Proc Biol Sci . The mutational spectrum of SARS-CoV-2 genomic and antigenomic RNA

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Proc Biol Sci


. 2022 Nov 30;289(1987):20221747.
doi: 10.1098/rspb.2022.1747. Epub 2022 Nov 16.
The mutational spectrum of SARS-CoV-2 genomic and antigenomic RNA


Lele Zhao ¹ , Matthew Hall ¹ , Mariateresa de Cesare ² , George MacIntyre-Cockett ³ , Katrina Lythgoe ¹ , Christophe Fraser ¹ , David Bonsall ^{1 3} , Tanya Golubchik ^{1 4} , COVID-19 Genomics UK (COG-UK) Consortium; Luca Ferretti ¹



Affiliations

• PMID: 36382519
• DOI: 10.1098/rspb.2022.1747

Abstract

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.

Keywords: RNA editing; SARS-CoV-2; antigenomes; mutational spectrum.