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

A fundamental question in evolutionary biology centers on the extent to which common genetic changes contribute to similar phenotypes in a certain environment. Here, we use genomic and experimental analyses to address this conundrum in the endemic mammals on the Qinghai-Tibet Plateau (QTP). We first obtain two draft genomes of plateau zokor and plateau pika by de novo sequencing and assembly. Combining with the published genomes of the other two QTP mammals, yak and Tibetan antelope, genome-wide analyses discover that all four QTP mammals share a parallel mutation Q247R in RETSAT. We further knocked in this mutation into C57BL/6 mice and found that the knock-in mice carrying this mutation display similar traits as demonstrated by QTP mammals such as larger heart mass and lower tissue hypoxia indices. Importantly, these mice were found to survive longer in hypoxic environments than their wild-type counterparts, strongly suggesting that this parallel mutation contributes to the hypoxia adaptation of mammals. Our findings highlight those convergent highland phenotypes can be determined by a single mutation.