Molecular Aspects of the Emergence of Monkeypox Virus Clades

Monkeypox virus (MPXV), which previously caused mainly zoonotic infections, is currently the causative agent of the mpox outbreak that began in 2022. Since the mpox outbreak is characterized by sustained human-to-human transmission, the evolutionary trajectory of MPXV is an important scientific issue. The prevailing hypothesis suggests that the modern orthopoxviruses originated from cowpox-like ancestors with larger genomes that infected a wide range of hosts. Subsequent evolution included the reduction of the genome and the accumulation of substitutions in key proteins. Molecular dating of MPXV evolution revealed 5-6-fold acceleration in the evolutionary rate that was observed in subclade IIb after 2018, reaching 1.8 × 10^-5 substitutions/site/year, likely due to virus' adaptation to humans. The origin of MPXV from its precursor was primarily driven by the accumulation of non-synonymous substitutions in the key host range genes, including those associated with the protein inhibiting host protein synthesis (OPG173) and host immune evasion (OPG027). The subsequent divergence of MPXV into clades I and II largely depended on mutations in the gene encoding the Bcl-2-like protein. Finally, the division of clade II into subclades IIa and IIb was facilitated by further non-synonymous substitutions in the soluble interferon alpha/beta receptor and hemagglutinin genes.