Genomic Evolution and Clade-Specific Mutation Signatures of Monkeypox Virus (Mpox) from 2022 to 2024 Reveal Distinct African Lineage Divergence

Abstract The genomic diversity of the Monkeypox virus (Mpox), mainly observed in Africa, remains poorly characterized despite the global outbreak from 2022 to 2024. This study aims to determine the genomic evolution and clade-specific variations of Mpox using 70 complete genomes from 2022 to 2024, predominantly from Africa. Phylogenetic analysis revealed 1,038 parsimony-informative sites, with clade Ia dominance at 44.4%. The A-T-rich genomes exhibit a 3.7-fold transition/transversion bias. We also identified 20,219 amino-acid substitutions, with nearly half occurring within clade Ia (48.70%). Clade-specific mutation profiling uncovered distinct signatures: clade Ia possessed unique indel-driven mutations (J1L_ins74DDEVSE, J3R_ins74DDEVSE), clade Ib showed recurrent substitutions (A25R_R273Q, A15L_P39H), and the globally dominant clade IIb harbored deletions absent in clade I (A33R_Y119del). These mutational profiles highlight a clear genomic divergence between African clades (Ia and Ib) and global clade IIb. Our findings demonstrate that African Mpox genomes exhibit strong clade Ia dominance and lineage-specific evolutionary patterns, suggesting distinct selective pressures. This marked difference underscores the critical need for enhanced Africa-focused genomic surveillance and development of region-specific diagnostics, therapeutics, and vaccines.