COVID-19: Omicron Might Be A Recombined Virus Containing Bits Of Genetic Material From The Common-Cold Virus

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A new preprint study by researchers from nference labs in Bengaluru-India, Massachusetts-USA and Toronto-Canada suggest that the Omicron variant may be a recombined virus containing bits of genetic material from the common-cold virus.

The study team hypothesizes that the insertion mutation ins214EPE that has not been previously observed in any other SARS-CoV-2 lineage other than Omicron might have originated as a result of a recombination event involving the SARS-CoV-2 coronavirus and another common human coronavirus that causes the common cold.

The recombined events involving the SARS-CoV-2 virus and other viruses are easily to achieve and might point to other possible recombined strains emerging especially in human hosts inflicted with other viruses.

The study findings were published on a reprint server and are currently being peer reviewed. https://osf.io/f7txy/


Comparison of mutations in Omicron to previous SARS-CoV-2 lineages shows the presence of a unique insertion mutation in Omicron’s N-terminal domain (NTD)

The Omicron variant harbors 37 mutations in the Spike protein, which include six deletion mutations, one insertion mutation and 30 substitution mutations.18 16 of the 37 mutations are surge-associated mutations19 (Table 1), i.e. their mutational prevalence increased during any three-month window when COVID-19 cases surged.

Comparing these Spike protein mutations in Omicron with pre-existing variants of concern (Alpha, Beta, Gamma and Delta) shows that 26 mutations are distinct to Omicron and 7 mutations overlap between Omicron and Alpha (Figure 1).

Figure 1. Venn diagram depicting the overlap of lineage specific spike mutations in the SARS-CoV- 2 variants of concern. The unique key mutations observed in the spike protein for each of the variants are highlighted (spheres) on the homo-trimeric Spike protein of SARS-CoV-2. The B.1.1.529 (Omicron) variant has the highest number (26) of unique mutations in the spike protein from this perspective, making its emergence a “step function” in evolution of SARS-CoV-2 strains.

We analyzed whether any of the 26 Omicron mutations appeared in the prior variants of interest (Lambda, Mu, Eta, Iota and Kappa) or prior SARS-CoV-2 lineages by comparing with mutations from 5,382,852 genomes corresponding to 1523 lineages from the GISAID database (Table 1; Figure S1).

Interestingly, the insertion mutation ins214EPE (Figure S2) has not been previously observed in any SARS-CoV-2 lineage other than Omicron, whereas the substitution and deletions mutations have appeared in previous SARS-CoV-2 lineages (Table S1).


Figure 2. a. Potential mechanism of template switching leading to the generation of the ins214EPE in Omicron. Schematic representations show human body and human cells being infected by Omicron’s predecessor variant (blue) and a human coronavirus HCoV-229E (orange). The box shows the potential steps in the template switching involving the genomic RNA (+) of Omicron’s predecessor variant and the anti-genomic RNA (-) of HCoV-229E. The steps involving the anti-genomic RNA are shown inside a grey box. b. Comparison of nucleotides corresponding to the Omicron insert with a homologous match from HCoV 229E. Sequence alignment of the genomic regions corresponding to Omicron Spike and HCoV- 229E Spike are shown.

The EPE insertion on Omicron maps to the N-terminal domain (NTD) distal from the antibody binding supersite.9 However, the loop where the insertion is present maps to a known human T-cell epitope on SARS-CoV-2.20 Further studies will be necessary to understand whether this insertion may help SARS-CoV-2 escape T-cell immunity.10

Given the importance of the PRRA insertion giving rise to a polybasic FURIN cleavage site in the original SARS-CoV-2 strain, it is important to understand the functional significance and evolutionary origins of the ins214EPE insertion in the Omicron variant.11–14

Origin of insEPE in Omicron potentially due to template switching using genome of co-infecting viruses or host

The mutational burden of Omicron is higher in the Spike protein than the rest of the proteome (Figure S3). This highly mutated Spike variant harbors a novel insertion mutation ins214EPE. Although the position 214 appears to be an insertion hotspot10 the EPE insertion in Omicron appears to be novel.

Previous analyses of sequences deposited in GISAID suggested that insertions in the SARS-CoV-2 genome likely arise from polymerase slippage or template switching.10,21 Template switching is a normal event during RNA synthesis for coronaviruses, as this process is used to generate sub-genomic RNAs (sgRNAs).22,23

In this process, also known as copy-choice recombination, the RNA-directed RNA polymerase (RdRp) and the nascent strand dissociate from the template RNA strand and reassociate with a new template (or the same template at a different position), and then RNA synthesis continues. Typically, such recombination involves templates with high sequence similarity (“homologous recombination”), although non- homologous (or “illegitimate”) recombination between dissimilar sequences can also occur.24

Recombination between SARS-CoV-2 lineages in the context of simultaneous co-infection has been observed, with particularly high recombination rates seen in the Spike protein sequence.22,25 The ins214EPE could have been acquired by template switching involving the genomes of SARS-CoV-2, other viruses that infect the same host cells as SARS-CoV-2, or the human transcriptome of host cells infected with SARS-CoV-2.

Indeed, there have been clinical reports of COVID-19 patients also being infected with seasonal coronaviruses such as HCoV- 229E26. Searching the HCoV-229E genome for homology to a nucleotide sequence encoding ins214EPE shows the presence of an identical sequence in HCoV-229E’s Spike protein, which could have been exploited for template switching (Figure 2).

Furthermore, based on analysis of single cell RNA seq data (Table S2), we see that the receptors of SARS-CoV-2 (ACE2) and HCoV-229E (ANPEP) are co-expressed in gastrointestinal (e.g. enterocytes) and respiratory tissues (e.g. respiratory ciliated cells).

This gives rise to the plausibility of such cells in co-infected individuals being exploited as sites of genomic interplay between different viruses. In addition to co-infection with different coronaviruses, there have been reports of co-infection with SARS-CoV- 2 and other respiratory pathogens including non-SARS-CoV-2 Coronaviridae.27,28

It has been suggested previously that insertion mutations in the SARS-CoV-2 genomes could have originated from the human host genome29. Indeed, numerous fragments of the human genome and transcriptome harbor nucleotide sequences that are identical to the coding sequence of ins214EPE. There are over 750 fragments of the human genome with nucleotide sequences identical to the coding sequence of ins214EPE, which include mRNAs of SLCA7 and TMEM245 as top hits (Figure S4).

Of these, the transcripts that are expressed specifically in human host cells (e.g. alveolar cells, enterocytes)30 that are infected by SARS-CoV-2 could be candidates for the origin of the ins214EPE sequence. Thus, the evolution of the unique insertion in Omicron could have been based on template switching during viral co-infections, or from prevalent templates in the human genome.

Even as the production of COVID-19 vaccines is being scaled up, vaccine inequity and vaccine hesitancy have been speculated as contributors to the emergence of Omicron31,32.

Since achieving global vaccination could take years, it is important to vigilantly monitor the changing mutational landscape that could lead to the emergence of new SARS-CoV-2 variants. Indeed, even among the Omicron variants there are differences in the prevalence of the constituent mutations (Figure S1).

Finally, there is a need to sequence SARS-CoV-2 genomes from individuals with viral co-infections and in general to develop a “variant warning system” for early detection of variants of concern based on their mutational profile.


 
The sudden 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.
 
The study team 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.
 
Importantly whereas most of 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.
 
There have been recent clinical reports of co-infections in COVID-19 patients with seasonal coronaviruses (e.g. HCoV-229E). https://pubmed.ncbi.nlm.nih.gov/32293646/
 

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