Systems Biology of High-Altitude Adaptation

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A very cold adult deer mouse. Shutterstock image

Extreme environments are fertile grounds for investigating the mechanisms of adaptation, since the selection pressures experienced there are few in number and severe in degree. High-altitude is one such environment, where Odeprivation (hypoxia) and cold are pervasive. High-altitude, winter-active mammals for example must extract Ofor thermoregulation from an Opoor environment. My work with Zac Cheviron explores the physiology, genetics, and functional genomics of adaptation to high altitude environments, which are characterized by extremes in hypoxia and cold. High-altitude deer mice (Peromyscus maniculatus) are a tractable model since they have a broad elevational distribution, occurring from sea level to the Rocky Mountains.

One of the most important adaptations to high-altitude is the generation of metabolic heat where O2is limited. Adult high-altitude mice can generate more heat under hypoxia in part because of an improved ability to perform shivering and non-shivering thermogenesis (e.g.,Velotta et al. 2016). A core goal of postdoctoral work has been to dissect the mechanisms by which deer have evolved improved heat generating abilities; common-garden, hypoxia-acclimation experiments on low- and high-altitude deer mice have been completed. Measurements of metabolic heat generation are being integrated with measurements of traits that influence O2transport to organs important for thermoregulation (e.g.,skeletal muscle, brown fat). I am leading efforts to characterize the transcriptomic and metabolomic profiles of these thermoregulatory organs. The goal is to parameterize a mathematical model of heat generation under hypoxia. By integrating genetic and physiological variation in multiple biological levels, this work will yield insight into how animals adapt to environmental challenges as integrated wholes.

This work is in collaboration with Jay Storz, Grant McClelland, Graham Scott, and Amina Qutub.

The Role of Phenotypic Plasticity in Adaptive Evolution

A controversial question in evolutionary biology is whether phenotypic plasticity (when one genotype produces multiple phenotypes) acts to promote or inhibit adaptive evolution. Early theory dismissed the importance of plasticity in evolution because environmentally induced phenotypes can shield genetic variation from natural selection when they perfectly match local adaptive optima [Schlichting and Pigliucci 1998]. Decades of work has demonstrated however that plasticity can indeed facilitate adaptation, most notably when that it brings individuals in the vicinity of the novel adaptive optimum. Very recent work now suggests that a great deal of phenotypic plasticity in novel environments is maladaptive (in that it lowers fitness), but that maladaptive responses themselves facilitate adaptation evolution through increasing the strength of natural selection. At this time, this work has been primarily theoretical (e.g.,Velotta and Cheviron 2018) and highly controversial (Stein and Huang 2017 Evol).

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The summit of Mt. Evans CO, 4350 m

In low-altitude mammals, physiological responses to high-altitude hypoxia are very often maladaptive. Common responses include an overproduction of red blood cells and a global constriction of the lung vasculature, which can lead to heart hypertrophy, limit aerobic capacity and can eventually cause chronic disease or death. As such, these maladaptive responses are often not present in high-altitude taxa, which is presumably the result of adaptation. We found recently (Velotta et al. 2018 Evolution) that maladaptive ancestral plasticity in heart hypertrophy is reduced in high-altitude deer mice. Analysis of the heart transcriptome suggests that changes in expression of inflammatory signaling genes, particularly interferon regulatory factors, contribute to the suppression of heart hypertrophy. Our studies suggest that selection to suppress ancestral maladaptive plasticity plays a role in adaptation.

Click here to view a presentation from the Evolution conference in France on how maladaptive phenotypic plasticity contributes to high-altitude adaptation!

Evolution of Osmoregulation in the Alewife

This work is the collaborative effort of many amazing people, including Eric Schultz (my PhD advisor) and Steve McCormick.

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A juvenile alewife. Photo by Kai Webler

Invasions into new and challenging environments are fundamental to the creation of biodiversity. One of the most important invasions in history is the invasion of freshwater by marine vertebrates, which is rooted in the diversification of fishes and the origin of tetrapods. My research fills a gap in our understanding of freshwater invasions: the adaptations that allow organisms to overcome the physiological barrier between freshwater and the sea. To do so, we use alewife (Alosa pseudoharengus) as a model. Dams built during European settlement of coastal New England blocked the anadromous migrations of alewives, which historically breed in freshwater, but live at sea. This damming has resulted in independently formed landlocked populations that live entirely in freshwater.

