Leary, Shay; Gaudieri, Silvana; Parker, Matthew D; Chopra, Abha; James, Ian; Pakala, Suman; Alves, Eric; John, Mina; Lindsey, Benjamin B; Keeley, Alexander J; +11 more... Rowland-Jones, Sarah L; Swanson, Maurice S; Ostrov, David A; Bubenik, Jodi L; Das, Suman R; Sidney, John; Sette, Alessandro; COVID-19 Genomics UK (COG-UK) consortium; de Silva, Thushan I; Phillips, Elizabeth; Mallal, Simon; COVID-19 Genomics UK (COG-UK) consortium; (2021) Generation of a Novel SARS-CoV-2 Sub-genomic RNA Due to the R203K/G204R Variant in Nucleocapsid: Homologous Recombination has Potential to Change SARS-CoV-2 at Both Protein and RNA Level. Pathogens & immunity, 6 (2). pp. 27-49. ISSN 2469-2964 DOI: https://doi.org/10.20411/pai.v6i2.460
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Abstract
BACKGROUND: Genetic variations across the SARS-CoV-2 genome may influence transmissibility of the virus and the host's anti-viral immune response, in turn affecting the frequency of variants over time. In this study, we examined the adjacent amino acid polymorphisms in the nucleocapsid (R203K/G204R) of SARS-CoV-2 that arose on the background of the spike D614G change and describe how strains harboring these changes became dominant circulating strains globally. METHODS: Deep-sequencing data of SARS-CoV-2 from public databases and from clinical samples were analyzed to identify and map genetic variants and sub-genomic RNA transcripts across the genome. Results: Sequence analysis suggests that the 3 adjacent nucleotide changes that result in the K203/R204 variant have arisen by homologous recombination from the core sequence of the leader transcription-regulating sequence (TRS) rather than by stepwise mutation. The resulting sequence changes generate a novel sub-genomic RNA transcript for the C-terminal dimerization domain of nucleocapsid. Deep-sequencing data from 981 clinical samples confirmed the presence of the novel TRS-CS-dimerization domain RNA in individuals with the K203/R204 variant. Quantification of sub-genomic RNA indicates that viruses with the K203/R204 variant may also have increased expression of sub-genomic RNA from other open reading frames. CONCLUSIONS: The finding that homologous recombination from the TRS may have occurred since the introduction of SARS-CoV-2 in humans, resulting in both coding changes and novel sub-genomic RNA transcripts, suggests this as a mechanism for diversification and adaptation within its new host.
Item Type | Article |
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Faculty and Department | Faculty of Infectious and Tropical Diseases > Dept of Clinical Research |
Research Centre | Covid-19 Research |
PubMed ID | 34541432 |
Elements ID | 169029 |
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Licence: Creative Commons: Attribution 4.0
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