Impact of clustered mutations in SARS-CoV-2 Omicron spike function

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In a recent study posted to the bioRxiv* preprint server, researchers explored the characteristics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant of concern (VOC) Omicron BA.1 sublineage clustered mutations.

Study: Selection analysis identifies unusual clustered mutational changes in Omicron lineage BA.1 that likely impact Spike function. Image Credit: Naeblys/Shutterstock


Compared to the SARS-CoV-2 Wuhan strain, the Omicron BA.1 sublineage has 30 non-synonymous mutations in its spike (S)-gene region and 13 mutations that have only rarely been seen in other SARS-CoV-2 sequences. These mutations in the S-gene of the three cluster regions of the SARS-CoV-2 BA.1 affect the interactions of S with angiotensin-converting enzyme 2 (ACE2), priming of S for membrane fusion, and interactions between subunits of the S trimer and the predisposition of subunits to shift from down to up configurations.

Due to the rapid increase in the number of Omicron cases, it is of prime importance to understand the complexity and adaptivity of mutations in the S-gene of the Omicron variant. Moreover, it is also crucial to determine the reason for the undetected early stages of the Omicron assembly, despite the global genomic surveillance effort.

The study

In the present study, the researchers explored the chances of prediction of mutations in Omicron before their emergence based on the rarity of the 13 mutations in intrapatient sequencing and patterns of selection at the codon sites where mutations develop in SARS-CoV-2 and other related sarbecoviruses. The team further demonstrated the interactions and adaptivity of the S-gene mutations among the three cluster regions in Omicron.


The results indicated that the S-gene mutations in the Omicron BA.1 are responsible for viral adaptability. The Omicron variant has a positive selection across 16 codon sites where the mutations occur with a fraction of 0.53 compared to the fraction of 0.14 in the SARS-CoV-2 genomic data before the detection of Omicron.

The Omicron BA.1 mutation at the 14 S codons showed either no evidence of selection or evidence of negative selection, which was rare in the previously screened SARS-CoV-2 sequences. However, these mutations are not commonly seen within-patient sequence datasets at sub-consensus allelic frequencies. By themselves, none of the 14 BA.1 mutations at the S codon site imparted any advantage to SARS-CoV-2.

In the nCoV clade with sarbecoviruses that closely resemble SARS-CoV-2, out of the 44 codon sites, one had the positive selection and 26 had been evolving under the negative selection. The eight cluster sites – cluster one sites S/373, S/339, S/375, cluster two site S/505, cluster three sites S/856, S/981, S/969, and S/764 – were under negative selection in the nCoV clade viruses, and the Wuhan-Hu-1 encoded amino acid state being favored at all sites.

Further, two of the remaining five cluster sites –  S/371 and S/954 – were not under negative selection in the nCoV clade and encoded the Wuhan-Hu-1 amino acid state in all sarbecoviruses. The cluster two sites – S/498, S/493, and S/496 – varied substantially across the sarbecovirus subgenus.    

The positive selection was associated with simultaneous changes at codons S/505H and S/493R, and they exhibited higher combined viral fitness than their individual effects termed as positive epistasis. During the co-occurrence of mutations at the cluster site one, two, and three, they interact with each other and become adaptive. Co-evolution was detected in six pairs of the three cluster sites in the 135247 BA.1 annotated S-gene sequences.

The S mutations in the cluster three regions that are responsible for the membrane fusion indicate that the BA.1 S’s membrane fusion machinery has been modified. Further, the mutations in the cluster one and two regions of BA.1 contribute to the changes in the S interaction with human and animal ACE2.

The existence of only three distinct Omicron lineages supports the surveillance failure hypothesis, that is, the Omicron progenitor might have existed during their prolonged evolution in an area with minimal genomic surveillance or poor access to healthcare.

Many instances of reversions of mutations were seen in the three cluster regions of the Omicron BA.1 sublineage. However, the number of reversion mutations in the S-gene at the three cluster regions of BA.1 was not higher than those present at other BA.1 lineage-defining mutation sites.


The study highlighted the concerning presence of epistatically interacting mutations in the three cluster regions of the SARS-CoV-2 BA.1 sublineage. The emergence of Omicron was a surprise due to the underestimation of SARS-CoV-2’s evolutionary capacity.

Moreover, balancing of various fitness trade-offs is evident in the evolution of the SARS-CoV-2 Omicron BA.1 sublineage, such as trade-offs between immune escape and affinity for ACE2 and between preferred tropism for cells in the lower and upper respiratory tracts. However, the mutations present in the BA.1 sublineage have tilted the balancing of these trade-offs, leading to a reduction in SARS-CoV-2 disease severity in humans. Further, the authors warn that this lowered disease severity may not necessarily be associated with the VOCs succeeding BA.1.

*Important notice

bioRxiv 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.

Source: News Medical

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