Rare C-to-G mutations occurred at an unexpectedly high frequency during the emergence of the SARS-CoV-2 delta variant

Tsukuba, Japan—SARS-CoV-2 possesses a characteristic surface protein, the spike protein, which plays a central role in viral entry into host cells. The evolution of spike protein mutations has been an important factor in the emergence of viral variants with altered transmissibility and immune-evasion properties. Previous studies have shown that SARS-CoV-2 evolution is strongly biased toward certain types of nucleotide substitutions, with C-to-G substitutions occurring only rarely.

In this study, the researcher focused on the Delta variant, of which caused a major global outbreak in 2021. The Delta variant's spike protein had acquired seven amino acid substitutions in addition to the D614G substitution common to most major SARS-CoV-2 variants. Notably, two of these seven substitutions—T19R and P681R—arose from C-to-G nucleotide substitutions. Analysis of SARS-CoV-2 genome sequences deposited in the NCBI GenBank and GISAID public databases revealed that C-to-G substitutions are generally rare throughout SARS-CoV-2 evolution. For example, among 865 spike protein mutations identified during the within-lineage diversification of the Alpha variant, only one resulted from a C-to-G substitution. Statistical analyses demonstrated that the proportion of C-to-G substitutions in the spike protein of the Delta variant (2 of 7 substitutions) was significantly higher than the proportions observed during other inter-lineage transitions or within-lineage evolution. These findings indicate that the Delta variant spike protein was unusually enriched for a mutation type that is otherwise strongly suppressed during SARS-CoV-2 evolution. This finding may offer new insights into the evolutionary processes associated with the emergence of highly transmissible variants.

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This research was funded by the Transdisciplinary Review Association, Japan.

_{Original Paper}

Title of original paper:
Unusual Enrichment of Rare C-to-G Transversions in the SARS-CoV-2 Delta Spike

Journal:
Infection, Genetics and Evolution

DOI:
10.1016/j.meegid.2026.105989

_{Correspondence}

Associate Professor KAKEYA, Hideki
Institute of Systems and Information Engineering, University of Tsukuba

_{Related Link}

Institute of Systems and Information Engineering