Figure 1.

Mutation mechanism and spectrum of CoVs

A. The horizontal bars display how the RNA genome mutates in the process of replication. The RNA synthesis begins from a positive-sense strand (labeled as plus-strand genome, blue), and two sets of four nucleotides, A, U, G, and C are used to represent two sequence contexts. The first round of synthesis happens by using the plus-strand as template and the mutated replicate is a negative-sense strand (labeled as minus-strand genome, green). Four mutations occur in the first synthesis (R1), U-to-G, C-to-A, A-to-C, and G-to-U, due to mismatching between A and G or U and C; all are transitional. These mutations are carried over to the next synthesis (R2) without further sequence change so that they are dominant permutations in a CoV-specific mutation spectrum: U-to-C, C-to-U, A-to-G, and G-to-A. B. a summary of all possible permutations in a CoV mutation spectrum; it is true for all RNA genomes and some may start with a negative sense genome, such as in the case of influenza viruses. The strands where mutations occur are labeled with plus or minus signs in parentheses and the three rounds of mutations are highlighted with yellow (R1), orange (R2), and blue (R12). We assume that abasic nucleotides are one of the repair mechanisms, leading to transversional permutations, and when mutations happen in different strands during synthesis, the intermediate nucleotides are labeled in the parentheses. Permutations lead to lower G + C content are underlined and labeled as L. Permutations lead to higher G + C content are labeled as H. Four permutations that do not vary G + C content are labeled NC (no change). Purine sensitive permutations are also scored in a similar way to the G + C content row. The molecular weight altering consequence are scored as small-to-large or SL and vice versa. The intermediates are also indicated in the parentheses. For instance, a G-to-U mutation as a permutation of the mutation spectrum happens when the positive-sense strand (+) is synthesized (the second-round replication or R2) where G supposed to pair with C but altered as U so that the mechanism has to be a C-by-U replacement that is a size increase. Another more complicated instance is G-to-C mutation, where it has to go through a first R1 mutation G-to-A (a negative sense strand mutation) and then a U-to-C mutation (a positive-sense strand mutation and thus labeled as R12 for double mutations of the positive-sense strand) follows to complete the permutation. CoV, coronavirus; R12, R1+R2; L, low; H, high; NC, no change; SL, small-to-large; LS, large-to-small; MW, molecular weight.