Omicron variant of SARS-CoV-2 harbors a unique insertion mutation of putative viral or human genomic origin

Abstract

The emergence of a heavily mutated SARS-CoV-2 variant (B.1.1.529, Omicron) and it’s spread to 6 continents within a week of initial discovery has set off a global public health alarm. Characterizing the mutational profile of Omicron is necessary to interpret its shared or distinctive clinical phenotypes with other SARS-CoV-2 variants. We compared the mutations of Omicron with prior variants of concern (Alpha, Beta, Gamma, Delta), variants of interest (Lambda, Mu, Eta, Iota and Kappa), and all 1523 SARS-CoV-2 lineages constituting 5.4 million SARS-CoV-2 genomes. Omicron’s Spike protein has 26 amino acid mutations (23 substitutions, two deletions and one insertion) that are distinct compared to other variants of concern. Whereas the substitution and deletion mutations have appeared in previous SARS-CoV-2 lineages, the insertion mutation (ins214EPE) has not been previously observed in any SARS-CoV-2 lineage other than Omicron. The nucleotide sequence encoding for ins214EPE could have been acquired by template switching involving the genomes of other viruses that infect the same host cells as SARS-CoV-2 or the human transcriptome of host cells infected with SARS-CoV-2. For instance, given recent clinical reports of co-infections in COVID-19 patients with seasonal coronaviruses (e.g. HCoV-229E), single cell RNA-sequencing data showing co-expression of the SARS-CoV-2 and HCoV-229E entry receptors (ACE2 and ANPEP) in respiratory and gastrointestinal cells, and HCoV genomes harboring sequences homologous to the nucleotide sequence that encodes ins214EPE, it is plausible that the Omicron insertion could have evolved in a co-infected individual. There is a need to understand the function of the Omicron insertion and whether human host cells are being exploited by SARS-CoV-2 as an ‘evolutionary sandbox’ for host-virus and inter-viral genomic interplay.

Evidence for a mouse origin of the SARS-CoV-2 Omicron variant

“…For example, it was noted that Omicron harbored a nine-nucleotide insertion (GAGCCAGAA, encoding the peptide EPE) after residue 214 in the spike protein. This insertion is identical to the sequence of TMEM245 in the human genome or that of ORF S in the human coronavirus hCoV-229E, which was used as evidence to support a human origin for Omicron ( Venkatakrishnan et al, 2021 ). However, we provide a simpler explanation for this insertion, namely that it was derived from an RNA fragment of ORF N in the SARS-CoV-2 genome ( Fig.…”

Emergence of SARS-CoV-2 Omicron (B.1.1.529) variant, salient features, high global health concerns and strategies to counter it amid ongoing COVID-19 pandemic

“…Insertional mutation ins214EPE is found in Omicron only and is absent in any of the previous SARS-CoV-2 lineage. Possibly this insertion has arose due to template switching during co-infection in the same host cell with other or SARS-CoV-2 virus ( Venkatakrishnan et al, 2021 ). Recently, Wei et al (2021) proposed a theory of mice origin of Omicron.…”

“…If any direct relationship between the electrostatic potential and receptor affinity and infectivity persists, Omicron is anticipated to have more transmissibility and interact with other molecules like antibodies ( Pascarella et al, 2021b ). In-vivo studies must support this in-vitro data since the interaction between ACE2 and RBD is a complex process and is affected by the presence of several other mutations present in the spike protein, including a unique insertion at position 214 that might significantly affect the structure and function ( Venkatakrishnan et al, 2021 ). Cryo-EM structural analysis of the Omicron variant spike protein complexed with human ACE2 showed formation of new salt bridges and hydrogen bonds involving the mutations at R493, S496 and R498 in RBD.…”

Viral Load in COVID-19 Patients: Implications for Prognosis and Vaccine Efficacy in the Context of Emerging SARS-CoV-2 Variants

“…Among the mutations, an insertion (ins214EPE) in spike that was not been previously observed in other SARS-CoV-2 variants (140). It has been hypothesized that this insertion could have been acquired by template switching involving the genome of a low pathogenic coronavirus which can cause the common cold: HCoV-229R (140). A recent study has been estimated that the omicron variant is least ten times more infectious than the wild-SARS-CoV-2 and about twice as infectious as the delta variant (87).…”

“…The omicron VOC is a heavily mutated SARS-CoV-2, with 30 amino acid substitutions, deletion of six residues, and insertion of three residues in the spike protein, mostly concentrated around the receptor binding motif (88). Among the mutations, an insertion (ins214EPE) in spike that was not been previously observed in other SARS-CoV-2 variants (140). It has been hypothesized that this insertion could have been acquired by template switching involving the genome of a low pathogenic coronavirus which can cause the common cold: HCoV-229R (140).…”