Freshwater and seawater present opposing environmental challenges that require opposing mechanisms of ion and water balance (osmoregulation). Because of this polarity, specializing on one salinity should reduce fitness in the other, though empirical demonstrations of this are exceedingly rare. By comparing landlocked to anadromous alewives in salinity challenge experiments, we found that landlocked alewives have evolved an improved tolerance of freshwater, which comes at the cost of tolerance and osmotic balance in saltwater (Velotta et al. 2014 Oecologia; Velotta et al. 2015 Evolution). That such trade-offs have occurred independently is indicative of local adaptation. My research suggests that adaptation to freshwater is mediated by the loss of ancestral physiological abilities.

An excised alewife gill
An excised alewife gill taken after salinity exposure experiments for measurement of activity and expression of ion transporters

Molecular Mechanisms of Adaptation to Freshwater

In addition to experimentally testing physiological responses, we use salinity challenge experiments to reveal what molecular mechanisms drive the evolution of osmoregulatory function in landlocked alewives. We have found that landlocked alewives exhibit lowered activity and expression of the gill ion transporters involved in salt secretion (Na+, K+-ATPase, Na+, K+, 2Cl co-transporter, and cystic fibrosis membrane conductance regulator homolog), which is likely to account for decreases in seawater osmotic balance among landlocked alewives.

Using alewives, we are exploring the transcriptional mechanisms that underlie adaptation to novel salinity regimes. We find that thousands of genes exhibiting salinity-dependent expression have differentiated between alewife life history forms. In particular, genes involved in the gill salt secretion pathway exhibit reduced transcriptional regulation in response to seawater among landlocked alewife populations, while genes involved in gill salt uptake and retention exhibit enhanced freshwater expression. A substantial proportion of the genes involved in osmoregulatory functions show parallel patterns of divergence among independently derived landlocked populations. Modifications to the expression of many well-known effectors of osmotic acclimation may underlie the evolution of osmoregulation upon adaptation to a novel salinity environment. See Velotta et al. (2017) Molecular Ecology for more details.

Transporting alewives to the USGS Conte Anadromous Fish Research Center
Transporting alewives to the USGS Conte Anadromous Fish Research Center. Photo by Jessie Rack

A collaborative project with the Michalak Lab at Virginia Tech has identified repeated selection on β-thymosin in several independently derived landlocked alewife populations across the United States (Michalak et al 2014 J Exp Zool). β-thymosin is involved in cell volume regulation and is thought to be an important component of osmoregulation in fish. Selection for the “freshwater” β-thymosin allele is correlated with increased mRNA expression among landlocked alewives, suggesting that it is under selection in the transition to freshwater.

Evolution of Whole-organism Performance

Swimming juvenile alewives. Photo by Kai Webler.
Swimming juvenile alewives in the lab. Photo by Kai Webler

Whole-organism performance can be broken into two integrated components: regulatory performance, which measures homeostatic capabilities, and dynamic performance, which measures physically challenging movements of the body. We use the alewife to examine whether evolutionary changes to regulatory performance (e.g., osmoregulation) can influence the evolution of dynamic performance (e.g., swimming ability). Compared to anadromous alewives, landlocked forms exhibit substantially reduced swimming performance after exposure to either freshwater or seawater, indicating that evolved differences in regulatory performance do not influence dynamic performance in this species. In addition, we have described body shape variation between alewife life history forms and found that landlocked alewives are more fusiform than their robust anadromous ancestor (also see Jones et al 2013 Evo Ecol). Although fusiform shapes should in theory provide a swimming advantage over robust shapes, the opposite is true in alewives. Reductions in swimming performance among landlocked Alewives are likely to be a function of relaxed selection on the capacity to migrate to and from breeding grounds (data presented in Velotta et al. 2018 Physiological and Biochemical Zoology).

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