Paralog switching facilitates diadromy: ontogenetic, microevolutionary and macroevolutionary evidence.

Identifying how the demands of migration are met at the level of gene expression is critical for understanding migratory physiology and can potentially reveal how migratory forms evolve from nonmigratory forms and vice versa. Among fishes, migration between freshwater and seawater (diadromy) requires considerable osmoregulatory adjustments, powered by the ion pump Na+, K+-ATPase (NKA) in the gills. Paralogs of the catalytic α-subunit of the pump (NKA α1a and α1b) are reciprocally upregulated in fresh- and seawater, a response known as paralog-switching, in gills of some diadromous species. We tested ontogenetic changes in NKA α-subunit paralog expression patterns, comparing pre-migrant and migrant alewife (Alosa pseudoharengus) sampled in their natal freshwater environment and after 24 h in seawater. In comparison to pre-migrants, juvenile out-migrants exhibited stronger paralog switching via greater downregulation of NKA α1a in seawater. We also tested microevolutionary changes in the response, exposing juvenile diadromous and landlocked alewife to freshwater (0 ppt) and seawater (30 ppt) for 2, 5, and 15 days. Diadromous and landlocked alewife exhibited salinity-dependent paralog switching, but levels of NKA α1b transcription were higher and the decrease in NKA α1a was greater after seawater exposure in diadromous alewife. Finally, we placed alewife α-subunit NKA paralogs in a macroevolutionary context. Molecular phylogenies show alewife paralogs originated independently of paralogs in salmonids and other teleosts. This study demonstrated that NKA paralog switching is tied to halohabitat profile and that duplications of the NKA gene provided the substrate for multiple, independent molecular solutions that support a diadromous life history.

Genetic variation in HIF-2α attenuates ventilatory sensitivity and carotid body growth in chronic hypoxia in high-altitude deer mice.

The gene encoding HIF-2α, Epas1, has experienced a history of natural selection in many high-altitude taxa, but the functional role of mutations in this gene is still poorly understood. We investigated the influence of the high-altitude variant of Epas1 in North American deer mice (Peromyscus maniculatus) on the control of breathing and carotid body growth during chronic hypoxia. We created hybrids between high- and low-altitude populations of deer mice to disrupt linkages between genetic loci so that the physiological effects of Epas1 alleles (Epas1H and Epas1L , respectively) could be examined on an admixed genomic background. In general, chronic hypoxia (4 weeks at 12 kPa O2 ) enhanced ventilatory chemosensitivity (assessed as the acute ventilatory response to hypoxia), increased total ventilation and arterial O2 saturation during progressive poikilocapnic hypoxia, and increased haematocrit and blood haemoglobin content across genotypes. However, the effects of chronic hypoxia on ventilatory chemosensitivity were attenuated in mice that were homozygous for the high-altitude Epas1 allele (Epas1H/H ). Carotid body growth and glomus cell hyperplasia, which was strongly induced in Epas1L/L mice in chronic hypoxia, was not observed in Epas1H/H mice. Epas1 genotype also modulated the effects of chronic hypoxia on metabolism and body temperature depression in hypoxia, but had no effects on haematological traits. These findings confirm the important role of HIF-2α in modulating ventilatory sensitivity and carotid body growth in chronic hypoxia, and show that genetic variation in Epas1 is responsible for evolved changes in the control of breathing and metabolism in high-altitude deer mice. KEY POINTS: High-altitude natives of many species have experienced natural selection on the gene encoding HIF-2α, Epas1, including high-altitude populations of deer mice. HIF-2α regulates ventilation and carotid body growth in hypoxia, and so the genetic variants in Epas1 in high-altitude natives may underlie evolved changes in control of breathing. Deer mice from controlled crosses between high- and low-altitude populations were used to examine the effects of Epas1 genotype on an admixed genomic background. The high-altitude variant was associated with reduced ventilatory chemosensitivity and carotid body growth in chronic hypoxia, but had no effects on haematology. The results help us better understand the genetic basis for the unique physiological phenotype of high-altitude natives.

Network analysis reveals that acute stress exacerbates gene regulatory responses of the gill to seawater in Atlantic salmon.

