104 developmental biology ,Biochemistry and Cell Biology ,orthology ,0301 basic medicine ,Candidate gene ,haplotype ,Acclimatization/genetics ,Gene Frequency ,single nucleotide polymorphism ,genetic variability ,2.1 Biological and endogenous factors ,Haplotype Allele Frequency score ,animal ,high-altitude ,COPS5 gene ,Drosophila/genetics ,Single Nucleotide ,Polymorphism, Single Nucleotide/genetics ,Phenotype ,Adaptation, Physiological ,female ,Gene Frequency/genetics ,SGK3 gene ,Drosophila ,Adult ,hypoxia inducible factor ,purl.org/pe-repo/ocde/ford#1.06.03 [https] ,animal experiment ,Biology ,Polymorphism, Single Nucleotide ,long term exposure ,Underpinning research ,Whole Genome Sequencing/methods ,Genetic model ,Animals ,controlled study ,Allele ,PRDM1 protein, human ,gene ,Gene ,Allele frequency ,Discoveries ,Evolutionary Biology ,algorithm ,nonhuman ,Whole Genome Sequencing ,B lymphocyte induced maturation protein 1 ,hypoxia ,Human Genome ,selection sweep ,Haplotypes ,physiology ,Chronic Disease ,Positive Regulatory Domain I-Binding Factor 1 ,metabolism - 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.
- Published
- 2017