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Altered subgenomic RNA abundance provides unique insight into SARS-CoV-2 B.1.1.7/Alpha variant infections

Parker, M.D., Stewart, H., Shehata, O.M., Lindsey, B.B., Shah, D.R., Hsu, S., Keeley, A.J., Partridge, D.G., Leary, S., Cope, A., State, A., Johnson, K., Ali, N., Raghei, R., Heffer, J., Smith, N., Zhang, P., Gallis, M., Louka, S.F., Hornsby, H.R., Alamri, H., Whiteley, M., Foulkes, B.H., Christou, S., Wolverson, P., Pohare, M., Hansford, S.E., Green, L.R., Evans, C., Raza, M., Wang, D., Firth, A.E., Edgar, J.R., Gaudieri, S., Mallal, S., Collins, M.O., Peden, A.A. and de Silva, T.I. (2022) Altered subgenomic RNA abundance provides unique insight into SARS-CoV-2 B.1.1.7/Alpha variant infections. Communications Biology, 5 (1). Art. 666.

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B.1.1.7 lineage SARS-CoV-2 is more transmissible, leads to greater clinical severity, and results in modest reductions in antibody neutralization. Subgenomic RNA (sgRNA) is produced by discontinuous transcription of the SARS-CoV-2 genome. Applying our tool (periscope) to ARTIC Network Oxford Nanopore Technologies genomic sequencing data from 4400 SARS-CoV-2 positive clinical samples, we show that normalised sgRNA is significantly increased in B.1.1.7 (alpha) infections (n = 879). This increase is seen over the previous dominant lineage in the UK, B.1.177 (n = 943), which is independent of genomic reads, E cycle threshold and days since symptom onset at sampling. A noncanonical sgRNA which could represent ORF9b is found in 98.4% of B.1.1.7 SARS-CoV-2 infections compared with only 13.8% of other lineages, with a 16-fold increase in median sgRNA abundance. We demonstrate that ORF9b protein levels are increased 6-fold in B.1.1.7 compared to a B lineage virus in vitro. We hypothesise that increased ORF9b in B.1.1.7 is a direct consequence of a triple nucleotide mutation in nucleocapsid (28280:GAT > CAT, D3L) creating a transcription regulatory-like sequence complementary to a region 3’ of the genomic leader. These findings provide a unique insight into the biology of B.1.1.7 and support monitoring of sgRNA profiles to evaluate emerging potential variants of concern.

Item Type: Journal Article
Murdoch Affiliation(s): Institute for Immunology and Infectious Diseases
Publisher: Nature Research
Copyright: © 2022 The Authors.
United Nations SDGs: Goal 3: Good Health and Well-Being
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