The transition from freshwater to seawater represents a physiological challenge for Atlantic salmon smolts preparing for downstream migration. Stressors occurring during downstream migration to the ocean impair the ability of smolts to maintain osmotic/ionic homeostasis in seawater. The molecular mechanisms underlying this interaction are not fully understood, especially at the organ level. We combined RNA-Seq with measures of whole-animal homeostasis to examine gene expression dynamics in the gills of smolts associated with impaired seawater tolerance after an aquaculture-related stressor. Smolts were given a 24 h seawater tolerance test before and after exposure to an acute handling/confinement stress. RNA-Seq followed by differential expression and weighted gene correlation network analysis (WGCNA) was used to quantify the transcriptional response of the gill to handling/confinement stress, seawater and their interaction. Exposure to acute stress was associated with a general stress response and impaired osmotic/ionic homeostasis in seawater. We identified gene networks in the gill exhibiting response to acute stress alone, seawater alone, and others exhibiting combined effects of both stress and seawater. Our findings indicate that acute handling/confinement stress increases the intensity of seawater-related gene expression and suggest that increased investment in mechanisms related to ion transport may be part of a compensatory response to impaired seawater tolerance in smolts.

Genetic variation in haemoglobin is associated with evolved changes in breathing in high-altitude deer mice.

Physiological systems often have emergent properties but the effects of genetic variation on physiology are often unknown, which presents a major challenge to understanding the mechanisms of phenotypic evolution. We investigated whether genetic variants in haemoglobin (Hb) that contribute to high-altitude adaptation in deer mice (Peromyscus maniculatus) are associated with evolved changes in the control of breathing. We created F2 inter-population hybrids of highland and lowland deer mice to test for phenotypic associations of α- and ß-globin variants on a mixed genetic background. Hb genotype had expected effects on Hb-O2 affinity that were associated with differences in arterial O2 saturation in hypoxia. However, high-altitude genotypes were also associated with breathing phenotypes that should contribute to enhancing O2 uptake in hypoxia. Mice with highland α-globin exhibited a more effective breathing pattern, with highland homozygotes breathing deeper but less frequently across a range of inspired O2, and this difference was comparable to the evolved changes in breathing pattern in deer mouse populations native to high altitude. The ventilatory response to hypoxia was augmented in mice that were homozygous for highland ß-globin. The association of globin variants with variation in breathing phenotypes could not be recapitulated by acute manipulation of Hb-O2 affinity, because treatment with efaproxiral (a synthetic drug that acutely reduces Hb-O2 affinity) had no effect on breathing in normoxia or hypoxia. Therefore, adaptive variation in Hb may have unexpected effects on physiology in addition to the canonical function of this protein in circulatory O2 transport.

Physiological and genomic evidence that selection on the transcription factor Epas1 has altered cardiovascular function in high-altitude deer mice.

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.

The adaptive benefit of evolved increases in hemoglobin-O2 affinity is contingent on tissue O2 diffusing capacity in high-altitude deer mice.

BACKGROUND: Complex organismal traits are often the result of multiple interacting genes and sub-organismal phenotypes, but how these interactions shape the evolutionary trajectories of adaptive traits is poorly understood. We examined how functional interactions between cardiorespiratory traits contribute to adaptive increases in the capacity for aerobic thermogenesis (maximal O2 consumption, V̇O2max, during acute cold exposure) in high-altitude deer mice (Peromyscus maniculatus). We crossed highland and lowland deer mice to produce F2 inter-population hybrids, which expressed genetically based variation in hemoglobin (Hb) O2 affinity on a mixed genetic background. We then combined physiological experiments and mathematical modeling of the O2 transport pathway to examine the links between cardiorespiratory traits and V̇O2max. RESULTS: Physiological experiments revealed that increases in Hb-O2 affinity of red blood cells improved blood oxygenation in hypoxia but were not associated with an enhancement in V̇O2max. Sensitivity analyses performed using mathematical modeling showed that the influence of Hb-O2 affinity on V̇O2max in hypoxia was contingent on the capacity for O2 diffusion in active tissues. CONCLUSIONS: These results suggest that increases in Hb-O2 affinity would only have adaptive value in hypoxic conditions if concurrent with or preceded by increases in tissue O2 diffusing capacity. In high-altitude deer mice, the adaptive benefit of increasing Hb-O2 affinity is contingent on the capacity to extract O2 from the blood, which helps resolve controversies about the general role of hemoglobin function in hypoxia tolerance.

