Periodically aperiodic pattern of SARS-CoV-2 mutations underpins the uncertainty of its origin and evolution

Abstract

Various lineages of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have contributed to prolongation of the coronavirus disease 2019 (COVID-19) pandemic. Several non-synonymous mutations in SARS-CoV-2 proteins have generated multiple SARS-CoV-2 variants. In our previous report, we have shown an evenly uneven distribution of unique protein variants of SARS-CoV-2 is geo-location or demography-specific. However, the correlation between the demographic transmutability of the SARS-CoV-2 infection and mutations in various proteins remains unknown due to hidden symmetry/asymmetry in the occurrence of mutations. This study tracked how these mutations are emerging in SARS-CoV-2 proteins in six model countries and globally. In a geo-location, considering the mutations having a frequency of detection of at least five hundred in each SARS-CoV-2 protein; we studied the country-wise percentage of invariant residues. Our data revealed that since October 2020, highly frequent mutations in SARS-CoV-2 have been observed mostly in the Open Reading Frames (ORF) 7b and ORF8, worldwide. No such highly frequent mutations in any of the SARS-CoV-2 proteins were found in the UK, India, and Brazil, which does not correlate with the degree of transmissibility of the virus in India and Brazil. However, we have found a signature that SARS-CoV-2 proteins were evolving at a higher rate, and considering global data, mutations are detected in the majority of the available amino acid locations. Fractal analysis of each protein's normalized factor time series showed a periodically aperiodic emergence of dominant variants for SARS-CoV-2 protein mutations across different countries. It was noticed that certain high-frequency variants have emerged in the last couple of months, and thus the emerging SARS-CoV-2 strains are expected to contain prevalent mutations in ORF3a, membrane, and ORF8 proteins. In contrast to other beta-coronaviruses, SARS-CoV-2 variants have rapidly emerged based on demographically dependent mutations. Characterization of the periodically aperiodic nature of the demographic spread of SARS-CoV-2 variants in various countries can contribute to the identification of the origin of SARS-CoV-2.

Understanding the Role of SARS-CoV-2 ORF3a in Viral Pathogenesis and COVID-19

“…Continued mutations of S protein are of major concern as they alter the ability of the virus to transmit, infect and cause COVID-19 ( Chakraborty et al, 2021 ; Changrob et al, 2021 ). Continued emergence of ORF3a protein variants might also be of concern as its mutations could affect its role in viral pathogenesis, severity of COVID-19, and contribution to post-COVID conditions as described above ( Majumdar and Niyogi, 2020 ; Hassan et al, 2021 ; Nagy et al, 2021 ). Using the first SARS-CoV-2 virus isolated from Wuhan, China as a reference sequence ( Wu et al, 2020 ), continual monitoring and comparison of genome sequences in the GISAID database collected worldwide since the onset of the pandemic has revealed a large numbers of natural non-synonymous mutations of SARS-CoV-2 ORF3a that span throughout the entire protein ( Issa et al, 2020 ; Azad and Khan, 2021 ; Bianchi et al, 2021 ; Nagy et al, 2021 ).…”

“…Trending of viral protein mutation frequencies among SARS-CoV-2 that are circulating worldwide showed an overall decline of mutation frequency of ORF3a over time ( Hassan et al, 2021 ). The significance of this decline in viral pathogenesis and ORF3a evolution is unclear.…”

Structural Dynamics of the SARS-CoV-2 Spike Protein: A 2-Year Retrospective Analysis of SARS-CoV-2 Variants (from Alpha to Omicron) Reveals an Early Divergence between Conserved and Variable Epitopes

“…SARS-CoV-2 evolution has been extensively studied by computational approaches [44,[57][58][59][60][61][62]. Our retrospective analysis of SARS-CoV-2 variants revealed an early divergence between conserved (ADE) and variable (neutralizing) epitopes which is based on their localization on the spike protein.…”

Unique truncated and non-synonymous mutations in functional domains of ORF3a SARS-CoV-2

“…These mutations in C148Y and A143S may increase the infectivity rate, even though these amino acid changes were neutral based on Provean score. 23 Domain V is responsible for Golgi to plasma membrane transport, and mutations in this site made ORF3a protein to be aggregated. It has a bulky hydrophobic residue YNSV, 160-163.…”

“…It has a bulky hydrophobic residue YNSV, 160-163. 3,9,23 Mutations at position 161 of asparagine (N)  serine (S) and position 163 of valine (V)  leusine (L) are deleterious although they do not change the polarity of amino acids. 3 Domain VI is a di-acidic peptide that has an SGD motif that is not conserved in SARS-CoV-2.…”