Genomic variant analysis of SARS-Co V-2 macrodomain from globally sampled population of virus.

Abstract

The outbreak of COVID-19 caused by SARS-Co V -2 originated in Wuhan, China in December 2019, has exacerbated human health across the globe by evolving into multiple waves. Since the SARS-CoV-2 is an RNA virus, it is constantly evolving and producing new varieties by changing the makeup of key component proteins, underlying different etiological effects. Though the pandemic has been over, understanding how the genetic variability of viral genome affects the innate immune response of host is critical. Since viral macrodomains within nsp3 of coronaviruses are prone to dysregulate host's ilmate immune response, this study has been designed to elucidate the impact of stmctural evolution ofnsp3 encoded macrodomain 1 on the pathogenicity of virus. Using stmctural analysis, we recapitulate the amino acid substitution that are found in macro domain encoded by nsp3 SARS-CoV-2 strains retrieved across the globe from December 2019 to May 2023. These substitutions may alter protein confonnation thereby, reducing the SARS-CoV-2 ability to inhibit host immune response. Furthennore, we hypothesized that the decreased virulence of variants is potentially the consequence of the epistatic effect of the mutation. We depict that the mutation in macrodomain-1 reduces the pathogenicity and virulence of SARS-Co V -2 due to its role in reversing the ADP-ribosylation, which counteracts the host's innate immunity. The most occurred (S370L) and least occurred (L214S) mutations of Macrodomain-1 may contribute to understanding the disease pathogenesis of future pandemics at the molecular level.