Key result
SARS-CoV-2 RdRp p.P323L mutation increases genome-wide mutations by ~33% versus wild-type strains.
Why the study?
It was unclear how featured co-occurring mutations of globally prevalent SARS-CoV-2 clades are linked with viral fitness, replication, and transmission.
Absolute Event Rate: 8% vs 6%
p-value: p=<0.0001
In silico modeling suggests that dominant SARS-CoV-2 mutations, such as Spike D614G and RdRp P323L, may enhance viral replication and transmission through altered protein interactions and structural flexibility.
RdRp p.P323L may increase viral mutagenesis in animal models; hypothesis-generating for human SARS-CoV-2 evolution.
SARS-CoV-2 is evolved into eight fundamental clades where four (G, GH, GR, and GV) are globally prevalent in 2020. How the featured co-occurring mutations of these clades are linked with viral fitness is the main question here and we thus proposed a hypothetical model using in silico approach to explain the plausible epistatic effects of those mutations on viral replication and transmission. Molecular docking and dynamics analyses showed the higher infectiousness of a spike mutant through more favorable binding of G 614 with the elastase-2. RdRp mutation p.P323L significantly increased genome-wide mutations (p<0.0001) since more flexible RdRp (mutated)-NSP8 interaction may accelerate replication. Superior RNA stability and structural variation at NSP3:C241T might impact protein and/or RNA interactions. Another silent 5’UTR:C241T mutation might affect translational efficiency and viral packaging. These four G-clade-featured co-occurring mutations might increase viral replication. Sentinel GH-clade ORF3a:p.Q57H constricted ion-channel through inter-transmembrane-domain interaction of cysteine(C81)-histidine(H57) and GR-clade N:p.RG203-204KR would stabilize RNA interaction by a more flexible and hypo-phosphorylated SR-rich region. GV-clade viruses seemingly gained the evolutionary advantage of the confounding factors; nevertheless, N:p.A220V might modulate RNA binding with no phenotypic effect. Our hypothetical model needs further retrospective and prospective studies to understand detailed molecular events featuring the fitness of SARS-CoV-2.
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Alam et al. (2021) studied SARS-CoV-2 (n=225,526). SARS-CoV-2 mutations (in silico analysis) vs. Wild-type sequences was evaluated on Genome-wide mutations frequency (median) (p=<0.0001). The SARS-CoV-2 RdRp mutation p.P323L significantly increased genome-wide mutations compared to wild-type strains (median 8 vs 6, p<0.0001).
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