The coronavirus disease 19 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a coronavirus that spilled over from the bat reservoir. Despite numerous clinical trials and vaccines, the burden remains immense, and the host determinants of SARS-CoV-2 susceptibility and COVID-19 severity remain largely unknown. Signatures of positive selection detected by comparative functional genetic analyses in primate and bat genomes can uncover important and specific adaptations that occurred at virus–host interfaces. We performed high-throughput evolutionary analyses of 334 SARS-CoV-2-interacting proteins to identify SARS-CoV adaptive loci and uncover functional differences between modern humans, primates, and bats. Using DGINN (Detection of Genetic INNovation), we identified 38 bat and 81 primate proteins with marks of positive selection. Seventeen genes, including the ACE2 receptor, present adaptive marks in both mammalian orders, suggesting common virus–host interfaces and past epidemics of coronaviruses shaping their genomes. Yet, 84 genes presented distinct adaptations in bats and primates. Notably, residues involved in ubiquitination and phosphorylation of the inflammatory RIPK1 have rapidly evolved in bats but not primates, suggesting different inflammation regulation versus humans. Furthermore, we discovered residues with typical virus–host arms race marks in primates, such as in the entry factor TMPRSS2 or the autophagy adaptor FYCO1, pointing to host-specific in vivo interfaces that may be drug targets. Finally, we found that FYCO1 sites under adaptation in primates are those associated with severe COVID-19, supporting their importance in pathogenesis and replication. Overall, we identified adaptations involved in SARS-CoV-2 infection in bats and primates, enlightening modern genetic determinants of virus susceptibility and severity.

中文翻译：

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蝙蝠和灵长类动物中 SARS-CoV-2 相互作用蛋白的不同进化轨迹确定了 COVID-19 的重要宿主决定因素

冠状病毒病 19 (COVID-19) 大流行是由严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 引起的，这是一种从蝙蝠宿主中溢出的冠状病毒。尽管进行了大量临床试验和疫苗，但负担仍然巨大，SARS-CoV-2 易感性和 COVID-19 严重程度的宿主决定因素在很大程度上仍然未知。通过灵长类动物和蝙蝠基因组的比较功能遗传分析检测到的正选择特征可以揭示在病毒-宿主界面发生的重要和特定的适应。我们对 334 种 SARS-CoV-2 相互作用蛋白进行了高通量进化分析，以确定 SARS-CoV 适应性基因座，并揭示现代人类、灵长类动物和蝙蝠之间的功能差异。使用 DGINN（基因创新检测），我们鉴定了 38 种蝙蝠蛋白和 81 种灵长类动物蛋白，并带有阳性选择标记。包括 ACE2 受体在内的 17 个基因在哺乳动物的两个目中都呈现出适应性标记，这表明病毒与宿主之间存在共同的界面，过去冠状病毒的流行也塑造了它们的基因组。然而，84 个基因在蝙蝠和灵长类动物中呈现出不同的适应性。值得注意的是，参与炎症 RIPK1 泛素化和磷酸化的残基在蝙蝠而非灵长类动物中迅速进化，表明炎症调节与人类不同。此外，我们在灵长类动物中发现了具有典型病毒-宿主军备竞赛标记的残留物，例如进入因子 TMPRSS2 或自噬适配器 FYCO1，指向可能是药物靶标的宿主特异性体内界面。最后，我们发现在灵长类动物中适应的 FYCO1 位点与严重的 COVID-19 相关，支持它们在发病机制和复制中的重要性。总体而言，我们确定了与蝙蝠和灵长类动物感染 SARS-CoV-2 相关的适应性，启发了病毒易感性和严重性的现代遗传决定因素。