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

Authors

Rena M. Schweizer, University of Montana, MissoulaFollow
Jonathan P. Velotta, University of Montana, Missoula
Catherine M. Ivy, McMaster University
Matthew R. Jones, University of Montana, Missoula
Sarah M. Muir, McMaster University
Gideon S. Bradburd, Michigan State University
Jay F. Storz, University of Nebraska-LincolnFollow
Graham R. Scott, McMaster University
Zachary A. Cheviron, University of Montana, Missoula

ORCID IDs

Rena M. Schweizer

Jonathan P. Velotta

Catherine M. Ivy

Matthew R. Jones

Graham R. Scott

Document Type

Article

Date of this Version

2019

Citation

PLoS Genet 15(11): e1008420

Comments

© 2019 Schweizer et al.

Open access

https://doi.org/10.1371/journal.pgen.1008420

Abstract

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.