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

Kirkness, Ewen F.; Bafna, Vineet; Wong, Emily H. M.; Haddad, Gabriel G.; Appenzeller, Otto; Venter, J. Craig; Telenti, Amalio; Gonzales Rengifo, Gustavo Francisco; Saini, Shubham; Akbari, Ali; Stobdan, Tsering; Poulsen, Orit; Azad, Priti; Zhou, Dan

dc.contributor.author	Stobdan, Tsering
dc.contributor.author	Akbari, Ali
dc.contributor.author	Azad, Priti
dc.contributor.author	Zhou, Dan
dc.contributor.author	Poulsen, Orit
dc.contributor.author	Appenzeller, Otto
dc.contributor.author	Gonzales Rengifo, Gustavo Francisco
dc.contributor.author	Telenti, Amalio
dc.contributor.author	Wong, Emily H. M.
dc.contributor.author	Saini, Shubham
dc.contributor.author	Kirkness, Ewen F.
dc.contributor.author	Venter, J. Craig
dc.contributor.author	Bafna, Vineet
dc.contributor.author	Haddad, Gabriel G.
dc.date.accessioned	2019-01-25T15:28:06Z
dc.date.available	2019-01-25T15:28:06Z
dc.date.issued	2017
dc.identifier.uri	https://hdl.handle.net/20.500.12866/4712
dc.description.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.	en_US
dc.language.iso	eng
dc.publisher	Oxford University Press
dc.relation.ispartofseries	Molecular Biology and Evolution
dc.rights	info:eu-repo/semantics/restrictedAccess
dc.rights.uri	https://creativecommons.org/licenses/by-nc-nd/4.0/deed.es
dc.subject	Acclimatization/genetics	en_US
dc.subject	adaptation	en_US
dc.subject	Adaptation, Physiological/genetics	en_US
dc.subject	Adult	en_US
dc.subject	Alleles	en_US
dc.subject	Altitude	en_US
dc.subject	Altitude Sickness/genetics/metabolism/physiopathology	en_US
dc.subject	Animals	en_US
dc.subject	Chronic Disease	en_US
dc.subject	Chronic Mountain Sickness	en_US
dc.subject	Drosophila/genetics	en_US
dc.subject	Evolution, Molecular	en_US
dc.subject	Gene Frequency/genetics	en_US
dc.subject	Haplotypes/genetics	en_US
dc.subject	high-altitude	en_US
dc.subject	Humans	en_US
dc.subject	hypoxia	en_US
dc.subject	Hypoxia/genetics/physiopathology	en_US
dc.subject	Male	en_US
dc.subject	Monge's disease	en_US
dc.subject	Peru	en_US
dc.subject	Polymorphism, Single Nucleotide/genetics	en_US
dc.subject	Positive Regulatory Domain I-Binding Factor 1/genetics/metabolism	en_US
dc.subject	selection sweep	en_US
dc.subject	Whole Genome Sequencing/methods	en_US
dc.title	New Insights into the Genetic Basis of Monge's Disease and Adaptation to High-Altitude	en_US
dc.type	info:eu-repo/semantics/article
dc.identifier.doi	https://doi.org/10.1093/molbev/msx239
dc.subject.ocde	https://purl.org/pe-repo/ocde/ford#1.06.03
dc.relation.issn	1537-1719

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

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