GWAS identifies more SARS-CoV-2 variants

Souradip Mallick, National Institute of Technology, Rourkela

The SARS-CoV-2 virus has mutated very frequently over time that resulted in genetic variation of circulating viral strains throughout the COVID-19 pandemic. Viral mutations can enhance virulence as well as transmissibility in humans. It affects the antigen and serology tests due to the inherent design differences of each test. Thus genome sequencing of each locus of the single-stranded RNA of the SARS-CoV-2 virus is very crucial for understanding the direct association with host/patient mortality.

In the analysis of SARS-CoV-2, it has been detected that the mutation at 25,088 bp occurs in the spike glycoprotein, which mediates viral attachment and cellular entry. The entry of SARS-CoV-2 into the host cells is mediated by spike glycoprotein (S protein) consisting of two functional subunits: S1, the receptor-binding domain, and S2 that fuse the viral membrane to the host cellular membrane. The mutation at 25,088 bp is in the S2 subunit and is cleaved by host proteases to activate membrane fusion. Also, the V1176F mutation in S2 is located in the Heptad repeat 2 domain, which is involved in the viral fusion machinery. The proteolysis cleavage causes the distinct furin cleavage site present in the SARS-CoV-2 S1/S2 site which is not found in SARS-CoV. This cleavage site can increase infectivity through enhanced membrane fusion activity. Consequently, mutations at these sites can alter the virulence by disrupting the multibasic nature of the S1/S2 site, thus affecting SARS-CoV-2 membrane fusion and entry into human lung cells. The enhanced infectivity does not always relate to a higher fatality rate. More infectious viruses can increase the viral load, which can impact symptom severity.

All carriers of a mutation at 25,088 bp exhibit a G to T missense mutation resulting in the change of amino acid from valine to phenylalanine. The phenylalanine has a bulkier aromatic structure than valine, resulting in structural constraints, stabilizing particular secondary structures, or introducing specific interactions which lead to preferential binding. The emergence of a more aggressive P.1 lineage having this mutation was responsible for the second wave of infection.

The mutation at 12,053 bp takes place within the ORF1ab gene, which expresses a polyprotein comprised of 16 nonstructural proteins. The mutation at 12,053 bp dimerizes NSP7 with NSP8 to form a heterodimer that complexes with NSP12 which is essential for genome replication and transcription. Also, the mutation at 12,053 bp exhibits a C to T missense mutation, the substitution of leucine phenylalanine resulting in structural rigidity which could alter the interactions with other components of replication and transcription machinery.

Genome-Wide Association Studies (GWAS) methodology is a tool for the early detection of new viral strains in global database systems such as GISAID, which contains the viral genomes with the meta/clinical information about the host. Moreover, GWAS methodology would be suitable to analyze the highly correlated viral genomes as the GWAS approach can simultaneously handle different subpopulations with different proportions. However, there are some limitations to applying GWAS methodology. More transmissible variants can alter the mutation frequencies and increase the case/control ratio. The vaccination or taking targeted monoclonal antibodies may exert immunologic pressure on the virus leading to selective viral evolution.

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References:  

1. Hahn, G., Wu, C. M., Lee, S., Lutz, S. M., Khurana, S., Baden, L. R., Haneuse, S., Qiao, D., Hecker, J., DeMeo, D. L., Tanzi, R. E., Choudhary, M. C., Etemad, B., Mohammadi, A., Esmaeilzadeh, E., Cho, M. H., Li, J. Z., Randolph, A. G., Laird, N. M., Weiss, S. T., … Lange, C. (2021). Genome-wide association analysis of COVID-19 mortality risk in SARS-CoV-2 genomes identifies mutation in the SARS-CoV-2 spike protein that colocalizes with P.1 of the Brazilian strain. Genetic epidemiology, 10.1002/gepi.22421. Advance online publication. https://doi.org/10.1002/gepi.22421

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