Abstract
Environmental hypoxia challenges female reproductive physiology in placental mammals, increasing rates of gestational complications. Adaptation to high elevation has limited many of these effects in humans and other mammals, offering potential insight into the developmental processes that lead to and protect against hypoxia-related gestational complications. However, our understanding of these adaptations has been hampered by a lack of experimental work linking the functional, regulatory, and genetic underpinnings of gestational development in locally-adapted populations. Here, we dissect high-elevation adaptation in the reproductive physiology of deer mice, (Peromyscus maniculatus), a rodent species with an exceptionally broad elevational distribution that has emerged as a model for hypoxia adaptation. Using experimental acclimations, we show that lowland mice experience pronounced fetal growth restriction when challenged with gestational hypoxia, while highland mice maintain normal growth by expanding the compartment of the placenta that facilitates nutrient and gas exchange between dam and fetus. We then use compartmentspecific transcriptome analyses to show that adaptive structural remodeling of the placenta is coincident with widespread changes in gene expression within this same compartment. Genes associated with fetal growth in deer mice significantly overlap with genes involved in human placental development, pointing to conserved or convergent pathways underlying these processes. Finally, we overlay our results with genetic data from natural populations to identify can-didate genes and genomic features that contribute to these placental adaptations. Collectively, these experiments advance our understanding of adaptation to hypoxic environments by revealing physiological and genetic mechanisms that shape fetal growth trajectories under maternal hypoxia.
Significance Statement Residence at high elevations is associated with higher risk pregnancies and low birth weight, yet the causal mechanisms remain poorly understood. Using a high elevation-adapted rodent model, we investigated the physiological traits that explain fetal growth trajectories in low oxygen environments, and how evolutionary adaptation has modified these traits. We showed that high- and low-elevation populations of deer mice differ in their susceptibility to fetal growth restriction during gestational hypoxia and that these population-level differences are associated with structural and transcriptomic changes in the placenta. We further link placental gene expression to genomic features under selection at high elevation. Our findings identify adaptations that are likely relevant to offsetting the effects of hypoxia on fetal and placental development across mammals.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
KW and ZAC conceived of the experiments with input from JMG. KW carried out all animal work and sample collection. KC conducted maternal trait data analysis. KW, ECM, and RMS carried out sequence data analyses and summary. KW completed all other data generation and statistical analyses using code generated by KC. KW wrote the manuscript with input and approval from all authors.
The authors have no competing interests to disclose.
Figures, new analysis, and textual edits.
