Comparative genomics reveals putative evidence for high-elevation adaptation in the American pika (Ochotona princeps).

High-elevation environments have lower atmospheric oxygen content, reduced temperatures, and higher levels of UV radiation than found at lower elevations. As such, species living at high elevations must overcome these challenges to survive, grow, and reproduce. American pikas (Ochotona princeps) are alpine lagomorphs that are habitat specialists typically found at elevations >2,000 m. Previous research has shown putative evidence for high-elevation adaptation; however, investigations to date have been limited to a fraction of the genome. Here, we took a comparative genomics approach to identify putative regions under selection using a chromosomal reference genome assembly for the American pika relative to 8 other mammalian species targeted based on phylogenetic relatedness and (dis)similarity in ecology. We first identified orthologous gene groups across species and then extracted groups containing only American pika genes as well as unclustered pika genes to inform functional enrichment analyses; among these, we found 141 enriched terms with many related to hypoxia, metabolism, mitochondrial function/development, and DNA repair. We identified 15 significantly expanded gene families within the American pika across all orthologous gene groups that displayed functionally enriched terms associated with hypoxia adaptation. We further detected 196 positively selected genes, 41 of which have been associated with putative adaptation to hypoxia, cold tolerance, and response to UV following a literature review. In particular, OXNAD1, NRDC, and those genes critical in DNA repair represent important targets for future research to examine their functional implications in the American pika, especially as they may relate to adaptation to rapidly changing environments.