The mutational spectrum of SARS-CoV-2 genomic and antigenomic RNA

Zhao, Lele, Hall, Matthew, de Cesare, Mariateresa, MacIntyre-Cockett, George, Lythgoe, Katrina, Fraser, Christophe, Bonsall, David, Golubchik, Tanya, Ferretti, Luca, The COVID-19 Genomics UK (COG-UK) Consortium, , Bashton, Matthew, Smith, Darren, Nelson, Andrew, Young, Greg and McCann, Clare (2022) The mutational spectrum of SARS-CoV-2 genomic and antigenomic RNA. Proceedings of the Royal Society B: Biological Sciences, 289 (1987). p. 20221747. ISSN 0962-8452

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The raw material for viral evolution is provided by intra-host mutations occurring during replication, transcription or post-transcription. Replication and transcription of Coronaviridae proceed through the synthesis of negative-sense ‘antigenomes’ acting as templates for positive-sense genomic and subgenomic RNA. Hence, mutations in the genomes of SARS-CoV-2 and other coronaviruses can occur during (and after) the synthesis of either negative-sense or positive-sense RNA, with potentially distinct patterns and consequences. We explored for the first time the mutational spectrum of SARS-CoV-2 (sub)genomic and anti(sub)genomic RNA. We use a high-quality deep sequencing dataset produced using a quantitative strand-aware sequencing method, controlled for artefacts and sequencing errors, and scrutinized for accurate detection of within-host diversity. The nucleotide differences between negative- and positive-sense strand consensus vary between patients and do not show dependence on age or sex. Similarities and differences in mutational patterns between within-host minor variants on the two RNA strands suggested strand-specific mutations or editing by host deaminases and oxidative damage. We observe generally neutral and slight negative selection on the negative strand, contrasting with purifying selection in ORF1a, ORF1b and S genes of the positive strand of the genome.

Item Type: Article
Additional Information: Matthew Bashton, Andrew Nelson, Clare McCann, Greg Young and Darren Smith are members of the COVID-19 Genomics UK consortium. Funding information: COG-UK is supported by funding from the Medical Research Council (MRC) part of UK Research & Innovation (UKRI), the National Institute of Health Research (NIHR) (grant code: MC_PC_19027), and Genome Research Limited, operating as the Wellcome Sanger Institute. This work was supported by a Li Ka Shing Foundation Grant awarded to C.F. The research was supported by the Wellcome Trust Core Award grant no. 203141/Z/16/Z with funding from the NIHR Oxford BRC. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.
Uncontrolled Keywords: SARS-CoV-2, antigenomes,mutational spectrum, RNA editing
Subjects: C500 Microbiology
C700 Molecular Biology, Biophysics and Biochemistry
Department: Faculties > Health and Life Sciences > Applied Sciences
Depositing User: Elena Carlaw
Date Deposited: 22 Feb 2023 15:19
Last Modified: 22 Feb 2023 15:19

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