Similar highland phenotypes have evolved in different endemic mammals in the Qinghai-Tibetan Plateau (QTP). However, until' now, we know little about genomic underpinnings of these convergent phenotypes. Here, we de novo sequenced genomes of plateau pika and plateau zokor. Along with yak and Tibetan antelope genomes, we discovered that all four QTP mammal species share a mutation Q247R in RETSAT. In vitro functional experiments indicate that this mutation significantly increases RETSAT enzymatic activity. Knock-in mice carrying this mutation can reproduce highland traits featuring larger heart size and lower pulmonary artery pressure, and importantly, survive longer under hypoxic conditions. Our findings identify a novel gene involved in hypoxia adaptation and heart enlargement and more importantly highlight that convergent highland phenotypes can be determined by a single mutation.

We collected the RETSAT protein from NCBI database. Some ruminats do not have published genomic annotation, we used genewise to extract their RETSAT protein sequences. Total, we obtained 137 RETSAT protein sequences in placental mammals after filtering sequences with large fragment gaps.