Adaptive Shifts in Gene Regulation Underlie a Developmental Delay in Thermogenesis in High-Altitude Deer Mice.

Aerobic performance is tied to fitness as it influences an animal's ability to find food, escape predators, or survive extreme conditions. At high altitude, where low O2 availability and persistent cold prevail, maximum metabolic heat production (thermogenesis) is an aerobic performance trait that is closely linked to survival. Understanding how thermogenesis evolves to enhance survival at high altitude will yield insight into the links between physiology, performance, and fitness. Recent work in deer mice (Peromyscus maniculatus) has shown that adult mice native to high altitude have higher thermogenic capacities under hypoxia compared with lowland conspecifics, but that developing high-altitude pups delay the onset of thermogenesis. This finding suggests that natural selection on thermogenic capacity varies across life stages. To determine the mechanistic cause of this ontogenetic delay, we analyzed the transcriptomes of thermoeffector organs-brown adipose tissue and skeletal muscle-in developing deer mice native to low and high altitude. We demonstrate that the developmental delay in thermogenesis is associated with adaptive shifts in the expression of genes involved in nervous system development, fuel/O2 supply, and oxidative metabolism pathways. Our results demonstrate that selection has modified the developmental trajectory of the thermoregulatory system at high altitude and has done so by acting on the regulatory systems that control the maturation of thermoeffector tissues. We suggest that the cold and hypoxic conditions of high altitude force a resource allocation tradeoff, whereby limited energy is allocated to developmental processes such as growth, versus active thermogenesis, during early development.

UNVEILing connections between genotype, phenotype, and fitness in natural populations.

Understanding the links between genetic variation and fitness in natural populations is a central goal of evolutionary genetics. This monumental task spans the fields of classical and molecular genetics, population genetics, biochemistry, physiology, developmental biology, and ecology. Advances to our molecular and developmental toolkits are facilitating integrative approaches across these traditionally separate fields, providing a more complete picture of the genotype-phenotype map in natural and non-model systems. Here, we summarize research presented at the first annual symposium of the UNVEIL Network, an NSF-funded collaboration between the University of Montana and the University of Nebraska, Lincoln, which took place from the 1st to the 3rd of June, 2018. We discuss how this body of work advances basic evolutionary science, what it implies for our ability to predict evolutionary change, and how it might inform novel conservation strategies.

Transcriptomic imprints of adaptation to fresh water: parallel evolution of osmoregulatory gene expression in the Alewife.

Comparative approaches in physiological genomics offer an opportunity to understand the functional importance of genes involved in niche exploitation. We used populations of Alewife (Alosa pseudoharengus) to explore the transcriptional mechanisms that underlie adaptation to fresh water. Ancestrally anadromous Alewives have recently formed multiple, independently derived, landlocked populations, which exhibit reduced tolerance of saltwater and enhanced tolerance of fresh water. Using RNA-seq, we compared transcriptional responses of an anadromous Alewife population to two landlocked populations after acclimation to fresh (0 ppt) and saltwater (35 ppt). Our results suggest that the gill transcriptome has evolved in primarily discordant ways between independent landlocked populations and their anadromous ancestor. By contrast, evolved shifts in the transcription of a small suite of well-characterized osmoregulatory genes exhibited a strong degree of parallelism. In particular, transcription of genes that regulate gill ion exchange has diverged in accordance with functional predictions: freshwater ion-uptake genes (most notably, the 'freshwater paralog' of Na+ /K+ -ATPase α-subunit) were more highly expressed in landlocked forms, whereas genes that regulate saltwater ion secretion (e.g. the 'saltwater paralog' of NKAα) exhibited a blunted response to saltwater. Parallel divergence of ion transport gene expression is associated with shifts in salinity tolerance limits among landlocked forms, suggesting that changes to the gill's transcriptional response to salinity facilitate freshwater adaptation.

Circulatory mechanisms underlying adaptive increases in thermogenic capacity in high-altitude deer mice.

