{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T19:55:43Z","timestamp":1784318143915,"version":"3.55.0"},"reference-count":78,"publisher":"Wiley","issue":"18","license":[{"start":{"date-parts":[[2022,7,31]],"date-time":"2022-07-31T00:00:00Z","timestamp":1659225600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2022,9]]},"abstract":"\n Abstract<\/jats:title>\n \n The gene encoding HIF\u20102\u03b1,\n Epas1<\/jats:italic>\n , has experienced a history of natural selection in many high\u2010altitude taxa, but the functional role of mutations in this gene is still poorly understood. We investigated the influence of the high\u2010altitude variant of\n Epas1<\/jats:italic>\n in North American deer mice (\n Peromyscus maniculatus<\/jats:italic>\n ) on the control of breathing and carotid body growth during chronic hypoxia. We created hybrids between high\u2010 and low\u2010altitude populations of deer mice to disrupt linkages between genetic loci so that the physiological effects of\n Epas1<\/jats:italic>\n alleles (\n Epas1<\/jats:italic>\n H<\/jats:sup>\n and\n Epas1<\/jats:italic>\n L<\/jats:sup>\n , respectively) could be examined on an admixed genomic background. In general, chronic hypoxia (4\u00a0weeks at 12\u00a0kPa O\n 2<\/jats:sub>\n ) enhanced ventilatory chemosensitivity (assessed as the acute ventilatory response to hypoxia), increased total ventilation and arterial O\n 2<\/jats:sub>\n saturation during progressive poikilocapnic hypoxia, and increased haematocrit and blood haemoglobin content across genotypes. However, the effects of chronic hypoxia on ventilatory chemosensitivity were attenuated in mice that were homozygous for the high\u2010altitude\n Epas1<\/jats:italic>\n allele (\n Epas1<\/jats:italic>\n H\/H<\/jats:sup>\n ). Carotid body growth and glomus cell hyperplasia, which was strongly induced in\n Epas1<\/jats:italic>\n L\/L<\/jats:sup>\n mice in chronic hypoxia, was not observed in\n Epas1<\/jats:italic>\n H\/H<\/jats:sup>\n mice.\n Epas1<\/jats:italic>\n genotype also modulated the effects of chronic hypoxia on metabolism and body temperature depression in hypoxia, but had no effects on haematological traits. These findings confirm the important role of HIF\u20102\u03b1 in modulating ventilatory sensitivity and carotid body growth in chronic hypoxia, and show that genetic variation in\n Epas1<\/jats:italic>\n is responsible for evolved changes in the control of breathing and metabolism in high\u2010altitude deer mice.\n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>\n \n Key points<\/jats:title>\n \n \n \n \n High\u2010altitude natives of many species have experienced natural selection on the gene encoding HIF\u20102\u03b1,\n Epas1<\/jats:italic>\n , including high\u2010altitude populations of deer mice.\n <\/jats:p>\n <\/jats:list-item>\n \n \n HIF\u20102\u03b1 regulates ventilation and carotid body growth in hypoxia, and so the genetic variants in\n Epas1<\/jats:italic>\n in high\u2010altitude natives may underlie evolved changes in control of breathing.\n <\/jats:p>\n <\/jats:list-item>\n \n \n Deer mice from controlled crosses between high\u2010 and low\u2010altitude populations were used to examine the effects of\n Epas1<\/jats:italic>\n genotype on an admixed genomic background.\n <\/jats:p>\n <\/jats:list-item>\n \n The high\u2010altitude variant was associated with reduced ventilatory chemosensitivity and carotid body growth in chronic hypoxia, but had no effects on haematology.<\/jats:p>\n <\/jats:list-item>\n \n The results help us better understand the genetic basis for the unique physiological phenotype of high\u2010altitude natives.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1113\/jp282798","type":"journal-article","created":{"date-parts":[[2022,7,7]],"date-time":"2022-07-07T15:39:26Z","timestamp":1657208366000},"page":"4207-4225","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Genetic variation in HIF\u20102\u03b1 attenuates ventilatory sensitivity and carotid body growth in chronic hypoxia in high\u2010altitude deer mice"],"prefix":"10.1113","volume":"600","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4713-4423","authenticated-orcid":false,"given":"Catherine M.","family":"Ivy","sequence":"first","affiliation":[{"name":"Department of Biology McMaster University Hamilton ON Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan P.","family":"Velotta","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences University of Denver Denver CO USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary A.","family":"Cheviron","sequence":"additional","affiliation":[{"name":"Division of Biological Sciences University of Montana Missoula MT USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4225-7475","authenticated-orcid":false,"given":"Graham R.","family":"Scott","sequence":"additional","affiliation":[{"name":"Department of Biology McMaster University Hamilton 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