Omicron Variant Has Increased Transmission, Immune Evasion And Viral Replication Properties

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A new detailed international study of the genome of the Omicron variant and its mutations and location of mutation clusters has revealed that the Omicron’s Spike protein structure has accommodated significant sequence changes, likely in response to selective pressures favoring increased transmission, immune evasion, or viral replication-either at the population level or in a single or group of chronically infected individuals and has potentially acquired new functionality.

The study findings were published on the Virological.org site.

 https://virological.org/t/selection-analysis-identifies-significant-mutational-changes-in-omicron-that-are-likely-to-influence-both-antibody-neutralization-and-spike-function-part-1-of-2/771
 
https://virological.org/t/selection-analysis-identifies-significant-mutational-changes-in-omicron-that-are-likely-to-influence-both-antibody-neutralization-and-spike-function-part-2-of-2/772

The Omicron (B.1.1.529) SARS-CoV-2 variant of concern (VOC) identified in Southern Africa in late November 2021 is the product of extensive evolution within an infection context that has so far left no obvious traces of intermediate forms since it diverged from the B.1.1 lineage (presumably at some time in mid to late 2020).

Three possible explanations for the missing intermediates are: (1) SARS-CoV-2 sampling in Southern Africa between May and September 2021 might have been too sparse or biased to detect low frequency variants amongst high numbers of Delta variant infections during this time period; (2) long-term evolution in one or more chronically infected people – similar to the proposed origin of lineages such as Alpha and C.1.2 (1) 5 (2) 2 (3) 1 – where intermediate forms would have remained unsampled within the individual(s); and (3) a reverse zoonosis to a non-human host, followed by undetected spread therein, and a spillover back into humans.

At present there is no direct evidence to support or reject any of these hypotheses on the origin of Omicron, but as new data are collected, its origin may be more precisely identified.

Regardless of the route that Omicron took to eventual community transmission, its genome accumulated 53 mutations relative to the Wuhan-Hu-1 reference strain, with 30 non-synonymous substitutions in the Spike encoding S gene alone.

Here, we characterize the selective pressures that may have acted during the genesis of the Omicron variant and curate available phenotypic and genomic variation data associated with Omicron mutations.

We are particularly interested in comparing evolutionary patterns at sites where Omicron has differences from the Wuhan-Hu-1 reference genome, most other SARS-CoV-2 lineages (including variation of SARS-CoV-2 in individual hosts), and closely related non-human sarbecoviruses.

We use these comparisons to identify which Omicron mutations might contribute to transmission advantages, immune escape, or novel spike functionality. Our analysis identifies three clustered sets of mutations in the Spike protein, involving 13 amino acids that have previously been highly conserved across SARS-CoV-2 and other Sarbecoviruses.

This dramatic about-face in evolutionary dynamics at these 13 sites suggests that Omicron’s Spike protein structure has accommodated significant sequence change, likely in response to selective pressures favoring increased transmission,immune evasion, or viral replication – either at the population level or in a single or group of chronically infected individuals—and has potentially acquired new functionality.

Many of the Omicron S-gene mutations are likely contributors to viral adaptation

Relative to the Wuhan-Hu-1 reference variant of SARS-CoV-2, Omicron has 30 non-synonymous substitutions in its S-gene. Sixteen of the codon sites where these mutations occur are presently, or have recently been, detectably evolving under positive selection when considering all SARS-CoV-2 genomic data prior to the discovery of Omicron (Table 1, Figure 1, Examining natural selection history on global SARS-CoV-2 genomes enabled by data from / Sergei Pond / Observable 15).

For context, this fraction of positively selected sites (0.53) is approximately four times higher than the fraction of all SARS-CoV-2 S-gene sites that have ever shown any signals of positive selection (0.14).

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Figure 2. Distribution of Omicron amino acid replacements on the three dimensional SARS-CoV-2 Spike trimer. In this rendering of the trimer, one subunit is shown in the “up” or “open” configuration while interacting with human ACE2 (9). The other two subunits are in the “down” or “closed” configurations. Amino acids are color coded according to their likely contribution to viral adaptation in a Wuhan-Hu-1-like genetic background based on (1) patterns of synonymous and nonsynonymous substitutions at the codons encoding these amino acids in non-Omicron sequences, (2) patterns of mutational convergence between viruses in different VOCs and (3) increases in the frequency over time of VOC sub-lineages encoding amino acids that match those found in Omicron. NTD = N-terminal domain, RBD = Receptor binding domain; RBM = receptor binding motif. Locations of sites in the three clusters of Omicron mutations that are rarely seen and fall at either negatively selected (dark blue) and neutrally evolving (light blue) sites. An interactive version of this figure can be found here: SARS-CoV-2 ACE2/protein interaction and evolution for Omicron variant / Stephen Shank / Observable 14

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