Spatiotemporal evolution of SARS-CoV-2 Omicron variant and its lineages in India: Insights from geographic zone-based phylogenomics

The Omicron variant (B.1.1.529) triggered an unprecedented third wave of COVID-19 in India despite widespread prior immunity. We present the first country-wide, zone-resolved phylogenetic analysis of 7846 high-quality Omicron whole-genome sequences collected across all 28 states and 8 union territories of India from November 2021 to April 2022. Sequences were grouped into six broad geographic zones (Central, East, North, Northeast, South, West) and separate maximum-likelihood phylogenies were constructed for each zone. Across all zones, an early, diverse BA.1 cluster was rapidly and synchronously replaced by BA.2.10 and BA.2.12 lineages, culminating in nationwide dominance by April 2022. Characteristic mutations (e.g., S:704L unique to BA.2.12) emerged concurrently in all regions. Results of one-way ANOVA on patristic distances showed that both geographical zone (F = 10.34, P < 0.001) and sampling month (F = 7.41, P < 0.001) as the strongest correlates of genetic divergence, with sampling month reflecting time since lineage introduction. Age group and gender exerted statistically significant but weak effects (P < 0.001 and P < 0.05, respectively), with post-hoc Tukey HSD and Benjamini-Hochberg FDR correction showing no robust pairwise gender differences and only minor age-group clustering. Individuals aged ≥50 years contributed the largest share of sequences (n = 1992), reflecting known clinical sampling bias toward severe cases rather than lineage-specific adaptation. The findings show that intrinsic viral fitness, combined with national human mobility, was stronger than local selection pressures driven by demographic or environmental factors. The continuous under-sampling of northern and northeastern regions highlights the importance of equitable genomic surveillance in identifying new genetic lineages in high-burden areas.