Translation-Associated Mutational U-Pressure in the First ORF of SARS-CoV-2 and Other Coronaviruses

Abstract

Within 4 months of the ongoing COVID-19 pandemic caused by SARS-CoV-2, more than 250 nucleotide mutations have been detected in ORF1ab of the virus isolated from infected persons from different parts of the globe. These observations open up an obvious question about the rate and direction of mutational pressure for further vaccine and therapeutics designing. In this study, we did a comparative analysis of ORF1a and ORF1b by using the first isolate (Wuhan strain) as the parent sequence. We observed that most of the nucleotide mutations are C to U transitions. The rate of synonymous C to U transitions is significantly higher than the rate of non-synonymous ones, indicating negative selection on amino acid substitutions. Further, trends in nucleotide usage bias have been investigated in 49 coronaviruses species. A strong bias in nucleotide usage in fourfold degenerate sites toward uracil residues is seen in ORF1ab of all the studied coronaviruses: both in the ORF1a and in the ORF1b translated thanks to the programmed ribosomal frameshifting that has an efficiency of 14 – 45% in different species. A more substantial mutational U-pressure is observed in ORF1a than in ORF1b perhaps because ORF1a is translated more frequently than ORF1b. Mutational U-pressure is there even in ORFs that are not translated from genomic RNA plus strands, but the bias is weaker than in ORF1ab. Unlike other nucleotide mutations, mutational U-pressure caused by cytosine deamination, mostly occurring during the RNA plus strand replication and also translation, cannot be corrected by the proof-reading machinery of coronaviruses. The knowledge generated on the mutational U-pressure that becomes stronger during translation of viral RNA plus strands has implications for vaccine and nucleoside analog development for treating COVID-19 and other coronavirus infections.

Stability of SARS-CoV-2 phylogenies

“…Hypermutation rather than positive selection may explain many remaining highly recurrent sites. Previous analyses have indicated that the number of C>U mutations is exceptionally high relative to other mutation types in the viral genome [11,26,45,49]. This class of mutations should show increased evidence of recurring multiple times because they experience elevated mutation rates [26].…”

“…Extremely rapid whole-genome sequencing has enabled nearly real-time tracing of the evolution of the SARS-CoV-2 pandemic [1][2][3][4][5][6]. By leveraging sequence data produced by labs throughout the world, researchers can trace the transmission of the virus across human populations [7][8][9][10][11][12][13][14][15]. Typically, viral evolution is encapsulated by a phylogenetic tree relating all of the virus samples in a large set to one another [6,[16][17][18][19][20].…”

Binding affinity improvement analysis of multiple-mutant Omicron on 2019-nCov to human ACE2 by In-silico predictions

“…In addition, this variant has 3 mutations on the Membrane site. The ORF1b and Nucleocapsid region also have 11 and 4 mutation sites respectively [19]. The Spike protein play a critical role in identifying and binding the host cell surface receptors, and mediating the fusion of viral envelope to the cell membrane.…”

Coronavirus, the King Who Wanted More Than a Crown: From Common to the Highly Pathogenic SARS-CoV-2, Is the Key in the Accessory Genes?

“…These transitions, mostly occurring during the RNA plus strand replication and translation, cannot be corrected by the proof-reading machinery of coronaviruses. Thus, this leads to amino-acid (a.a) substitutions that can be quite drastic for the fitness of a virus or may help the virus to escape the immune response (Di Giorgio et al, 2020;Khrustalev et al, 2020;Ratcliff and Simmonds, 2021). Third, coronaviruses have the capacity to undergo both inter-molecular recombination between 2 distinct molecules and intra-molecular recombination within the same molecule.…”