Comparison of the mutational profile of Omicron with other SARS-CoV-2 lineages

Since coronavirus disease 2019 (COVID-19) first arose, it has spread to nearly every country worldwide, and many governments were forced to enact costly and restrictive measures to limit the spread of the disease. These included social distancing guidelines, mandatory face masks in public places, and even full lockdowns/stay-at-home orders. While many of these measures were dismantled following the development and mass administration of several vaccines, multiple countries have re-introduced them following the rise of several dangerous variants of concern (VOCs).

Study: Omicron variant of SARS-CoV-2 harbors a unique insertion mutation of putative viral or human genomic origin. Image Credit: PHOTOCREO Michal Bednarek/ShutterstockStudy: Omicron variant of SARS-CoV-2 harbors a unique insertion mutation of putative viral or human genomic origin. Image Credit: PHOTOCREO Michal Bednarek/Shutterstock

VOCs such as Delta and Omicron have mutations that allow them to evade both traditional and vaccine-induced immunity, as well as increased transmission rates. Researchers from nference labs in Massachusetts have been examining the origins of a particular mutation in the Omicron variant.

Most mutations arise in the spike protein, a homotrimeric transmembrane protein essential for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogenicity. It is formed of two subunits – S1, which contains a receptor-binding domain (RBD) that binds to angiotensin-converting enzyme 2 (ACE2) to permit viral cell entry, and S2, which is responsible for mediating membrane fusion. Most mutations of concern arise in the RBD, which is the target for most vaccines.

A preprint version of the study is available on the OSF Preprints* server while the article undergoes peer review.

The study

The researchers compared 37 spike protein mutations in the Omicron variant to other VOCs, discovering that 26 of these were distinct to Omicron and seven overlapped between Omicron and Alpha. Further comparing these mutations to variants of interest by examining mutations from over five million genomes that corresponded to 1523 lineages, the scientists discovered that at least one mutation, the insertion mutation ins214EPE, had not been previously observed in any SARS-CoV-2 lineage except for Omicron.

The EPE insertion on Omicron maps to the N-terminal domain distal from the antibody binding site, but the loop where the insertion is present does map to a known T-cell epitope. This could suggest that this particular mutation may help give rise to a level of T-cell immunity. While position 214 does appear to be an insertion hotspot, this particular mutation is novel. The researchers examined previous analyses of sequences deposited in GISAID and concluded that the insertions in this position of the SARS-CoV-2 genome are likely caused by polymerase slippage or template switching.

Recombination between different SARS-CoV-2 lineages has been observed before, especially in the spike protein. It has even been observed in the context of simultaneous co-infection. The scientists suggest that the ins214EPE mutation could potentially have been acquired by template switching either with other viruses infecting the same host cells or the human transcriptome of infected cells. As there has been previous evidence of simultaneous infection with SARS-CoV-2 and the seasonal coronavirus HCoV-229E, they searched the HCoV-229E genome for a similar nucleotide sequence that encodes for ins214EPE. They found an identical sequence in the spike protein.

Further examining single-cell RNA seq data, they could examine the receptors of both coronaviruses, which are expressed in both gastrointestinal and respiratory tissues. As this raises the possibility of the two viruses coming into contact during a co-infection, it raises the plausibility of the theory that SARS-CoV-2 may have acquired traits from HCoV-229E.

Another possibility is that the insertion mutation could have originated from the human genome of the host – and this has been observed before. Several fragments of the human genome and transcriptome harbor nucleotide sequences are identical to the coding sequence of the insertion mutation. Over 750 fragments are identical to the sequence, including the mRNAs of SLCA7 and TMEM245. Any of these transcripts expressed in cells that SARS-CoV-2 can infect could potentially be the origin of the ins214EPE mutation sequence.

Conclusion

The authors highlight that it is increasingly important to monitor the mutations arising within new SARS-CoV-2 variants, especially as vaccine inequity and vaccine hesitancy are increasingly being identified as contributing factors to the emergence of new variants. The need to sequence genomes from individuals with co-infections is becoming increasingly apparent. Hopefully, the information contained within this paper could help researchers create a warning system for early detection of new variants of concern based on their mutational profile and could help identify any changes caused by novel mutations before any new strains become dominant.

*Important notice

OSF Preprints publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
  • Venkatakrishnan, A., Anand, P., Lenehan, P., Suratekar, R., Raghunathan, B., Niesen, M. J., & Soundararajan, V. 2021. Omicron variant of SARS-CoV-2 harbors a unique insertion mutation of putative viral or human genomic origin. SF Preprints. doi: https://doi.org/10.31219/osf.io/f7txy https://osf.io/f7txy/
Sam Hancock

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Sam Hancock

Sam completed his MSci in Genetics at the University of Nottingham in 2019, fuelled initially by an interest in genetic ageing. As part of his degree, he also investigated the role of rnh genes in originless replication in archaea.

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