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Meeting Abstract
The high-altitude environment, characterized by severe and unremitting hypobaric hypoxia, provides a unique testing ground for investigating the mechanisms of adaptation. Recent studies suggest that mammals living at high altitude tolerate low O2 pressure by modifying a key hypoxia-signaling pathway known as the hypoxia-inducible factor (HIF) cascade. One gene that is consistently under positive selection in highland specialists is Epas1, a transcription factor and master regulator of the HIF cascade. Here we report the finding that highland and lowland populations of deer mice (Peromyscus maniculatus) exhibit extreme allele frequency variation at Epas1. Transcriptome scans indicate that these differences in Epas1 allele frequency stem from a history of spatially varying selection between high and low altitudes. Subsequent genotyping in populations from multiple elevations across the western United States shows that Epas1 allele frequency varies clinally with elevation. We characterized genotypic differences in the physiological response to hypoxia within an admixed population on the summit of Mt Evans, CO. We find that Epas1 genotype influences heart rate under hypoxia, with homozygotes for the highland allele maintaining higher heart rate under severe hypoxia, which likely improves O2 transport to metabolizing tissues. Moreover, we find that Epas1 genotype also influences the expression of genes that may contribute to physiological responses to hypoxia. Our results indicate that selection on hypoxia signaling contributes to high-altitude adaptation in deer mice via modification to the regulation of the HIF cascade.