Perspectives: SARS-CoV-2 Spike Convergent Evolution as a Guide to Explore Adaptive Advantage

Abstract

Viruses rapidly co-evolve with their hosts. The 9 million sequenced SARS-CoV-2 genomes by March 2022 provide a detailed account of viral evolution, showing that all amino acids have been mutated many times. However, only a few became prominent in the viral population. Here, we investigated the emergence of the same mutations in unrelated parallel lineages and the extent of such convergent evolution on the molecular level in the spike (S) protein. We found that during the first phase of the pandemic (until mid 2021, before mass vaccination) 31 mutations evolved independently ≥3-times within separated lineages. These included all the key mutations in SARS-CoV-2 variants of concern (VOC) at that time, indicating their fundamental adaptive advantage. The omicron added many more mutations not frequently seen before, which can be attributed to the synergistic nature of these mutations, which is more difficult to evolve. The great majority (24/31) of S-protein mutations under convergent evolution tightly cluster in three functional domains; N-terminal domain, receptor-binding domain, and Furin cleavage site. Furthermore, among the S-protein receptor-binding motif mutations, ACE2 affinity-improving substitutions are favoured. Next, we determined the mutation space in the S protein that has been covered by SARS-CoV-2. We found that all amino acids that are reachable by single nucleotide changes have been probed multiple times in early 2021. The substitutions requiring two nucleotide changes have recently (late 2021) gained momentum and their numbers are increasing rapidly. These provide a large mutation landscape for SARS-CoV-2 future evolution, on which research should focus now.

Virological characteristics of the SARS-CoV-2 Omicron BA.2.75

“…On the other hand, the majority of BA.2.75 S bears nine mutations: K147E, W152R, F157L, I210V, and G257S substitutions are located in the NTD, while D339H, G446S, N460K, and R493Q substitutions are located in the RBD. The mutation number in the BA.2.75 S is larger than that in the BA.4/5 S, and notably, some of the substitutions detected in the BA.2.75 S show the signs of convergent evolution (Zahradnik et al, 2022). These notions raise the possibility that the phenotype of BA.2.75 S is critically different from previous BA.2 subvariants.…”

Evaluation of immune evasion in SARS-CoV-2 Delta and Omicron variants

“…Initial findings suggests that Omicron BA.2 variant is having considerable transmission advantages including the reinfections and resistance to the monoclonal antibody (mAbs) neutralization, yet its severity and virulence needs to be further studied at the molecular level [1] . It is clear that the transmission of BA.2 could pose a significant threat to global health in the near future due to its greater effective reproduction number and pronounced immune resistance [60] , [62] .…”

A Tale of Two Waves: Diverse Genomic and Transmission Landscapes Over 15 Months of the COVID-19 Pandemic in Pune, India

“…The changing pattern for G142 to D142 or G142-and V213 to G213 or G213-observed at multiple time points and across Delta VOC sub-lineages indicates the rapid generation of multiple variants for selection. Although the etiology of these recurrent mutations is unclear, it could potentially result from host-cell induced RNA editing for the emergence and or re-emergence of mutations for the selection of more biologically 'fit' genotypes [25][26][27] .…”

“…The two dominant substitutions and SNP types across the genome and in Spike are C > T and G > T (Table 1). This could be potentially due to the innate host immune response via Apolipoprotein B mRNA editing enzyme, catalytic polypeptide (APOBEC), and Adenosine deaminase acting on RNA (ADAR) gene editing [25][26][27] . Adaptive evolution rates suggest positive selection for the Spike, E, and Orf3a genes and purifying selection for Helicase and RdRp genes (Table 2, Supplemental data) 28 Spike protein that facilitates virus entry into the host cells is a trimeric glycoprotein, that binds to the 'angiotensin-converting enzyme 2' (ACE2) surface receptors of the host 25,29 .…”

“…The changing pattern for G142 to D142 or G142-and V213 to G213 or G213-observed at multiple time points and across Delta VOC sub-lineages indicates the rapid generation of multiple variants for selection. Although the etiology of these recurrent mutations is unclear, it could potentially result from host-cell induced RNA editing for the emergence and or re-emergence of mutations for the selection of more biologically 'fit' genotypes[25][26][27] .The heatmap (Fig4c) further highlights the differential distribution of the lineage-defining mutations across the different geographical locations. For example, in the sub-lineage BA.1, deletion mutations such as S:H69-and S: V70-, S: G142-, S: V143-, S: Y144-and SNPs like T95I were highly prevalent and drop out in BA.2.…”