We examined the circulatory mechanisms underlying adaptive increases in thermogenic capacity in deer mice (Peromyscus maniculatus) native to the cold hypoxic environment at high altitudes. Deer mice from high- and low-altitude populations were born and raised in captivity to adulthood, and then acclimated to normoxia or hypobaric hypoxia (simulating hypoxia at ∼4300 m). Thermogenic capacity [maximal O2 consumption (V̇O2,max), during cold exposure] was measured in hypoxia, along with arterial O2 saturation (SaO2 ) and heart rate (fH). Hypoxia acclimation increased V̇O2,max by a greater magnitude in highlanders than in lowlanders. Highlanders also had higher SaO2  and extracted more O2 from the blood per heartbeat (O2 pulse=V̇O2,max/fH). Hypoxia acclimation increased fH, O2 pulse and capillary density in the left ventricle of the heart. Our results suggest that adaptive increases in thermogenic capacity involve integrated functional changes across the O2 cascade that augment O2 circulation and extraction from the blood.

Transcriptomic plasticity in brown adipose tissue contributes to an enhanced capacity for nonshivering thermogenesis in deer mice.

For small mammals living at high altitude, aerobic heat generation (thermogenesis) is essential for survival during prolonged periods of cold, but is severely impaired under conditions of hypobaric hypoxia. Recent studies in deer mice (Peromyscus maniculatus) reveal adaptive enhancement of thermogenesis in high- compared to low-altitude populations under hypoxic cold stress, an enhancement that is attributable to modifications in the aerobic metabolism of muscles used in shivering. However, because small mammals rely heavily on nonshivering mechanisms for cold acclimatization, we tested for evidence of adaptive divergence in nonshivering thermogenesis (NST) under hypoxia. To do so, we measured NST and characterized transcriptional profiles of brown adipose tissue (BAT) in high- and low-altitude deer mice that were (i) wild-caught and acclimatized to their native altitude, and (ii) born and reared under common garden conditions at low elevation. We found that NST performance under hypoxia is enhanced in wild-caught, high-altitude deer mice, a difference that is associated with increased expression of coregulated genes that influence several physiological traits. These traits include vascularization and O2 supply to BAT, brown adipocyte proliferation and the uncoupling of oxidative phosphorylation from ATP synthesis in the generation of heat. Our results suggest that acclimatization to hypoxic cold stress is facilitated by enhancement of nonshivering heat production, which is driven by regulatory plasticity in a suite of genes that influence intersecting physiological pathways.

Relaxed selection causes microevolution of seawater osmoregulation and gene expression in landlocked Alewives.

Ecological transitions from marine to freshwater environments have been important in the creation of diversity among fishes. Evolutionary changes associated with these transitions likely involve modifications of osmoregulatory function. In particular, relaxed selection on hypo-osmoregulation should strongly affect animals that transition into novel freshwater environments. We used populations of the Alewife (Alosa pseudoharengus) to study evolutionary shifts in hypo-osmoregulatory capacity and ion regulation associated with freshwater transitions. Alewives are ancestrally anadromous, but multiple populations in Connecticut have been independently restricted to freshwater lakes; these landlocked populations complete their entire life cycle in freshwater. Juvenile landlocked and anadromous Alewives were exposed to three salinities (1, 20 and 30 ppt) in small enclosures within the lake. We detected strong differentiation between life history forms: landlocked Alewives exhibited reduced seawater tolerance and hypo-osmoregulatory performance compared to anadromous Alewives. Furthermore, gill Na(+)/K(+)-ATPase activity and transcription of genes for seawater osmoregulation (NKCC-Na(+)/K(+)/2Cl(-) cotransporter and CFTR-cystic fibrosis transmembrane conductance regulator) exhibited reduced responsiveness to seawater challenge. Our study demonstrates that adaptations of marine-derived species to completely freshwater life cycles involve partial loss of seawater osmoregulatory performance mediated through changes to ion regulation in the gill.

Temperature-dependent gene regulatory divergence underlies local adaptation with gene flow in the Atlantic silverside.

