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A molnupiravir-associated mutational signature in global SARS-CoV-2 genomes

Sanderson et al., Nature, doi:10.1038/s41586-023-06649-6
Sep 2023  
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Identification of SARS-CoV-2 variants created by molnupiravir treatment, including cases of onwards transmission. Authors find a class of long phylogenetic branches almost exclusively matching the time period, location, and age groups of widespread molnupiravir treatment. There were extreme cases with >100 molnupiravir-associated mutations, and confirmed cases where molnupiravir-derived sequences were transmitted to others. For more discussion see twitter.com.
Concerns have been raised that the mutagenic mechanism of action may create dangerous variants or cause cancer Chamod, Gruber, Hadj Hassine, Huntsman, Marikawa, Swanstrom, Waters, Zhou, Zibat. Multiple analyses have identified variants potentially created by molnupiravir Fountain-Jones, Kosakovsky Pond, Sanderson, twitter.com (B).
Sanderson et al., 25 Sep 2023, peer-reviewed, 7 authors. Contact: theo.sanderson@crick.ac.uk (corresponding author), cr628@cam.ac.uk.
This PaperMolnupiravirAll
Identification of a molnupiravir-associated mutational signature in SARS-CoV-2 sequencing databases
Theo Sanderson, Ryan Hisner, I’ah Donovan-Banfield, Thomas Peacock, Christopher Ruis
doi:10.1101/2023.01.26.23284998
Molnupiravir, an antiviral medication that has been widely used against SARS-CoV-2, acts by inducing mutations in the virus genome during replication. Most random mutations are likely to be deleterious to the virus, and many will be lethal. Molnupiravirinduced elevated mutation rates have been shown to decrease viral load in animal models. However, it is possible that some patients treated with molnupiravir might not fully clear SARS-CoV-2 infections, with the potential for onward transmission of molnupiravir-mutated viruses. We set out to systematically investigate global sequencing databases for a signature of molnupiravir mutagenesis. We find that a specific class of long phylogenetic branches appear almost exclusively in sequences from 2022, after the introduction of molnupiravir treatment, and in countries and agegroups with widespread usage of the drug. We calculate a mutational spectrum from the AGILE placebo-controlled clinical trial of molnupiravir and show that its signature, with elevated G-to-A and C-to-T rates, largely corresponds to the mutational spectrum seen in these long branches. Our data suggest a signature of molnupiravir mutagenesis can be seen in global sequencing databases, in some cases with onwards transmission.
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..
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