Integrative genomic study of mutation dynamics and Evolutionary trends in SARS-CoV-2 omicron BA.3

Abstract

This study investigates the evolutionary dynamics of the SARS-CoV-2 BA.3 lineage with an emphasis on saltation-driven adaptation. Using 81 high-coverage BA.3 genome sequences and 1,011 complete patient status records obtained from GISAID, we conducted a comprehensive analysis that integrated temporal, mutational, phylogenetic, and selection pressure assessments. Temporal analysis of patient records revealed that BA.3 sequences were predominantly collected between November 2021 and March 2022, with highly mutated variants emerging in the last quarter of 2024. Pairwise alignment of the spike gene demonstrated near-identical sequences among recent isolates from Gauteng Province and subtle yet significant differences in a KwaZulu Natal isolate when compared to the Wuhan Hu-1 reference strain. Domain-specific mutation mapping showed that mutations were concentrated in key functional regions of the spike protein, particularly within the receptor-binding domain and its binding motif. Phylogenetic reconstruction and pervasive selection analysis further revealed that recent BA.3 variants form a divergent clade characterized by extensive adaptive mutations. These findings indicate that saltatory events play a critical role in shaping the genetic landscape of BA.3, with important implications for viral infectivity, immune escape, and the design of next-generation vaccines.