Gene regulatory divergence is thought to play an important role in adaptation, yet its extent and underlying mechanisms remain largely elusive for local adaptation with gene flow. Local adaptation is widespread in marine species despite generally high connectivity and is often associated with tightly linked genomic architectures, such as chromosomal inversions. To investigate gene regulatory evolution under gene flow and the role of inversions associated with local adaptation to a steep thermal gradient, we generated RNA-seq data from Atlantic silversides (Menidia menidia) from two locally adapted populations and their F1 hybrids, reared under two temperatures. We found substantial divergence in gene expression and thermal plasticity between populations, with up to 31% of genes being differentially expressed. Reduced thermal plasticity, temperature-dependent gene misexpression, and the disruption of coexpression networks in hybrids point toward a role of regulatory incompatibilities in local adaptation, particularly under colder temperatures. Chromosomal inversions show an accumulation of regulatory incompatibilities but are not consistently enriched for differentially expressed genes. Together, these results suggest that gene regulation can diverge substantially among populations despite gene flow, partly due to the accumulation of temperature-dependent regulatory incompatibilities within inversions.

Repeated Genetic Targets of Natural Selection Underlying Adaptation of Fishes to Changing Salinity.

Ecological transitions across salinity boundaries have led to some of the most important diversification events in the animal kingdom, especially among fishes. Adaptations accompanying such transitions include changes in morphology, diet, whole-organism performance, and osmoregulatory function, which may be particularly prominent since divergent salinity regimes make opposing demands on systems that maintain ion and water balance. Research in the last decade has focused on the genetic targets underlying such adaptations, most notably by comparing populations of species that are distributed across salinity boundaries. Here, we synthesize research on the targets of natural selection using whole-genome approaches, with a particular emphasis on the osmoregulatory system. Given the complex, integrated and polygenic nature of this system, we expected that signatures of natural selection would span numerous genes across functional levels of osmoregulation, especially salinity sensing, hormonal control, and cellular ion exchange mechanisms. We find support for this prediction: genes coding for V-type, Ca2+, and Na+/K+-ATPases, which are key cellular ion exchange enzymes, are especially common targets of selection in species from six orders of fishes. This indicates that while polygenic selection contributes to adaptation across salinity boundaries, changes in ATPase enzymes may be of particular importance in supporting such transitions.

Comparing the relative amount of testosterone required to restore sexual arousal, motivation, and performance in male rats.

It is well established that male rat reproductive behaviors including sexual arousal, motivation, and performance are dependent on circulating levels of testosterone (T). The present study was designed to (1) compare the relative amount of T required to restore these different aspects of behavior in castrated rats, and (2) create an animal model for clinical populations with sexual impairments. Twenty-nine male Long-Evans rats were tested before and after castration for sexual performance (copulation), motivation (partner preference), and arousal (50 kHz ultrasonic vocalizations; measured together with scent marking). Sexual arousal was also inferred from copulation data. Rats were then assigned to one of four groups, and T was re-introduced via Silastic capsule implants varying in length and content: No T (empty capsules), Low T (2mm capsules), Medium T (5mm capsules), or High T (two 10mm capsules). The highest dose was intended to restore physiological levels. Results indicate that High T is required for 50 kHz vocalizations, while Medium T was sufficient for the restoration of copulation, partner preference, and scent marking. These data suggest that sexual arousal may be most sensitive to reductions in testosterone. The role of T levels in measures of generalized and specific (sexual) arousal is discussed in the context of other reproductive behaviors. Furthermore, because the Low T group showed impairments across all behaviors during post-implant tests, we propose that these animals may provide a good animal model for studying clinical conditions marked by reduced motivation and arousal, including Hypoactive Sexual Desire Disorder.

Selection on adaptive and maladaptive gene expression plasticity during thermal adaptation to urban heat islands.

Phenotypic plasticity enables a single genotype to produce multiple phenotypes in response to environmental variation. Plasticity may play a critical role in the colonization of novel environments, but its role in adaptive evolution is controversial. Here we suggest that rapid parallel regulatory adaptation of Anolis lizards to urban heat islands is due primarily to selection for reduced and/or reversed heat-induced plasticity that is maladaptive in urban thermal conditions. We identify evidence for polygenic selection across genes of the skeletal muscle transcriptome associated with heat tolerance. Forest lizards raised in common garden conditions exhibit heat-induced changes in expression of these genes that largely correlate with decreased heat tolerance, consistent with maladaptive regulatory response to high-temperature environments. In contrast, urban lizards display reduced gene expression plasticity after heat challenge in common garden and a significant increase in gene expression change that is congruent with greater heat tolerance, a putatively adaptive state in warmer urban environments. Genes displaying maladaptive heat-induced plasticity repeatedly show greater genetic divergence between urban and forest habitats than those displaying adaptive plasticity. These results highlight the role of selection against maladaptive regulatory plasticity during rapid adaptive modification of complex systems in the wild.

