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

Hypoxia at high elevations 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 functional region of the placenta that facilitates nutrient and gas exchange between dam and fetus. We then use region-specific 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 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 a subset of genes that may form the genetic basis of these placental adaptations. Collectively, these experiments advance our understanding of placental adaptation to hypoxic environments and reveal physiological and genetic mechanisms underlying fetal growth trajectories. Significance Statement Residence at high elevation is associated with increased risk for gestational complications, including fetal growth restriction. The underlying drivers of these complications remain poorly understood. Using a high elevation-adapted rodent model, we asked which physiological factors correlated with fetal growth outcomes under hypoxia, and how evolutionary adaptation has modified these traits. We show that deer mice derived from high- and low-elevation populations differ in their susceptibility to fetal growth restriction during gestational hypoxia and that these population-level differences are associated with structural changes in the placenta and broad-scale shifts in gene expression. Our findings point towards structural phenotypes and gene expression profiles that are likely relevant to offsetting the effects of hypoxia on fetal and placental development across mammals.