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

Abstract

Hypoxia at high elevations challenges gestational 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 limited 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 placental compartment that facilitates nutrient and gas exchange between dam and fetus. We then use layer-enriched transcriptome analyses to show that adaptive structural remodeling of the placenta is coincident with widespread changes in gene expression localized to 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 overlayed our results with genetic data from natural populations to identify the subset of placental genes that form the genetic basis of placental adaptations. Collectively, these experiments advance our understanding of placental adaptation to hypoxic environments and illuminate physiological mechanisms underlying fetal growth trajectories during a key gestational window.

Evolution of parent-of-origin effects on placental gene expression in house mice

“…Furthermore, despite the diversity of placental functions and cell types (Pavličev et al 2017), it remains unclear if and how tissue specialization in the mammalian placenta influences the evolution of genomic imprinting. Specialized placental layers evolve under distinct evolutionary pressures (e.g., (Sandovici et al 2022;Suhail et al 2022;Wilsterman et al 2023) and show differences in the extent of inter-specific epigenetic divergence (Decato et al 2017). Thus, specialization of placental tissues may influence regulatory divergence and select for different patterns of genomic imprinting across functional layers.…”