A single mutation underlying phenotypic convergence for hypoxia adaptation on the Qinghai-Tibetan Plateau

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.