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1. Developmental and reproductive physiology of small mammals at high altitude: challenges and evolutionary innovations

   https://doi.org/10.1242/jeb.215350  

   Robertson, Cayleih E. ; Wilsterman, Kathryn ( December 2020 , Journal of Experimental Biology)

   null (Ed.)

   ABSTRACT High-altitude environments, characterized by low oxygen levels and low ambient temperatures, have been repeatedly colonized by small altricial mammals. These species inhabit mountainous regions year-round, enduring chronic cold and hypoxia. The adaptations that allow small mammals to thrive at altitude have been well studied in non-reproducing adults; however, our knowledge of adaptations specific to earlier life stages and reproductive females is extremely limited. In lowland natives, chronic hypoxia during gestation affects maternal physiology and placental function, ultimately limiting fetal growth. During post-natal development, hypoxia and cold further limit growth both directly by acting on neonatal physiology and indirectly via impacts on maternal milk production and care. Although lowland natives can survive brief sojourns to even extreme high altitude as adults, reproductive success in these environments is very low, and lowland young rarely survive to sexual maturity in chronic cold and hypoxia. Here, we review the limits to maternal and offspring physiology – both pre-natal and post-natal – that highland-adapted species have overcome, with a focus on recent studies on high-altitude populations of the North American deer mouse (Peromyscus maniculatus). We conclude that a combination of maternal and developmental adaptations were likely to have been critical steps in the evolutionary history of high-altitude native mammals. 

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2. Fetal growth, high altitude, and evolutionary adaptation: a new perspective

   https://doi.org/10.1152/ajpregu.00067.2021  

   Wilsterman, Kathryn ; Cheviron, Zachary A. ( September 2021 , American Journal of Physiology-Regulatory, Integrative and Comparative Physiology)

   null (Ed.)

   Residence at high altitude is consistently associated with low birthweight among placental mammals. This reduction in birthweight influences long-term health trajectories for both the offspring and mother. However, the physiological processes that contribute to fetal growth restriction at altitude are still poorly understood, and thus our ability to safely intervene remains limited. One approach to identify the factors that mitigate altitude-dependent fetal growth restriction is to study populations that are protected from fetal growth restriction through evolutionary adaptations (e.g., high altitude-adapted populations). Here, we examine human gestational physiology at high altitude from a novel evolutionary perspective that focuses on patterns of physiological plasticity, allowing us to identify 1) the contribution of specific physiological systems to fetal growth restriction and 2) the mechanisms that confer protection in highland-adapted populations. Using this perspective, our review highlights two general findings: first, that the beneficial value of plasticity in maternal physiology is often dependent on factors more proximate to the fetus; and second, that our ability to understand the contributions of these proximate factors is currently limited by thin data from altitude-adapted populations. Expanding the comparative scope of studies on gestational physiology at high altitude and integrating studies of both maternal and fetal physiology are needed to clarify the mechanisms by which physiological responses to altitude contribute to fetal growth outcomes. The relevance of these questions to clinical, agricultural, and basic research combined with the breadth of the unknown highlight gestational physiology at high altitude as an exciting niche for continued work. 

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

   https://doi.org/10.1093/molbev/msaa086  

   Velotta, Jonathan P ; Robertson, Cayleih E ; Schweizer, Rena M ; McClelland, Grant B ; Cheviron, Zachary A ( April 2020 , Molecular Biology and Evolution)

   Ruvinsky, Ilya (Ed.)

   Abstract 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. 

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4. The genomic basis of high-elevation adaptation in wild house mice ( Mus musculus domesticus ) from South America

   https://doi.org/10.1093/genetics/iyab226  

   Beckman, Elizabeth J. ; Martins, Felipe ; Suzuki, Taichi A. ; Bi, Ke ; Keeble, Sara ; Good, Jeffrey M. ; Chavez, Andreas S. ; Ballinger, Mallory A. ; Agwamba, Kennedy ; Nachman, Michael W. ; et al ( December 2021 , Genetics)

   Understanding the genetic basis of environmental adaptation in natural populations is a central goal in evolutionary biology. The conditions at high elevation, particularly the low oxygen available in the ambient air, impose a significant and chronic environmental challenge to metabolically active animals with lowland ancestry. To understand the process of adaptation to these novel conditions and to assess the repeatability of evolution over short timescales, we examined the signature of selection from complete exome sequences of house mice (Mus musculus domesticus) sampled across two elevational transects in the Andes of South America. Using phylogenetic analysis, we show that house mice colonized high elevations independently in Ecuador and Bolivia. Overall, we found distinct responses to selection in each transect and largely nonoverlapping sets of candidate genes, consistent with the complex nature of traits that underlie adaptation to low oxygen availability (hypoxia) in other species. Nonetheless, we also identified a small subset of the genome that appears to be under parallel selection at the gene and SNP levels. In particular, three genes (Col22a1, Fgf14, and srGAP1) bore strong signatures of selection in both transects. Finally, we observed several patterns that were common to both transects, including an excess of derived alleles at high elevation, and a number of hypoxia-associated genes exhibiting a threshold effect, with a large allele frequency change only at the highest elevations. This threshold effect suggests that selection pressures may increase disproportionately at high elevations in mammals, consistent with observations of some high-elevation diseases in humans.

    

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

   https://doi.org/10.1242/jeb.243595  

   Ivy, Catherine M. ; Wearing, Oliver H. ; Natarajan, Chandrasekhar ; Schweizer, Rena M. ; Gutiérrez-Pinto, Natalia ; Velotta, Jonathan P. ; Campbell-Staton, Shane C. ; Petersen, Elin E. ; Fago, Angela ; Cheviron, Zachary A. ; et al ( January 2022 , Journal of Experimental Biology)

   ABSTRACT 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 β-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 β-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. 

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