Comparative Analysis of SARS-CoV-2 Variants of Concern, Including Omicron, Highlights Their Common and Distinctive Amino Acid Substitution Patterns, Especially at the Spike ORF

In order to gain a deeper understanding of the recently emerged and highly divergent Omicron variant of concern (VoC), a study of amino acid substitution (AAS) patterns was performed and compared with those of the other four successful variants of concern (Alpha, Beta, Gamma, Delta) and one closely related variant of interest (VoI-Lambda). The Spike ORF consistently emerges as an AAS hotspot in all six lineages, but in Omicron this enrichment is significantly higher. The progenitors of each of these VoC/VoI lineages underwent positive selection in the Spike ORF. However, once they were established, their Spike ORFs have been undergoing purifying selection, despite the application of global vaccination schemes from 2021 onwards. Our analyses reject the hypothesis that the heavily mutated receptor binding domain (RBD) of the Omicron Spike was introduced via recombination from another closely related Sarbecovirus. Thus, successive point mutations appear as the most parsimonious scenario. Intriguingly, in each of the six lineages, we observed a significant number of AAS wherein the new residue is not present at any homologous site among the other known Sarbecoviruses. Such AAS should be further investigated as potential adaptations to the human host. By studying the phylogenetic distribution of AAS shared between the six lineages, we observed that the Omicron (BA.1) lineage had the highest number (8/10) of recurrent mutations.

Automated summary

In order to understand the Omicron variant of concern better, a study of amino acid substitution patterns was conducted and compared with other variants of concern. The Spike ORF was identified as a hotspot for amino acid substitutions in all lineages, with Omicron showing a significantly higher enrichment. Despite global vaccination efforts, the Spike ORFs in these variants have been undergoing purifying selection. Interestingly, a significant number of amino acid substitutions in all lineages were not present in other known Sarbecoviruses, suggesting potential adaptations to the human host. The Omicron lineage showed the highest number of recurrent mutations among the six lineages studied.