Remodeling Ancestral Phenotypic Plasticity in Local Adaptation: A New Framework to Explore the Role of Genetic Compensation in the Evolution of Homeostasis.

Phenotypic plasticity is not universally adaptive. In certain cases, plasticity can result in phenotypic shifts that reduce fitness relative to the un-induced state. A common cause of such maladaptive plasticity is the co-option of ancestral developmental and physiological response systems to meet novel challenges. Because these systems evolved to meet specific challenges in an ancestral environment (e.g., localized and transient hypoxia), their co-option to meet a similar, but novel, stressor (e.g., reductions in ambient pO2 at high elevation) can lead to misdirected responses that reduce fitness. In such cases, natural selection should act to remodel phenotypic plasticity to suppress the expression of these maladaptive responses. Because these maladaptive responses reduce the fitness of colonizers in new environments, this remodeling of ancestral plasticity may be among the earliest steps in adaptive walks toward new local optima. Genetic compensation has been proposed as a general form of adaptive evolution that leads to the suppression of maladaptive plasticity to restore the ancestral trait value in the face of novel stimuli. Given their central role in the regulation of basic physiological functions, we argue that genetic compensation may often be achieved by modifications of homeostatic regulatory systems. We further suggest that genetic compensation to modify homeostatic systems can be achieved by two alternative strategies that differ in their mechanistic underpinnings; to our knowledge, these strategies have not been formally recognized by previous workers. We then consider how the mechanistic details of these alternative strategies may constrain their evolution. These considerations lead us to argue that genetic compensation is most likely to evolve by compensatory physiological changes that safeguard internal homeostatic conditions to prevent the expression of maladaptive portions of conserved reaction norms, rather than direct evolution of plasticity itself. Finally, we outline a simple experimental framework to test this hypothesis. Our goal is to stimulate research aimed at providing a deeper mechanistic understanding of whether and how phenotypic plasticity can be remodeled following environmental shifts that render ancestral responses maladaptive, an issue with increasing importance in our current era of rapid environmental change.

Reduced Swimming Performance Repeatedly Evolves on Loss of Migration in Landlocked Populations of Alewife.

Whole-organism performance tasks are accomplished by the integration of morphological traits and physiological functions. Understanding how evolutionary change in morphology and physiology influences whole-organism performance will yield insight into the factors that shape its own evolution. We demonstrate that nonmigratory populations of alewife (Alosa pseudoharengus) have evolved reduced swimming performance in parallel, compared with their migratory ancestor. In contrast to theoretically and empirically based predictions, poor swimming among nonmigratory populations is unrelated to the evolution of osmoregulation and occurs despite the fact that nonmigratory alewives have a more fusiform (torpedo-like) body shape than their ancestor. Our results suggest that elimination of long-distance migration from the life cycle has shaped performance more than changes in body shape and physiological regulatory capacity.

Maladaptive phenotypic plasticity in cardiac muscle growth is suppressed in high-altitude deer mice.

How often phenotypic plasticity acts to promote or inhibit adaptive evolution is an ongoing debate among biologists. Recent work suggests that adaptive phenotypic plasticity promotes evolutionary divergence, though several studies have also suggested that maladaptive plasticity can potentiate adaptation. The role of phenotypic plasticity, adaptive, or maladaptive, in evolutionary divergence remains controversial. We examined the role of plasticity in evolutionary divergence between two species of Peromyscus mice that differ in native elevations. We used cardiac mass as a model phenotype, since ancestral hypoxia-induced responses of the heart may be both adaptive and maladaptive at high-altitude. While left ventricle growth should enhance oxygen delivery to tissues, hypertrophy of the right ventricle can lead to heart failure and death. We compared left- and right-ventricle plasticity in response to hypoxia between captive-bred P. leucopus (representing the ancestral lowland condition) and P. maniculatus from high-altitude. We found that maladaptive ancestral plasticity in right ventricle 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 right ventricle hypertrophy. We found weak evidence that adaptive plasticity of left ventricle mass contributes to evolution. Our results suggest that selection to suppress ancestral maladaptive plasticity plays a role in adaptation.