The animal origin of HCoVs is supported by similarities in genome organization and phylogenetic relatedness of animal CoVs and HCoVs as well as the geographical coincidence of these viruses and plausible routes of cross-species transmission such as petting, butchering and close contact. Error-prone RNA-dependent RNA polymerase creates diversity in the CoV genome, enabling them to jump across the species barrier. However, HCoVs encode a proofreading exoribonuclease (ExoN) that plays a crucial role in RNA synthesis and replication fidelity [22]. This serves to reduce errors in RNA replication. The inactivation of ExoN causes a mutator phenotype and the resultant virus is either attenuated or inviable. In addition, other structural and non-structural genes might also contribute to the genomic diversity of CoVs by modulating polymerase and ExoN activity [23]. In addition to mutations, recombination and deletion also play an important role in host switching and adaptation. Among SARS-CoV, SARS-CoV-2, and MERS-CoV, a mutation rate as high as 0.80–2.38 × 10−3 nucleotide substation per base per year has been documented for SARS-CoV [24]. This is comparable to those of primate lentiviruses, including HIVs. Compared to SARS-CoV, the variabilities in SARS-CoV-2 and MERS-CoV genomes are much less dramatic. It will be of interest to clarify how this might relate to their host adaptability. In this regard, adaptive mutations in the S protein of SARS-CoV have been found during the outbreak to result in better binding with the ACE2 receptor. Cryo-EM analysis has provided structural evidence that S protein of SARS-CoV-2 binds with ACE2 with higher affinity. It will be of interest to see whether SARS-CoV-2 might be further adapted to ACE2 in the near future. Since the receptor-binding domain also contains predominant neutralizing epitopes, variations in this domain are only relevant to the development of a vaccine against SARS-CoV-2 [25].