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 preexisting 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.