Identification of a molnupiravir-associated mutational signature in SARS-CoV-2 sequencing databases

AUTHOR CONTRIBUTIONS RH identified initial branches, and their likely connection to molnupiravir. TS performed analyses of mutation-annotated tree and global metadata. CR performed all mutational spectra analyses. ID-B created bioinformatic pipelines for the AGILE trial data. All authors participated in mansuscript writing. Supplementary Information T Figure S1. Possible outcomes from MTP incorporation This figure depicts some of the mutational pathways related to MTP incorporation into MTP. The first column shows what may be a common event, but is not detectable by sequencing. MTP can be incorporated into RNA (pairing with G) and then pair with G again in the next round of synthesis, which will result in no mutation in the final sequence. However if the MTP takes on an alternative tautomeric form after incorporation it can bind to A, creating a G-to-A mutation. The third column shows that if the positive-sense base is C, then this will bind to a G in the formation of the negative-sense genome. In subsequent replication this negative sense genome can undergo the same G-to-A mutation seen in the second column, which ultimately results in a positive sense C-to-T mutation. Although the biases of tautomeric forms for the free and incorporated MTP nucleotides appear to favour these directionalities of mutations, the reverse is also possible, resulting in A-to-G and T-to-C mutations. Figure S2. High G-to-A branches involve the same number of mutations occurring in a..