During the first year of the SARS-CoV-2 pandemic, international monitoring of SARS-CoV-2 genomic RNA revealed that the virus accumulated roughly 2 mutations per month. Nonetheless, one nonsynonymous mutation in the viral S gene, D614G, was first detected at the end of January 2020, and already by June this mutation had gone to fixation. We showed that D614G increased virion infectivity, and that this was associated with increased stability of S1 on virions and with a change in Spike trimer conformation such that the receptor binding domain was dramatically more open and available for interaction with the ACE2 receptor (Cell 183:739). Towards the end of 2020, with the first waves of infection by Variants of Concern, a sudden and unexplained jump in the frequency of mutations was observed. Here we will discuss several hypotheses about the origin of these highly mutated variants and present data that support each of them.
1. Discuss how coronaviruses have the largest genomes of any RNA viruses and this is made possible by the fact that they encode a proof-reading enzyme.
2. Discuss the large numbers of mutations that suddenly appeared in Variants of Concern that were likely generated in people with persistent infection.
3. Explain how the SARS-CoV-2 nonsynonymous Spike mutation D614G is required to maintain the functional integrity of the highly mutated Spike proteins found in the Variants of Concern.