Mutational spectra of SARS-CoV-2 orf1ab polyprotein and signature mutations in the United States of America

Abstract

The pandemic COVID-19 outbreak has been caused due to SARS-CoV-2 pathogen, resulting in millions of infections and deaths worldwide, the United States being on top at the present moment. The long, complex orf1ab polyproteins of SARS-CoV-2 play an important role in viral RNA synthesis. To assess the impact of mutations in this important domain, we analyzed 1134 complete protein sequences of the orf1ab polyprotein from the NCBI virus database from affected patients across various states of the United States from December 2019 to 25 April 2020. Multiple sequence alignment using Clustal Omega followed by statistical significance was calculated. Four significant mutations T265I (nsp 2), P4715L (nsp 12), and P5828L and Y5865C (both at nsp 13) were identified in important nonstructural proteins, which function either as replicase or helicase. A comparative analysis shows 265 T→I, 5828 P→L, and 5865Y→C are unique to the United States and not reported from Europe or Asia; while one, 4715 P→L is predominant in both Europe and the United States. Mutational changes in amino acids are predicted to alter the structure and function of the corresponding proteins, thereby, it is imperative to consider the mutational spectra while designing new antiviral therapeutics targeting viral orf1ab.

Keywords: COVID-19; ORF1ab polyprotein; SARS-CoV-2; United States of America; mutational spectra; pandemic.

Figure 1

Mutational hotspots and the corresponding variants found in different geographical regions of the United States

Figure 2

Mapping of orf1ab polyprotein and four signature mutations of the United States

Figure 3

Structural comparison of nsp 2, nsp 12, and nsp 13 by superimposing the mutant structure over the wild type; (A) mutant nsp2 with corresponding wild type; (B) mutant nsp12 with corresponding wild type and (C) mutant nsp13 with corresponding wild type, compared through superimposition