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. 

进化生物学领域的一个核心问题，聚焦于常见遗传变异在特定环境中促使相似表型产生的作用程度。本研究针对青藏高原（Qinghai-Tibet Plateau, QTP）特有哺乳动物类群，借助基因组学与实验分析手段解析这一未解难题。我们首先通过从头测序与组装技术，获取了高原鼢鼠与高原鼠兔的两份基因组草图。结合另外两种青藏高原特有哺乳动物——牦牛与藏羚羊的已发表基因组，全基因组分析发现，这四种青藏高原哺乳动物均携带RETSAT基因上的平行突变Q247R。我们进一步将该突变位点敲入C57BL/6小鼠基因组中，结果显示，携带该突变的敲入小鼠呈现出与青藏高原哺乳动物一致的性状特征，如更大的心脏质量与更低的组织低氧指数。尤为重要的是，相较于野生型对照小鼠，这些敲入小鼠在低氧环境中的存活时长更长，这强烈表明该平行突变有助于哺乳动物的低氧适应。本研究结果表明，趋同演化的高原表型可由单个突变决定。