Evolutionary Adaptations to High Elevations

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Evolutionary Adaptations to High Elevations

Specialized deer mice have evolved physiological adaptations geared towards better fetal growth outcomes in spite of low-oxygen environments.

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Oxygen has been deemed the ‘elixir of life’ ever since its atomic discovery in the 1770’s (Lane, 2002). This is due to the crucial role it plays in sustaining the majority of life on Earth. However, a delicate balance exists between life and oxygen, and the presence of too much or too little oxygen has the ability to throw off this balance. This can cause several physiological challenges for organisms that can lead to severe illness or death (Webster and Abela 2007; Wilsterman et al. 2023). Despite this, organisms across the animal kingdom have evolved different ways of coping with various oxygen levels. One such example exists in deer mice, which have evolved structural and functional reproductive adaptations to thrive in high-elevation, hypoxic environments. 

Deer mice are well-established models for studying adaptive evolution because they have well characterized genetic differentiation/variation among wild populations and high-elevation populations are known to be derived from low-elevation populations (Wilsterman et al. 2023). Furthermore, deer mice genes associated with fetal growth and placental development are highly conserved between deer mice and humans; thus, by understanding these genetic pathways in deer mice, we can also better understand them in humans. 

This research began with collecting both lowland and highland deer mice. Lowland deer mice refer to mice adapted to lower altitudes and highland mice refer to mice adapted to higher altitudes. Given higher altitudes generally have lower levels of oxygen compared to lower altitudes, the initial hypothesis was that lowland mice would theoretically suffer greater consequences from a hypoxic environment than highland mice would. This was confirmed after experiments done exposing both lowland and highland mice to hypoxic conditions resulted in highland offspring being unaffected by hypoxic conditions; whereas lowland offspring were nearly 20% smaller in mass than their normoxia-gestated counterparts. Wilsterman et al. hypothesized two biological explanations to account for this adaptive disparity: maternal physiology and placental development. 

Maternal physiology was analyzed under two separate conditions, nutrient acquisition and cardiopulmonary function. Generally in rodents, both nutrient acquisition and cardiopulmonary function are lowered in hypoxic environments, and decreases in either of these conditions are broadly associated with reduced fetal health outcomes (Wilsterman et al. 2023). Wilsterman et al. made the assumption that if maternal physiology is responsible for the adaptive disparity seen between highland and lowland mice, then these two conditions would alter fetal growth outcomes in hypoxic environments. While maternal cardiopulmonary function was found to be affected under hypoxic conditions, no correlation was established between maternal cardiopulmonary function and fetal growth in hypoxic conditions. On the other hand, food consumption was not suppressed at all in highland or lowland deer mice under hypoxic conditions; likewise no changes were observed in maternal or fetal health as a result of decreased food intake. Under the Wilsterman et al. assumption, these experiments suggest the hypoxic-resistant, reproductive adaptations of highland mice may be less reliant on maternal physiology than previously thought. 

Subsequently, Wilsterman et al. examined placental structure and function to explain fetal growth adaptations seen in deer mice because placental mass and fetal mass are generally known to be positively correlated. The rodent placenta is organized into three different layers: the decidua, the junctional zone, and the labyrinth zone. Each plays a slightly different, yet essential role in typical fetal development. The decidua is where blood flow is established between the mother and placenta. The junctional zone produces many of the hormones responsible for vascularization. Lastly, the labyrinth zone is where nutrient and gas exchange is facilitated between fetal and maternal circulatory systems. The unique function of each layer allows researchers to more easily associate a seen phenotype with its biological determinants. 

Initial immunohistochemistry results under hypoxic conditions showed that highland mice had larger labyrinth zones than their lowland counterparts. More specifically, the labyrinth zones of these mice had more volume dedicated to blood space which could possibly allow for increased blood flow for greater nutrient and gas exchange. A weighted correlation network analysis (WGCNA) found the labyrinth zone was the only placental layer to contain sets of genes correlated with fetal growth. Similarly, RNA-seq identified over 1300 expressed genes in the labyrinth zone and only 3 expressed genes in the junctional zone/decidua that correlated with fetal growth. Gene ontology (GO) analysis of the sets of genes positively correlated with fetal growth found an enrichment of genes linked to blood vessel growth and development. Furthermore, of the 1300 genes expressed in the labyrinth zone, 228 of them showed hypoxia-sensitive expression and differed between highland and lowland mice. Other genes were also identified depending on their level of differentiation across mouse populations, 626 of the 993 of which were in the labyrinth zone. Overall, Wilsterman et al, made strong connections between fetal growth outcomes under hypoxic conditions and genes in the labyrinth zone responsible for vascularization. This suggests these genes likely contribute to the genetic adaptation in the labyrinth zone of highland deer mice that allow them to facilitate better in-utero nutrient and gas exchange in hypoxic conditions. However, the exact pathways and biological mechanisms behind these genes remain poorly characterized- each of these genes likely play different roles in various pathways which all ultimately contribute to fetal development. 

Understanding how our environment affects our own physiology is becoming an increasingly important area of study. This paper addresses the prevalence of high-risk pregnancies and low birth weights associated with high elevation residency using deer mice as models. It provided strong association-based evidence for the genetic underpinnings of fetal growth in hypoxic environments, but additional research is needed to characterize many of the complex physiological traits observed. Furthermore, hypoxia is only one of the numerous environmental factors capable of infringing upon maternal and fetal health outcomes. Political, socioeconomic, and discriminatory factors also play large roles in maternal and fetal health outcomes in people (Morello-Frosch and Shenassa 2006). Therefore, expanding this research to include other external stressors may help to address further disparities in maternal and fetal health.

Article by Tate Weston. Contact the author at tapeterson@davidson.edu

Original Article: Adaptive structural and functional evolution of the placenta protects fetal growth in high-elevation deer mice

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