Emergence of SARS-CoV-2 subgenomic RNAs that enhance viral fitness and immune evasion.
Coronaviruses express their structural and accessory genes via a set of subgenomic RNAs, whose synthesis is directed by transcription regulatory sequences (TRSs) in the 5' genomic leader and upstream of each body open reading frame. In SARS-CoV-2, the TRS has the consensus AAACGAAC; upon search...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2025-01-01
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| Series: | PLoS Biology |
| Online Access: | https://doi.org/10.1371/journal.pbio.3002982 |
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| author | Harriet V Mears George R Young Theo Sanderson Ruth Harvey Jamie Barrett-Rodger Rebecca Penn Vanessa Cowton Wilhelm Furnon Giuditta De Lorenzo Margaret Crawford Daniel M Snell Ashley S Fowler Anob M Chakrabarti Saira Hussain Ciarán Gilbride Edward Emmott Katja Finsterbusch Jakub Luptak Thomas P Peacock Jérôme Nicod Arvind H Patel Massimo Palmarini Emma Wall Bryan Williams Sonia Gandhi Charles Swanton David L V Bauer |
| author_facet | Harriet V Mears George R Young Theo Sanderson Ruth Harvey Jamie Barrett-Rodger Rebecca Penn Vanessa Cowton Wilhelm Furnon Giuditta De Lorenzo Margaret Crawford Daniel M Snell Ashley S Fowler Anob M Chakrabarti Saira Hussain Ciarán Gilbride Edward Emmott Katja Finsterbusch Jakub Luptak Thomas P Peacock Jérôme Nicod Arvind H Patel Massimo Palmarini Emma Wall Bryan Williams Sonia Gandhi Charles Swanton David L V Bauer |
| author_sort | Harriet V Mears |
| collection | DOAJ |
| description | Coronaviruses express their structural and accessory genes via a set of subgenomic RNAs, whose synthesis is directed by transcription regulatory sequences (TRSs) in the 5' genomic leader and upstream of each body open reading frame. In SARS-CoV-2, the TRS has the consensus AAACGAAC; upon searching for emergence of this motif in the global SARS-CoV-2 sequences, we find that it evolves frequently, especially in the 3' end of the genome. We show well-supported examples upstream of the Spike gene-within the nsp16 coding region of ORF1b-which is expressed during human infection, and upstream of the canonical Envelope gene TRS, both of which have evolved convergently in multiple lineages. The most frequent neo-TRS is within the coding region of the Nucleocapsid gene, and is present in virtually all viruses from the B.1.1 lineage, including the variants of concern Alpha, Gamma, Omicron and descendants thereof. Here, we demonstrate that this TRS leads to the expression of a novel subgenomic mRNA encoding a truncated C-terminal portion of Nucleocapsid, which is an antagonist of type I interferon production and contributes to viral fitness during infection. We observe distinct phenotypes when the Nucleocapsid coding sequence is mutated compared to when the TRS alone is ablated. Our findings demonstrate that SARS-CoV-2 is undergoing evolutionary changes at the functional RNA level in addition to the amino acid level. |
| format | Article |
| id | doaj-art-221751f24ca94b9485c64aed93b696a3 |
| institution | Kabale University |
| issn | 1544-9173 1545-7885 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj-art-221751f24ca94b9485c64aed93b696a32025-02-05T05:30:21ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852025-01-01231e300298210.1371/journal.pbio.3002982Emergence of SARS-CoV-2 subgenomic RNAs that enhance viral fitness and immune evasion.Harriet V MearsGeorge R YoungTheo SandersonRuth HarveyJamie Barrett-RodgerRebecca PennVanessa CowtonWilhelm FurnonGiuditta De LorenzoMargaret CrawfordDaniel M SnellAshley S FowlerAnob M ChakrabartiSaira HussainCiarán GilbrideEdward EmmottKatja FinsterbuschJakub LuptakThomas P PeacockJérôme NicodArvind H PatelMassimo PalmariniEmma WallBryan WilliamsSonia GandhiCharles SwantonDavid L V BauerCoronaviruses express their structural and accessory genes via a set of subgenomic RNAs, whose synthesis is directed by transcription regulatory sequences (TRSs) in the 5' genomic leader and upstream of each body open reading frame. In SARS-CoV-2, the TRS has the consensus AAACGAAC; upon searching for emergence of this motif in the global SARS-CoV-2 sequences, we find that it evolves frequently, especially in the 3' end of the genome. We show well-supported examples upstream of the Spike gene-within the nsp16 coding region of ORF1b-which is expressed during human infection, and upstream of the canonical Envelope gene TRS, both of which have evolved convergently in multiple lineages. The most frequent neo-TRS is within the coding region of the Nucleocapsid gene, and is present in virtually all viruses from the B.1.1 lineage, including the variants of concern Alpha, Gamma, Omicron and descendants thereof. Here, we demonstrate that this TRS leads to the expression of a novel subgenomic mRNA encoding a truncated C-terminal portion of Nucleocapsid, which is an antagonist of type I interferon production and contributes to viral fitness during infection. We observe distinct phenotypes when the Nucleocapsid coding sequence is mutated compared to when the TRS alone is ablated. Our findings demonstrate that SARS-CoV-2 is undergoing evolutionary changes at the functional RNA level in addition to the amino acid level.https://doi.org/10.1371/journal.pbio.3002982 |
| spellingShingle | Harriet V Mears George R Young Theo Sanderson Ruth Harvey Jamie Barrett-Rodger Rebecca Penn Vanessa Cowton Wilhelm Furnon Giuditta De Lorenzo Margaret Crawford Daniel M Snell Ashley S Fowler Anob M Chakrabarti Saira Hussain Ciarán Gilbride Edward Emmott Katja Finsterbusch Jakub Luptak Thomas P Peacock Jérôme Nicod Arvind H Patel Massimo Palmarini Emma Wall Bryan Williams Sonia Gandhi Charles Swanton David L V Bauer Emergence of SARS-CoV-2 subgenomic RNAs that enhance viral fitness and immune evasion. PLoS Biology |
| title | Emergence of SARS-CoV-2 subgenomic RNAs that enhance viral fitness and immune evasion. |
| title_full | Emergence of SARS-CoV-2 subgenomic RNAs that enhance viral fitness and immune evasion. |
| title_fullStr | Emergence of SARS-CoV-2 subgenomic RNAs that enhance viral fitness and immune evasion. |
| title_full_unstemmed | Emergence of SARS-CoV-2 subgenomic RNAs that enhance viral fitness and immune evasion. |
| title_short | Emergence of SARS-CoV-2 subgenomic RNAs that enhance viral fitness and immune evasion. |
| title_sort | emergence of sars cov 2 subgenomic rnas that enhance viral fitness and immune evasion |
| url | https://doi.org/10.1371/journal.pbio.3002982 |
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