The P323L substitution in the SARS-CoV-2 polymerase (NSP12) confers a selective advantage during infection
1
Issued Date
2023-12-01
Resource Type
ISSN
14747596
eISSN
1474760X
Scopus ID
2-s2.0-85150101231
Pubmed ID
36915185
Journal Title
Genome Biology
Volume
24
Issue
1
Rights Holder(s)
SCOPUS
Bibliographic Citation
Genome Biology Vol.24 No.1 (2023)
Suggested Citation
Goldswain H., Dong X., Penrice-Randal R., Alruwaili M., Shawli G.T., Prince T., Williamson M.K., Raghwani J., Randle N., Jones B., Donovan-Banfield I., Salguero F.J., Tree J.A., Hall Y., Hartley C., Erdmann M., Bazire J., Jearanaiwitayakul T., Semple M.G., Openshaw P.J.M., Baillie J.K., Baillie J.K., Semple M.G., Openshaw P.J.M., Carson G., Alex B., Andrikopoulos P., Bach B., Barclay W.S., Bogaert D., Chand M., Chechi K., Cooke G.S., da Silva Filipe A., de Silva T., Docherty A.B., dos Santos Correia G., Dumas M.E., Dunning J., Fletcher T., Green C.A., Greenhalf W., Griffin J.L., Gupta R.K., Harrison E.M., Hiscox J.A., Ho A.Y.W., Horby P.W., Ijaz S., Khoo S., Klenerman P., Law A., Lewis M.R., Liggi S., Lim W.S., Maslen L., Mentzer A.J., Merson L., Meynert A.M., Moore S.C., Noursadeghi M., Olanipekun M., Osagie A., Palmarini M., Palmieri C., Paxton W.A., Pollakis G., Price N., Rambaut A., Robertson D.L., Russell C.D., Sancho-Shimizu V., Sands C.J., Scott J.T., Sigfrid L., Solomon T., Sriskandan S., Stuart D., Summers C., Swann O.V., Takats Z., Takis P., Tedder R.S., Thompson A.A.R., Thomson E.C., Thwaites R.S., Zambon M., Hardwick H., Donohue C., Griffiths F., Oosthuyzen W., Donegan C., Spencer R.G., Norman L., Pius R., Drake T.M., Fairfield C.J., Knight S.R., Mclean K.A., Murphy D. The P323L substitution in the SARS-CoV-2 polymerase (NSP12) confers a selective advantage during infection. Genome Biology Vol.24 No.1 (2023). doi:10.1186/s13059-023-02881-5 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/81309
Title
The P323L substitution in the SARS-CoV-2 polymerase (NSP12) confers a selective advantage during infection
Author(s)
Goldswain H.
Dong X.
Penrice-Randal R.
Alruwaili M.
Shawli G.T.
Prince T.
Williamson M.K.
Raghwani J.
Randle N.
Jones B.
Donovan-Banfield I.
Salguero F.J.
Tree J.A.
Hall Y.
Hartley C.
Erdmann M.
Bazire J.
Jearanaiwitayakul T.
Semple M.G.
Openshaw P.J.M.
Baillie J.K.
Baillie J.K.
Semple M.G.
Openshaw P.J.M.
Carson G.
Alex B.
Andrikopoulos P.
Bach B.
Barclay W.S.
Bogaert D.
Chand M.
Chechi K.
Cooke G.S.
da Silva Filipe A.
de Silva T.
Docherty A.B.
dos Santos Correia G.
Dumas M.E.
Dunning J.
Fletcher T.
Green C.A.
Greenhalf W.
Griffin J.L.
Gupta R.K.
Harrison E.M.
Hiscox J.A.
Ho A.Y.W.
Horby P.W.
Ijaz S.
Khoo S.
Klenerman P.
Law A.
Lewis M.R.
Liggi S.
Lim W.S.
Maslen L.
Mentzer A.J.
Merson L.
Meynert A.M.
Moore S.C.
Noursadeghi M.
Olanipekun M.
Osagie A.
Palmarini M.
Palmieri C.
Paxton W.A.
Pollakis G.
Price N.
Rambaut A.
Robertson D.L.
Russell C.D.
Sancho-Shimizu V.
Sands C.J.
Scott J.T.
Sigfrid L.
Solomon T.
Sriskandan S.
Stuart D.
Summers C.
Swann O.V.
Takats Z.
Takis P.
Tedder R.S.
