Wat weten “we” van de Britse mutatie? Deze is besmettelijker, weet men ook waardoor dat komt en is het ziekte verloop verder wel gelijk, of verschilt dat ook?
Potential biological significance of mutations
Table 1 provides details of the B.1.1.7 lineage-specific non-synonymous mutations and deletions. We note that many occur in the virus spike protein. These include spike position 501, one of the key contact residues in the receptor binding domain (RBD), and experimental data suggests mutation N501Y can increase ACE2 receptor affinity (Starr et al. 2020) and P681H, one of 4 residues comprising the insertion that creates a furin cleavage site between S1 and S2 in spike. The S1/S2 furin cleavage site of SARS-CoV-2 is not found in closely related coronaviruses and has been shown to promote entry into respiratory epithelial cells and transmission in animal models (Hoffmann, Kleine-Weber, and Pöhlmann 2020; Peacock et al. 2020; Zhu et al. 2020). N501Y has been associated with increased infectivity and virulence in a mouse model (Gu et al. 2020). Both N501Y and P681H have been observed independently but not to our knowledge in combination before now.
Also present is the deletion of two amino acids at sites 69-70 in spike - this mutation is one of a number of recurrent deletions observed in the N terminal domain of Spike (McCarthy et al. 2020; Kemp et al. 2020) and has been seen in multiple lineages linked to several RBD mutations. For example, it arose in the mink-associated outbreak in Denmark on the background of the Y453F RBD mutation, and in humans in association with the N439K RBD mutation, accounting for its relatively high frequency in the global genome data (~3000 sequences).
Outside of spike, the ORF8 Q27stop mutation truncates the ORF8 protein or renders it inactive and thus allows further downstream mutations to accrue. Early on during the pandemic multiple virus isolates with deletions leading to loss of ORF8 expression were isolated worldwide, including a large cluster in Singapore with a deletion leading to both a truncated Orf7b and ablated ORF8 expression. The Singaporean strain, which had a 382nt deletion, was associated with a milder clinical infection and less post-infection inflammation, however this cluster died out at the end of March after Singapore successfully implemented control measures (Young et al. 2020). Subsequent work has found that the ORF8 deletion has only a very modest effect on virus replication in human primary airway cells compared to viruses without the deletion, leading to a slight replication lag compared to viruses with the deletion (Gamage et al. 2020). As ORF8 is usually 121 amino acids long it is likely the stop codon at position 27 observed in lineage B.1.1.7 results in a loss of function.
Finally there are 6 synonymous mutations with 5 in ORF1ab (C913T, C5986T, C14676T, C15279T, C16176T), and one in the M gene (T26801C).
Preliminary genomic characterisation of an emergent SARS-CoV-2 lineage in the UK defined by a novel set of spike mutations Report written by: Andrew Rambaut1, Nick Loman2, Oliver Pybus3, Wendy Barclay4, Jeff Barrett5, Alesandro Carabelli6, Tom Connor7, Tom Peacock4, David L Robertson8, Erik...
virological.org
Intriguingly, SARS-CoV-2 variants isolated in the beginning of the coronavirus disease 2019 (Covid-19) pandemic that were deleted of the
ORF8 gene have been associated to milder symptoms and better disease outcome. This minireview summarizes the current knowledge on the SARS-CoV-2 ORF8 protein in perspective to its potential as antiviral target and with special emphasis on the biochemical, biophysical and structural aspects of its molecular biology.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome contains nine open reading frames (ORFs) that encode for accessory proteins wh…
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