SARS-CoV-2 genomic surveillance identifies intricacies of stabilizing vs. destabilizing mutations

The rapid outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for millions of infections and deaths worldwide. The emergence of this RNA virus was first reported in 2019 in Wuhan, China, and within a very short period, it spread to 220 countries and territories across the globe.

The development of vaccines and therapeutics has reduced the mortality rate. However, the continual emergence of SARS-CoV-2 variants has called into question the efficacy of the available vaccines.

Some of these variants, known as variants of concern (VoC), have a much higher rate of transmission and increased mortality than the original SARS-CoV-2 strain. Therefore, it is imperative to assess the efficacy of the available vaccines against the circulating SARS-CoV-2 strains. In addition, tracking the continuously evolving genetic variants is also vital to prevent future outbreaks.

Tracking the evolution of transmissibility and virulence of SARS-CoV-2

The evolution of transmissibility and virulence of SARS-CoV-2 has occurred due to functional mutations. These mutations help viruses to adapt to the changes in the host. For example, owing to these mutations, the virus can evade the host’s immune system. Therefore, evaluating the changes in the genetic sequences is vital to determine the evolutionary distance and stability of SARS-CoV-2 variants from the sequence of the original strain isolated in Wuhan.

Owing to the availability of the whole-genome sequences of the virus in public repositories, such as the Global Initiative on Sharing All Influenza Data (GISAID), and the collection of open-source tools for instantaneous visualization of the genetics behind the virus outbreak, e.g., NextStrain, scientists have been able to track the evolutionary path of this virus.

Phylogenetic Assignment of Named Global Outbreak LINeages tool (PANGOLIN) is widely used to track down the lineage of newly emerging variants. In the current scenario, tracking the evolution and assigning lineages to SARS-CoV-2 variants has been difficult because of frequent mutations. A detailed map of mutations, with their potential role, can help develop therapeutics and vaccines to combat the circulating strain. This could also help prevent and prepare for future waves due to transmission of SARS-CoV-2 VoC.

A new study published in the journal mBio has developed a catalog comprising the most important SARS-CoV-2 genomic mutations recorded between December 2019 and November 2020. The authors of this study have also highlighted the possible impact of these mutations on the stability of protein candidates based on which the vaccines and therapeutics have been designed.  

Mapping of mutations and their consequences

The researchers of this study have developed a phylogenetic tree including 513 genomes that have been purposefully selected to reflect the genomic diversity of the virus covering all the PANGOLIN lineages. They found a total of 61 lineages and sublineages of SARS-Cov-2 circulating concurrently in many countries around the world.

The mutation mapping of the 513 genomes showed a total of 106 amino acid substitutions. This study revealed 36 mutations in >5% of genome sequences with 12 major substitutions that have been regarded as lineage-defining mutations. In 8.6% of the genomes, L84S in ORF8 appeared and was considered to be the first significant mutation. The amino acid substitution in 13.3% of genomes was found to be L37F in ORF3a, and in 1.4% of genomes was G251V in nsp6.

In late January 2020, predominant lineage-defining mutations in the whole data set were reported to be D614G and P323L. These two mutations were found in nsp12 of SARS-CoV-2. The sequences with these mutations were designated as B.1 lineage. Several other mutations have been reported as the pandemic has progressed. Amino acid substitutions found at T428I and G15S in ORF1a have been designated as the sublineage C.1 and C.2, whereas the S477N substitution in the spike (S) protein and I120F in nsp2 are known to be the sublineage D.2.

The current study analyzed the structural consequences after the 11 clade-defining mutations. Among these mutations, three were found to stabilize the respective protein structures, while six mutations were destabilizing. The researchers have traced 4,170 missense mutations in the spike protein, with 683 on the RBD domain alone. The authors of the current study revealed an intriguing balance of stabilizing and destabilizing mutations. Such a balance could be the reason behind the evolution of SARS-CoV-2 without losing its pathogenicity.

Significance of the study

This study highlights the significance of persistent genomic surveillance, mutation mapping, and cataloging of potential mutations during pre-and post-vaccination periods. This should help in developing, epidemiologically, the best vaccination programs. The tracking of the evolution of the virus revealed an overall low variation of SARS-CoV-2 sequences when compared to other RNA viruses. This might be due to the low mutation rate for the lack of neutralizing antibodies or the selective pressure. However, an increase in vaccination programs and the use of monoclonal antibodies therapeutics will challenge the virus population. This will lead to rapid structural mutations for their survival. These mutations must be monitored to prevent future outbreaks.

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