Universidad Peruana Cayetano Heredia

High-Altitude Andean H194R HIF2A Allele Is a Hypomorphic Allele

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dc.contributor.author Jorgensen, Kelsey
dc.contributor.author Song, Daisheng
dc.contributor.author Weinstein, Julien
dc.contributor.author Garcia, Obed A.
dc.contributor.author Pearson, Laurel N.
dc.contributor.author Inclán, María
dc.contributor.author Rivera Chira, Maria Concepcion
dc.contributor.author León-Velarde, Fabiola
dc.contributor.author Kiyamu Tsuchiya, Melisa
dc.contributor.author Brutsaert, Tom D.
dc.contributor.author Bigham, Abigail W.
dc.contributor.author Lee, Frank S.
dc.coverage.spatial Cerro de Pasco, Pasco, Perú
dc.date.accessioned 2023-09-06T20:45:08Z
dc.date.available 2023-09-06T20:45:08Z
dc.date.issued 2023
dc.identifier.uri https://hdl.handle.net/20.500.12866/14071
dc.description.abstract For over 10,000 years, Andeans have resided at high altitude where the partial pressure of oxygen challenges human survival. Recent studies have provided evidence for positive selection acting in Andeans on the HIF2A (also known as EPAS1) locus, which encodes for a central transcription factor of the hypoxia-inducible factor pathway. However, the precise mechanism by which this allele might lead to altitude-adaptive phenotypes, if any, is unknown. By analyzing whole genome sequencing data from 46 high-coverage Peruvian Andean genomes, we confirm evidence for positive selection acting on HIF2A and a unique pattern of variation surrounding the Andean-specific single nucleotide variant (SNV), rs570553380, which encodes for an H194R amino acid substitution in HIF-2α. Genotyping the Andean-associated SNV rs570553380 in a group of 299 Peruvian Andeans from Cerro de Pasco, Peru (4,338 m), reveals a positive association with increased fraction of exhaled nitric oxide, a marker of nitric oxide biosynthesis. In vitro assays show that the H194R mutation impairs binding of HIF-2α to its heterodimeric partner, aryl hydrocarbon receptor nuclear translocator. A knockin mouse model bearing the H194R mutation in the Hif2a gene displays decreased levels of hypoxia-induced pulmonary Endothelin-1 transcripts and protection against hypoxia-induced pulmonary hypertension. We conclude the Andean H194R HIF2A allele is a hypomorphic (partial loss of function) allele. 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 Andean evolution en_US
dc.subject EPAS1 en_US
dc.subject HIF2A en_US
dc.subject High-altitude adaptation en_US
dc.subject Hypoxia en_US
dc.subject Hypoxia-inducible factor en_US
dc.subject.mesh Ecosistema Andino
dc.subject.mesh Proteínas
dc.subject.mesh Factor 1 Inducible por Hipoxia
dc.subject.mesh Adaptación Biológica
dc.subject.mesh Hipoxia
dc.title High-Altitude Andean H194R HIF2A Allele Is a Hypomorphic Allele en_US
dc.type info:eu-repo/semantics/article
dc.identifier.doi https://doi.org/10.1093/molbev/msad162
dc.subject.ocde https://purl.org/pe-repo/ocde/ford#1.06.03
dc.relation.issn 1537-1719


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