Four coronaviruses (HCoV-OC43, HCoV-HKU1, HCoV-NL63, and HCoV-229E) are endemic in human populations. All these viruses are seasonal and generate short-term immunity. Like the highly pathogenic coronaviruses, the endemic coronaviruses have zoonotic origins. Thus, understanding the evolutionary dynamics of these human viruses might provide insight into the future trajectories of SARS-CoV-2 evolution. Because the zoonotic sources of HCoV-OC43 and HCoV-229E are known, we applied a population genetics–phylogenetic approach to investigate which selective events accompanied the divergence of these viruses from the animal ones. Results indicated that positive selection drove the evolution of some accessory proteins, as well as of the membrane proteins. However, the spike proteins of both viruses and the hemagglutinin-esterase (HE) of HCoV-OC43 represented the major selection targets. Specifically, for both viruses, most positively selected sites map to the receptor-binding domains (RBDs) and are polymorphic. Molecular dating for the HCoV-229E spike protein indicated that RBD Classes I, II, III, and IV emerged 3–9 years apart. However, since the appearance of Class V (with much higher binding affinity), around 25 years ago, limited genetic diversity accumulated in the RBD. These different time intervals are not fully consistent with the hypothesis that HCoV-229E spike evolution was driven by antigenic drift. An alternative, not mutually exclusive possibility is that strains with higher affinity for the cellular receptor have out-competed strains with lower affinity. The evolution of the HCoV-OC43 spike protein was also suggested to undergo antigenic drift. However, we also found abundant signals of positive selection in HE. Whereas such signals might result from antigenic drift, as well, previous data showing co-evolution of the spike protein with HE suggest that optimization for human cell infection also drove the evolution of this virus. These data provide insight into the possible trajectories of SARS-CoV-2 evolution, especially in case the virus should become endemic.

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地方性冠状病毒 HCoV-OC43 和 HCoV-229E 对人类宿主的适应

四种冠状病毒（HCoV-OC43、HCoV-HKU1、HCoV-NL63 和 HCoV-229E）在人群中流行。所有这些病毒都是季节性的，会产生短期免疫力。与高致病性冠状病毒一样，地方性冠状病毒也有人畜共患病起源。因此，了解这些人类病毒的进化动力学可能会提供对 SARS-CoV-2 进化未来轨迹的洞察。由于 HCoV-OC43 和 HCoV-229E 的人畜共患来源是已知的，我们应用群体遗传学 - 系统发育方法来研究哪些选择性事件伴随着这些病毒与动物病毒的分化。结果表明，正选择驱动了一些辅助蛋白以及膜蛋白的进化。然而，两种病毒的刺突蛋白和 HCoV-OC43 的血凝素酯酶 (HE) 代表了主要的选择目标。具体来说，对于这两种病毒，大多数积极选择的位点都映射到受体结合域 (RBD) 并且是多态的。HCoV-229E 刺突蛋白的分子测年表明 RBD I、II、III 和 IV 类出现相隔 3-9 年。然而，自从大约 25 年前出现 V 类（具有更高的结合亲和力）以来，RBD 中积累的遗传多样性有限。这些不同的时间间隔与 HCoV-229E 尖峰进化是由抗原漂移驱动的假设并不完全一致。另一种不相互排斥的可能性是对细胞受体具有较高亲和力的菌株与具有较低亲和力的菌株竞争。HCoV-OC43 刺突蛋白的进化也被认为会经历抗原漂移。然而，我们还在HE中发现了丰富的正选择信号。尽管这些信号也可能是由抗原漂移引起的，但先前显示刺突蛋白与 HE 共同进化的数据表明，人类细胞感染的优化也推动了这种病毒的进化。这些数据提供了对 SARS-CoV-2 进化可能轨迹的深入了解，尤其是在病毒成为地方病的情况下。