ACE2 diversity in placental mammals reveals the evolutionary strategy of SARS-CoV-2

Abstract The recent emergence of SARS-CoV-2 is responsible for the current pandemic of COVID-19, which uses the human membrane protein ACE2 as a gateway to host-cell infection. We performed a comparative genomic analysis of 70 ACE2 placental mammal orthologues to identify variations and contribute to the understanding of evolutionary dynamics behind this successful adaptation to infect humans. Our results reveal that 4% of the ACE2 sites are under positive selection, all located in the catalytic domain, suggesting possibly taxon-specific adaptations related to the ACE2 function, such as cardiovascular physiology. Considering all variable sites, we selected 30 of them located at the critical ACE2 binding sites to the SARS-CoV-like viruses for analysis in more detail. Our results reveal a relatively high diversity of ACE2 between placental mammal species, while showing no polymorphism within human populations, at least considering the 30 inter-species variable sites. A perfect scenario for natural selection favored this opportunistic new coronavirus in its trajectory of infecting humans. We suggest that SARS-CoV-2 became a specialist coronavirus for human hosts. Differences in the rate of infection and mortality could be related to the innate immune responses, other unknown genetic factors, as well as non-biological factors.

摘要：严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）的出现引发了当前的COVID-19大流行，该病毒以人类膜蛋白血管紧张素转换酶2（ACE2）作为宿主细胞感染的门户。我们对70种胎盘哺乳动物的ACE2直向同源基因开展了比较基因组分析，以识别序列变异，助力解析该病毒成功适应人类感染背后的进化动力学机制。研究结果显示，4%的ACE2位点处于正选择压力之下，且全部位于催化结构域内，这提示可能存在与ACE2功能相关的类群特异性适应机制，例如与心血管生理相关的适应。综合所有变异位点，我们选取了其中30个位于类SARS冠状病毒关键ACE2结合位点的位点进行更细致的分析。研究结果表明，不同胎盘哺乳动物物种的ACE2基因存在较高的多样性，但在人类群体中未检测到多态性（至少针对这30个种间变异位点而言）。自然选择的有利态势助力这一机会主义新型冠状病毒完成向人类宿主的感染路径适配。我们认为，SARS-CoV-2已演变为专门感染人类宿主的冠状病毒。不同个体的感染率与死亡率差异，可能与固有免疫应答、其他未知遗传因素以及非生物因素相关。