Deleterious Mutation

Variant-specific deleterious mutations in the SARS-CoV-2 genome reveal immune responses

Coronavirus disease 2019 (COVID-19),(COVID-19), caused by SARS-CoV-2, has had a disastrous effect worldwide during the previous two years due to widespread infections with SARS-CoV-2 and its emerging variations.

Figure 1. Most significant two mutations of spike proteins of delta variant with a comparative overview of molecular interaction (A) V915S-chain A-absence of 9 hydrophobic bonds, 2 polar bonds, and 1 Vander Waals bond in the mutein. Chain B- the absence of 9 hydrophobic bonds, 1 polar bond, and 1 Vander Waals bond in the mutein. Chain C- absence of 9 hydrophobic bonds, 1 polar bond, and 1 Vander Waals bond in the mutein. (B) L916S-chain A-the absence of 12 hydrophobic bonds in the mutein. Chain B- absence of 17 hydrophobic bonds, increase of 3 polar bonds and 1 hydrogen bond, decrease of clash in the mutein. Chain C- the absence of around 10 hydrophobic bonds, 1 carbonyl bond, and 1 clash in the mutein. Clashes are defined as unfavorable interactions where atoms are too close together.

More than 650 million confirmed cases and over 6.6 million deaths have been attributed to successive waves of SARS-CoV-2 infections as of 07th December 2022. Similar to other RNA viruses, SARS-CoV-2 is more susceptible to genetic evolution and spontaneous mutations over time, resulting in the continual emergence of variants with distinct characteristics. Spontaneous mutations of SARS-CoV-2 variants increase its transmissibility, virulence, and disease severity and diminish the efficacy of therapeutics and vaccines, resulting in vaccine-breakthrough infections and re-infection, leading to high mortality and morbidity rates.

Figure 2. Comparison of the B cell epitope for spike (S) protein of SARS-CoV-2 Delta variant. (A) B cell epitope prediction score from 100 to 400 amino acids (aa) of the S protein. (B) B cell epitope prediction score from 400 to 650 aa of the S protein. (C) B cell epitope prediction score from 720 to 900 aa of S protein. (D) B cell epitope prediction score from 900 to 1050 aa of the S protein. (E) B cell epitope prediction score from 1150 to 1280 aa of the S protein.

In this study, we evaluated 10,531 full genome sequences of all reported variants globally through a computational approach to assess the spread and emergence of the mutations in the SARS-CoV-2 genome. The publically available data sources of NextCladeCLI 2.3.0 (https://clades.nextstrain.org/) and NextStrain (https://nextstrain.org/) were searched for tracking SARS-CoV-2 mutations, analyzed using the PROVEAN, Polyphen, and Predict SNP mutational analysis tools and validated by Machine Learning models. Compared to the Wuhan-Hu-1 reference strain NC 045512.2, genome-wide annotations showed 16,954 mutations in the SARSCoV-2 genome. We determined that the Omicron variation had 6,307 mutations (retrieved sequence:1947), including 67.8% unique mutations, more than any other variant evaluated in this study.

Figure 3. Comparison of common and unique deleterious mutation patterns in different variants. (A) Frequency of top common deleterious mutations of different proteins in twelve variants. (B) Deleterious mutation score of common mutations. (C) Frequency of top unique deleterious mutations of different proteins in twelve variants. (D) Deleterious mutation score of unique mutations.

The spike protein of the Omicron variant harbored 876 mutations, including 512 unique and 443 deleterious mutations. Among these deleterious mutations, 187 were common and 256 In review were unique non-synonymous mutations. In contrast, after analyzing 1,884 sequences of the Delta variant, we discovered 4,468 mutations, of which 66% were unique, and not previously reported in other variants. Mutations affecting spike proteins are mostly found in RBD regions for omicron whereas most of the delta variant mutations drawn focus on amino acid regions ranging from 911 to 924 in the context of B cell epitope prediction, T cell epitope prediction, and mutational stability impact analysis protruding that omicron is more transmissible. The pathogenesis of the Omicron variant could be prevented if the deleterious and persistent unique immunosuppressive mutations can be targeted for vaccination or small-molecule inhibitor designing. Thus, our findings will help researchers to monitor and track the continuously evolving nature of SARS-CoV-2 strains, the associated genetic variants, and their implications for the development of effective control and prophylaxis strategies.