Virology
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sent with the addition of ten ORF coding for accessory proteins. The genome follows the sequence; 5’-cap, 5’ UTR, ORF1a/b (replicase gene), spike (S), ORF3a, ORF3b, envelope (E), Membrane (M), ORF6, ORF7a, ORF7b, OPRF8, nucleocapsid (N), ORF9, ORF10, 3’ UTR, 3’-tail, (Sardar 2020, Romano 2020). Mutations are the main source of variation within a viral genome and drive viral evolution. There can be numerous consequences on the virion ranging from detrimental (death or incompetent virus) to inconsequential, to favourable (increased virulence, transmissibility or pathogenicity capabilities, immune escape, and drug resistance). Generally, RNA viruses are susceptible to high mutation rates due to their lack of proof reading mechanism. Unique to CoV RNA is NSP14, a 3’ to 5’ exoribonuclease enzyme with proofreading capabilities. It is speculated this assists in maintaining the uncharacteristically large RNA genome. All human SARS-CoV-2 genomes sequenced to dateare extremely similar to one another demonstrating low heterogenicity. Intersequence identity among all isolates to date is reported to be above 99% suggesting that the genome is mostly stable (Ceraolo 2020, Zhang X 2020). Despite this high level of conservation, there are notable regions in the genome of high variability. Mutations in NSP3 and NSP12, both of which are key proteins in viral RNA synthesis, are speculated to confer unfavourable effects on replication and pathogenicity(Sardar 2020, Pachetti 2020). Other mutations such as those seen in NSP14, may lead to a significant increase in rate of viral mutations due to loss of proofreading activity (Sardar 2020). The S1 subunit of the Sglycoprotein is subject to higher variability in comparison to the stable S2 subunit. Mutations most commonly affect the RBM and receptor binding motif with the resultant effect a decrease in protein stability. On the contrary, there have been over 2300 nonsynonymous substitution mutations identified in the SARS-CoV-2 genome of which none have shown to have any significant functional implications (MacLean 2020). Disease severity appears to be associated with host factors, rather than genetic variability (Zhang X 2020). Determining genomic features and mutation hotspots of SARS-CoV-2 may provide insight into various properties such as virulence, pathogenicity and transmissibility. This could be crucial in identifying targets for diagnostics, prognostication and treatment interventions.
References Almeida “Virology: Coronaviruses”. Nature. 220 (5168): 650. Bibcode:1968Natur.220..650.. Fulltext: https://doi.org/10.1038/220650b0 Andersen KG, Rambaut A, Lipkin WI, Holmes EC, Garry RF. The proximal origin of SARS-CoV2. Nat Med. 2020 Apr;26(4):450-452. PubMed: https://pubmed.gov/32284615. Fulltext: https://doi.org/10.1038/s41591-020-0820-9
COVID Reference ENG 006.9
