What are the different factors causing mutation in a virus?

Mutation simply means a change in genetic terms, either in the DNA or the RNA (genome). These nuclear changes help in the survival and evolution of several species, especially viruses. The immune system can develop machinery to fight off an infection. The same system can also remember to use the same machinery if the infection were to take place again (anamnestic immunity). Viruses undergo several mutations. Sometimes these mutations won’t make a difference (silent mutation), sometimes it can be harmful or lethal to the virus itself (loss of function mutation) or it can strengthen the virus’s capacity (gain of function mutation).

Mutations can happen via three mechanisms: (1) Effect of physical agents like UV light or X-rays on the nucleic acids (2) Changes in the conformational states of the nucleic acid or (3) Improper functioning of the enzymes required to make the nucleic acids. These mechanisms can bring about either a change or a rearrangement in the nucleotide sequences. The effect of the first two mechanisms is quite constant. The fidelity of the enzymes that are responsible for the replication of the nucleic acids heavily determines the differences in the mutation rates amongst different viruses. 

When the nuclear information is converted to proteins, structural changes can take place. With DNA viruses, the mutation rates are quite low as they rely on the host’s machinery to replicate. Any mutations with these viruses are hence corrected by the stringent proofreading mechanism. In contrast, RNA viruses rely on their own replication machinery. Hence they have very high mutation rates as they lack a proofreading mechanism. Mutated viruses have the ability to escape the anamnestic immune response and re-infect the host. These mutations can also make it quite difficult to develop the appropriate vaccines.

The most common RNA virus that has high mutation rates is the influenza virus a.k.a the seasonal flu virus. A lot of the research on viral mutations and how they escape both the host’s as well as the vaccine-induced immunity is based on the influenza virus. These viruses change in two different ways- antigenic drift and antigenic shift. Coronaviruses are also RNA viruses that have often been compared to the influenza virus, with a few key differences. Coronaviruses are larger viruses (having around 29,903 nucleotides) have a slightly developed proofreading mechanism that can confer stability to their genome, and possess lower mutation rates. 

Antigenic Drift

The mutations that occur in the genome over time can bring about many changes in the virus along with alterations on the surface proteins, which acts as antigens. A “drift” in the antigens occurs making the virus appear different than the original strain, allowing it to evade the immune system and cause the infection. A mild antigenic drift is observed with the spike protein of the SARS-CoV-2 virus due to the D614G mutation (an aspartic acid residue changes to the glycine residue at the 614th position of the protein) on 3089 sequences of the S gene despite having a mutation rate four times lower than that of the influenza virus. 

Antigenic Shift

This phenomenon is less frequent than antigenic drift in the influenza virus. It occurs when two different but related strains of a virus infects the host cell at the same time. These viruses then go on to “mate” through “reassortment” giving rise to a new subtype of the virus. This new subtype has a mixture of genomes from the original strains. Since a shift is happening, an immune response may not be ready to tackle this new subtype. These ‘chimeric’ viruses are most likely to trigger a pandemic. Coronaviruses cannot reassort themselves as their genome is just a singular long RNA strand. However, if two coronavirus strains were to infect an individual, the genomes undergo recombination and form a new RNA genome resulting in a ‘novel’ form of coronavirus. Although not as effective as the assortment process, newer coronavirus strains have the power to set off a pandemic. 

Nguyen et. al went on to sequence the genome of the SARS-CoV-2 virus to find out the possible mutation sites and these mutations can bring about a change in the structures of the surface proteins. They were also able to detect stable sites on the genome such which could be possible targets for vaccines and drugs. Active mutations indicate that the viruses have evolutionarily adapted themselves to the environment as compared to inactive mutations. Analysing the viral genome and mutation rates is significant in understanding the evolution of the SARS-CoV-2 virus and thereby proposing measures that can curb the pandemic.

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