Physiological and genomic evidence that selection on the transcription factor Epas1 has altered cardiovascular function in high-altitude deer mice

Autoři: Rena M. Schweizer aff001;  Jonathan P. Velotta aff001;  Catherine M. Ivy aff002;  Matthew R. Jones aff001;  Sarah M. Muir aff002;  Gideon S. Bradburd aff003;  Jay F. Storz aff004;  Graham R. Scott aff002;  Zachary A. Cheviron aff001
Působiště autorů: Division of Biological Sciences, University of Montana, Missoula, Montana, United States of America aff001;  Department of Biology, McMaster University, Hamilton, ON, Canada aff002;  Ecology, Evolutionary Biology, and Behavior Graduate Group, Department of Integrative Biology, Michigan State University, East Lansing, Michigan, United States of America aff003;  School of Biological Sciences, University of Nebraska, Lincoln, Nebraska, United States of America aff004
Vyšlo v časopise: Physiological and genomic evidence that selection on the transcription factor Epas1 has altered cardiovascular function in high-altitude deer mice. PLoS Genet 15(11): e32767. doi:10.1371/journal.pgen.1008420
Kategorie: Research Article


Evolutionary adaptation to extreme environments often requires coordinated changes in multiple intersecting physiological pathways, but how such multi-trait adaptation occurs remains unresolved. Transcription factors, which regulate the expression of many genes and can simultaneously alter multiple phenotypes, may be common targets of selection if the benefits of induced changes outweigh the costs of negative pleiotropic effects. We combined complimentary population genetic analyses and physiological experiments in North American deer mice (Peromyscus maniculatus) to examine links between genetic variation in transcription factors that coordinate physiological responses to hypoxia (hypoxia-inducible factors, HIFs) and multiple physiological traits that potentially contribute to high-altitude adaptation. First, we sequenced the exomes of 100 mice sampled from different elevations and discovered that several SNPs in the gene Epas1, which encodes the oxygen sensitive subunit of HIF-2α, exhibited extreme allele frequency differences between highland and lowland populations. Broader geographic sampling confirmed that Epas1 genotype varied predictably with altitude throughout the western US. We then discovered that Epas1 genotype influences heart rate in hypoxia, and the transcriptomic responses to hypoxia (including HIF targets and genes involved in catecholamine signaling) in the heart and adrenal gland. Finally, we used a demographically-informed selection scan to show that Epas1 variants have experienced a history of spatially varying selection, suggesting that differences in cardiovascular function and gene regulation contribute to high-altitude adaptation. Our results suggest a mechanism by which Epas1 may aid long-term survival of high-altitude deer mice and provide general insights into the role that highly pleiotropic transcription factors may play in the process of environmental adaptation.

Klíčová slova:

Catecholamines – Deer – Evolutionary adaptation – Gene expression – Heart rate – Hypoxia – Medical hypoxia – Variant genotypes


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