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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

Authors :
Abha Chopra
Simon Mallal
Suman B. Pakala
Suman R. Das
Jodi L. Bubenik
Benjamin B Lindsey
Mina John
Maurice S. Swanson
Matthew Parker
Alexander J Keeley
Covid Genomics Uk
Eric Alves
T I de Silva
Ian James
Shay Leary
Elizabeth J. Phillips
David A. Ostrov
Sarah Rowland-Jones
Alessandro Sette
John Sidney
Silvana Gaudieri
Source :
Pathogens and Immunity. 6:27-49
Publication Year :
2021
Publisher :
Case Western Reserve University, 2021.

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.

Details

ISSN :
24692964
Volume :
6
Database :
OpenAIRE
Journal :
Pathogens and Immunity
Accession number :
edsair.doi...........afa13b7ba41d105a6b19ef57028b0197
Full Text :
https://doi.org/10.20411/pai.v6i2.460