The storm after the calm: the alpha, beta and gamma variants of SARS-CoV-2 are converging on similar adaptive endpoints

2 Aug 2021 - 09:15

The SARS-CoV-2 genome was relatively unchanging during the first eleven months of the current pandemic. However, this quiescent period ended in late 2020 when three variants—alpha, beta and gamma—emerged in rapid succession. All three have multiple signature deletions and amino acid changes, many of which impact key domains of the spike protein, and all three share a change in the receptor binding domain of the spike protein at position 501, where the amino acid asparagine (N) has been replaced with tyrosine (Y). The spike protein is the primary target of both infection- and vaccine-induced immune responses.

While alpha, beta and gamma characteristically share the N501Y change, many versions of these variants share other changes and deletions, such as the E484K change, and a deletion between genomic coordinates 11288-11296, shared by versions of all three variants.

The shared constellation of changes appears to have arisen independently in all three variants, which suggests that these changes are advantageous. CIDRI-Africa Contributing Investigator Associate Professor Darren Martin and colleagues employed a suite of phylogenetics-based natural selection analysis techniques to examine patterns of positive selection acting on these three variants and identified the specific mutations that are at present most likely contributing to this increased adaptation. The pre-print describing their results and analysis was recently posted to medRxiv.

Through their analyses, the team were able to compute an “ideal constellation” (or “meta-signature”) of the most adaptive amino acid states at 35 sites within the SARS-CoV2 genome. When comparing real-world sequences with the computed ideal constellation, the team found that before March 2021 most versions of the alpha, beta and gamma variants respectively carried 10, 13 and 11 of the mutations of this ideal constellation. By the 1st of June 2021, 17 different versions of the alpha variant matched 13 of the ideal constellation sites, two different versions of the beta variant matched 16 of the sites, and one version of the gamma variant matched 14 of the sites. Versions of all three variants were circulating that had taken three additional mutational steps to converge on the computed ideal constellation.

The team anticipate that the ongoing evolutionary convergence of the alpha, beta and gamma variants will yield a succession of new variants possessing increasing subsets of the ideal constellation mutations. The convergent mutations that are continuing to arise, both in the alpha, beta and gamma variants and those of other SARS-CoV-2 lineages such as B.1.620, B1.621 and B1.526, imply that all these viruses are presently on, and are actively scaling, the same broad peak in the fitness landscape. Any SARS-CoV-2 variant eventually summiting that peak might have any combination of increased transmissibility, altered virulence and/or increased capacity to escape population immunity.

 

Preprint:

Martin DP, Weaver S, Tegally H, et al. The emergence and ongoing convergent evolution of the N501Y lineages coincides with a major global shift in the SARS-CoV-2 selective landscape. medRxiv 2021: 2021.02.23.21252268.

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