Comparative genomic analysis reveals varying levels of mammalian adaptation to coronavirus infections

Abstract

Severe acute respiratory coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, is of zoonotic origin. Evolutionary analyses assessing whether coronaviruses similar to SARS-CoV-2 infected ancestral species of modern-day animal hosts could be useful in identifying additional reservoirs of potentially dangerous coronaviruses. We reasoned that if a clade of species has been repeatedly exposed to a virus, then their proteins relevant for viral entry may exhibit adaptations that affect host susceptibility or response. We perform comparative analyses across the mammalian phylogeny of angiotensin-converting enzyme 2 (ACE2), the cellular receptor for SARS-CoV-2, in order to uncover evidence for selection acting at its binding interface with the SARS-CoV-2 spike protein. We uncover that in rodents there is evidence for adaptive amino acid substitutions at positions comprising the ACE2-spike interaction interface, whereas the variation within ACE2 proteins in primates and some other mammalian clades is not consistent with evolutionary adaptations. We also analyze aminopeptidase N (APN), the receptor for the human coronavirus 229E, a virus that causes the common cold, and find evidence for adaptation in primates. Altogether, our results suggest that the rodent and primate lineages may have had ancient exposures to viruses similar to SARS-CoV-2 and HCoV-229E, respectively. Author summary SARS-like coronaviruses, such as SARS-CoV and SARS-CoV-2, are a class of pathogens that have been a significant threat to human health. Across the animal kingdom, we see considerable differences in the severity of symptoms caused by these types of viruses. Previous research has shown adaptations to SARS-like viruses in known viral vectors such as Chinese Horseshoe bats. Uncovering evidence of adaptations to SARS-like viral infections in proteins of other hosts would shed light on whether additional mammalian clades have been previously exposed to these viruses. In our study, we characterize the evolution of the mammalian host receptor of SARS-like viruses, ACE2, across a broad mammalian phylogeny. Our comparative genomic insights reveal a pattern of rapid evolution of the ACE2/virus binding interface within the rodent clade, while finding little adaptation within primates or among other mammals not already known to be SARS hosts. These results suggest that some rodent species may have acquired some form of tolerance or resistance to infections from SARS-like coronaviruses, while non-adapted mammals and primates may be more susceptible to symptomatic disease.