The COVID-19 pandemic caused by SARS-CoV-2 has raised questions about the virus’s ability to mutate and adapt. SARS-CoV-2, an RNA virus, has a higher mutation rate compared to DNA viruses due to its error-prone RNA-dependent RNA polymerase. However, the virus has a mechanism to correct errors through an exonuclease called NSP14. This proofreading mechanism is crucial for maintaining the accuracy of the viral RNA genome and preventing the accumulation of harmful mutations.
Despite the presence of the NSP14 proofreading exonuclease, SARS-CoV-2 has still managed to adapt to the human host through the acquisition of mutations. The rate at which advantageous mutations emerge is influenced by the interplay between NSP14 and the RNA polymerase. Recombination also adds complexity to the virus’s evolutionary dynamics. Understanding the mutational processes in SARS-CoV-2 is essential for comprehending the factors driving diversity within the virus population.
The NSP14 exonuclease plays a vital role in maintaining replication accuracy by removing incorrectly incorporated nucleotides. Specific amino acid residues within the enzyme’s active site coordinate magnesium ions that activate water molecules for removing these nucleotides.
Previous research has shown that inactivation of the exonuclease in related coronaviruses results in the inability to generate viable virions. Inactivation experiments on SARS-CoV-1 and murine hepatitis virus (MHV) produced viable virions with compromised fidelity, leading to an increased burden of mutations and reduced fitness. Mutations within the exonuclease have been associated with an increased mutation rate in SARS-CoV-2.
The exonuclease activity of NSP14 is modulated by its interaction with NSP10. Mutations at the NSP14/NSP10 interface have been shown to reduce exonuclease activity and make the virus less viable. This interaction is critical for maintaining replication fidelity.
A specific mutation, F60S, located at the interface of NSP14 and NSP10, may alter the interaction network within this interface, potentially impacting the exonuclease’s efficiency. This alteration could lead to an increased mutation rate.
The SARS-CoV-2 lineage carrying the F60S mutation has exhibited an elevated evolutionary rate compared to other lineages. This high mutation rate allowed these viruses to acquire mutations associated with improved fitness and virulence. However, the lineage eventually went extinct due to an overwhelming burden of detrimental mutations.
Analysis of Spike protein mutations within the F60S lineage revealed changes linked to Variants of Concern, immune escape, receptor binding, and furin cleavage site adaptations. The extinction of the F60S lineage suggests that there is a threshold where the negative impact of detrimental mutations outweighs the benefits from advantageous mutations.
This research highlights the potential for rapid mutation generation in SARS-CoV-2, adding to the virus’s capacity for recombination and diversity generation. Understanding the impact of exonuclease mutations on mutational dynamics is essential for deciphering the virus’s evolutionary trajectory.
In conclusion, the NSP14 exonuclease plays a crucial role in maintaining replication fidelity in SARS-CoV-2. The F60S mutation serves as an example of how a single mutation at the NSP14/NSP10 interface can affect the virus’s evolutionary rate. This research not only enhances our understanding of SARS-CoV-2 mutational dynamics but also provides insights into the mechanisms governing virus evolution, which can inform future research and interventions to combat the ongoing global health impact of this virus.