The genomic & physiological basis of high altitude adaptation in North American deer mice

In biology, there are many ways to solve evolutionary ‘challenges’ so it always amazes me when organisms solve them in similar ways. And I love a good paper that adds to our attempts to dissect multi-trait adaptations. Recently, Schweizer et al. 2019 examined the genetic and physiological basis of high altitude adaptation in North American deer mice (Peromyscus maniculatus) by combining population genetics with physiological experiments.

The authors genotyped highland (Mt. Evans, CO – 4350 meters above sea level) and lowland (Lincoln, NE – 430 meters above sea level) mice and identified SNPs that exhibit extreme allele frequency changes in the highland population. Among the top SNPs were several in EPAS1, a gene that encodes the O2-sensitive subunit of hypoxia inducible factor 2 (HIF-2). HIF-2 is one of a critical family of transcription factors that are responsible for ensuring that O2 supply matches O2 demand, and transcription factors are exactly where you might expect to find the genetic basis of multi-trait adaptations, because they regulate the expression of many genes and potentially many traits. Thus, changes in the expression or binding capacity of a transcription factor can simultaneously affect many phenotypes. Sampling across a wide range of deer mice populations in the Southwest (see figure below) showed an EPAS1 allelic frequency distribution that positively correlates with altitude distribution.

Figure 1B reproduced from Schweizer et al. 2019 – Geographic and altitudinal variation in EPAS1 high-altitude (H) and low-altitude (L) variants across the Rocky Mountains and Great Plains, USA. Map is colored according to altitude. 23 populations were sampled, with pie chart coloring indicating frequency of H or L allele and pie chart size indicating number of mice sampled from each population.

Interestingly, EPAS1 is a well-know target of selection for high-altitude adaptation in human and non-human populations (e.g., highland Tibetan humans: Beall et al. 2010; grey wolves: Zhang et al. 2014; saker falcon: Pan et al. 2017).

The authors then tested mice from the high altitude population for a range of physiological changes that might be associated with variation in EPAS1. They found differences in traits like resting heart rate in hypoxic conditions, but not in traits like hemoglobin concentration (the physiological adaptation associated with indigenous Tibetan people; Beall et al. 2010). To further explore the basis of high-altitude adaptation, the authors assessed the transcriptome in the heart (left ventricle) and adrenal gland (which affects heart rate by secreting catecholamines) of these mice after exposure to hypoxic conditions. Although the authors found no significant overall differences in gene expression in either tissue between mice with the high- and low-altitude variants, they found more subtle differences when they restricted their analyses to the expression of sets of a priori candidate genes: 1) HIF target genes (reminder: HIF transcription factors control O2 supply) and 2) genes involved in catecholamine biosynthesis, secretion, and signaling (reminder: catecholamines affect heart rate). The authors discovered that mice with the high-altitude EPAS1 variant exhibited higher expression of HIF-related candidate genes in the heart (but not catecholamine-related genes), including several genes involved in vasodilation. In contrast, in the adrenal glands of mice with the high-altitude EPAS1 variant, catecholamine-related candidate genes exhibited lower expression but HIF-related genes did not. These results may explain previous results showing reduced catecholamine secretion in high altitude mice (Brown et al. 2009), as this may be due to overall reduced enzyme expression leading to reduced catecholamine synthesis and subsequent reduced catecholamine release.  Finally, a scan for areas under positive selection identified EPAS1 as one of many genes under selection in high-altitude mice.

Thus, although EPAS1 is involved in high altitude adaptation across multiple species in different geographic areas, the physiological mechanism by which changes in EPAS1 lead to this adaptation differ. This paper, as the authors point out, demonstrates that in some cases, adaptation in complex traits may still be regulated by relatively simple genetic changes.


Beall CM, Cavalleri GL, Deng L. Natural selection on EPAS1 (HIF2α) associated with low hemoglobin concentration in Tibetan highlanders. Proc Natl Acad Sci. 2010; 107: 11459–11464. PMID: 20534544

Brown ST, Kelly KF, Daniel JM, Nurse CA. Hypoxia inducible factor (HIF)-2α is required for the development of the catecholaminergic phenotype of sympathoadrenal cells. Journal of Neurochemistry. 2009; 110: 622–630. PMID: 19457096

Pan S, Zhang T, Rong Z, Hu L, Gu Z, Wu Q, et al. Population transcriptomes reveal synergistic responses of DNA polymorphism and RNA expression to extreme environments on the Qinghai-Tibetan Plateau in a predatory bird. Molecular Ecology. 2017; 26: 2993–3010. PMID: 28277617

Zhang W, Fan Z, Han E, Hou R, Zhang L, Galaverni M, et al. Hypoxia Adaptations in the Grey Wolf (Canis lupus chanco) from Qinghai-Tibet Plateau. PLoS Genet. 2014; 10: e1004466. PMID: 25078401

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