Thompson A.A.R.
Thomson E.C.
Thwaites R.S.
Zambon M.
Hardwick H.
Donohue C.
Griffiths F.
Oosthuyzen W.
Donegan C.
Spencer R.G.
Norman L.
Pius R.
Drake T.M.
Fairfield C.J.
Knight S.R.
Mclean K.A.
Murphy D.
Dong X.
Penrice-Randal R.
Alruwaili M.
Shawli G.T.
Prince T.
Williamson M.K.
Raghwani J.
Randle N.
Jones B.
Donovan-Banfield I.
Salguero F.J.
Tree J.A.
Hall Y.
Hartley C.
Erdmann M.
Bazire J.
Jearanaiwitayakul T.
Semple M.G.
Openshaw P.J.M.
Baillie J.K.
Baillie J.K.
Semple M.G.
Openshaw P.J.M.
Carson G.
Alex B.
Andrikopoulos P.
Bach B.
Barclay W.S.
Bogaert D.
Chand M.
Chechi K.
Cooke G.S.
da Silva Filipe A.
de Silva T.
Docherty A.B.
dos Santos Correia G.
Dumas M.E.
Dunning J.
Fletcher T.
Green C.A.
Greenhalf W.
Griffin J.L.
Gupta R.K.
Harrison E.M.
Hiscox J.A.
Ho A.Y.W.
Horby P.W.
Ijaz S.
Khoo S.
Klenerman P.
Law A.
Lewis M.R.
Liggi S.
Lim W.S.
Maslen L.
Mentzer A.J.
Merson L.
Meynert A.M.
Moore S.C.
Noursadeghi M.
Olanipekun M.
Osagie A.
Palmarini M.
Palmieri C.
Paxton W.A.
Pollakis G.
Price N.
Rambaut A.
Robertson D.L.
Russell C.D.
Sancho-Shimizu V.
Sands C.J.
Scott J.T.
Sigfrid L.
Solomon T.
Sriskandan S.
Stuart D.
Summers C.
Swann O.V.
Takats Z.
Takis P.
Tedder R.S.
Thompson A.A.R.
Thomson E.C.
Thwaites R.S.
Zambon M.
Hardwick H.
Donohue C.
Griffiths F.
Oosthuyzen W.
Donegan C.
Spencer R.G.
Norman L.
Pius R.
Drake T.M.
Fairfield C.J.
Knight S.R.
Mclean K.A.
Murphy D.
Author's Affiliation
UK Health Security Agency
Northern Border University
University of Oxford
University of Edinburgh, Roslin Institute
Alder Hey Children's Hospital
University of Liverpool
University of Bristol
Mahidol University
National Heart and Lung Institute
NIHR Health Protection Research Unit in Emerging and Zoonotic Infections
Northern Border University
University of Oxford
University of Edinburgh, Roslin Institute
Alder Hey Children's Hospital
University of Liverpool
University of Bristol
Mahidol University
National Heart and Lung Institute
NIHR Health Protection Research Unit in Emerging and Zoonotic Infections
Other Contributor(s)
Abstract
Background: The mutational landscape of SARS-CoV-2 varies at the dominant viral genome sequence and minor genomic variant population. During the COVID-19 pandemic, an early substitution in the genome was the D614G change in the spike protein, associated with an increase in transmissibility. Genomes with D614G are accompanied by a P323L substitution in the viral polymerase (NSP12). However, P323L is not thought to be under strong selective pressure. Results: Investigation of P323L/D614G substitutions in the population shows rapid emergence during the containment phase and early surge phase during the first wave. These substitutions emerge from minor genomic variants which become dominant viral genome sequence. This is investigated in vivo and in vitro using SARS-CoV-2 with P323 and D614 in the dominant genome sequence and L323 and G614 in the minor variant population. During infection, there is rapid selection of L323 into the dominant viral genome sequence but not G614. Reverse genetics is used to create two viruses (either P323 or L323) with the same genetic background. L323 shows greater abundance of viral RNA and proteins and a smaller plaque morphology than P323. Conclusions: These data suggest that P323L is an important contribution in the emergence of variants with transmission advantages. Sequence analysis of viral populations suggests it may be possible to predict the emergence of a new variant based on tracking the frequency of minor variant genomes. The ability to predict an emerging variant of SARS-CoV-2 in the global landscape may aid in the evaluation of medical countermeasures and non-pharmaceutical interventions.