Collaborative Research: Physiological and regulatory mechanisms of the attenuation of maladaptive plasticity in highland deer mice

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Many physiological systems buffer organisms against environmental perturbations by safeguarding their internal conditions against changes in the environment. Upon colonization of new environments, however, physiological systems that evolved in one environmental context may produce misdirected responses when they are inappropriately coopted to respond to novel challenges. Prominent examples of this phenomenon include several physiological responses to high-elevation environments in native lowlanders. For example, exposure to high elevation induces excessive red blood cell production, constriction of pulmonary blood vessels, and other physiological changes in lowlanders that may be considered maladaptive because they contribute to high-altitude diseases (e.g. chronic mountain sickness, pulmonary edema). In such cases, natural selection should favor attenuation of these maladaptive responses. This research focuses on understanding the evolutionary, physiological, and genetic mechanisms that allow such maladaptive ancestral responses to blunted, without simultaneously impacting beneficial responses. The project PIs will use a series of acclimation experiments and field studies of high- and low-altitude populations of deer mice to explore the adaptive modification of physiological responses to high-altitude stressors. Like indigenous high-elevation human populations, highland deer mice exhibit blunted maladaptive responses to hypoxia. The results of this research will also be used to develop a public outreach program that illustrates the value of comparative physiology for informing applied problems in human health using high-altitude environments and the animals that inhabit them as its centerpiece. These outreach efforts will be centered on the development of short films that will serve as springboards for interactive discussions between researchers and the general public.Many physiological responses to hypoxia are largely coordinated by a family of master transcription factors, known as hypoxia-inducible factors (HIF1-3). Because mutations that alter the function of transcription factors like HIF (i.e. trans-regulatory mutations) are prone to pleiotropic effects, evolutionary theory suggests that they should be rare in the adaptive modification of regulatory networks compared to changes that are more modular in their phenotypic effects. Nonetheless, recent genomic studies of high-elevation human populations, and several other species have shown that allelic variation in a gene (EPAS1) that encodes a specific HIF isoform (HIF2) has been the target of natural selection, and is associated with the attenuation of maladaptive responses to hypoxia. Thus, adaptive modification of regulatory networks that coordinate hypoxia responses seems to have repeatedly proceeded through modification of trans-regulatory factors in high-elevation specialists. This poses interesting physiological and evolutionary questions because HIF2 also coordinates a number of beneficial physiological changes to maintain O2 homeostasis. Given that alteration of HIF2 induce deleterious pleiotropic effects, how can maladaptive responses be attenuated while adaptive responses are maintained? Does alteration of HIF function require compensatory cis-regulatory mutations in HIF targets that coordinate adaptive responses or can compensatory modifications be achieved through epigenetic changes? This research will address these questions using a series of physiological, genetic, and transcriptomic experiments on highland and lowland deer mice. Like other highland specialists, patterns of allele frequency variation at EPAS1 suggest local adaptation in deer mice, and this variation is associated with the attenuation of maladaptive hypoxia responses.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.