Unusual enrichment of rare C-to-G transversions in the SARS-CoV-2 delta spike

SARS-CoV-2 evolution is typically characterized by strong mutational biases, with C → G transversions being consistently rare. This study investigates a unique violation of this constraint specifically within the Delta variant spike protein. By analyzing nucleotide substitution spectra from GenBank sequences, we compared C → G transversion frequencies across early variants, Omicron, and Delta lineages, including both inter-lineage and intra-lineage diversification. Statistical validation using Fisher's exact tests revealed a significant enrichment of C → G substitutions in the Delta spike (e.g., T19R, P681R). This pattern contrasts sharply with non-Delta lineages and within-lineage diversification, where such mutations remain nearly absent. Furthermore, analysis of sequences preceding the emergence of Delta suggests that this mutational signature is not readily explained by pre-existing lineage recombination. These findings indicate that the Delta spike exhibits an unusual enrichment of C → G substitutions relative to other SARS-CoV-2 lineages, suggesting lineage-specific differences in mutation patterns. These observations may contribute to a better understanding of the evolutionary mechanisms associated with the emergence of highly transmissible variants.