Monkeypox virus pangenomics reveals determinants of clade Ib

Mpox, formerly monkeypox, is a viral zoonotic disease caused by the mpox virus (MPXV). MPXV, which is phylogenetically divided into Clades I and II, was declared a Public Health Emergency of International Concern for the second time in August 2024 due to rapid geographic expansion of Clade I viruses including the newly identified subclade Ib. With a unique set of genomic mutations and sustained human-to-human transmission, subclade Ib has rapidly spread throughout the eastern Democratic Republic of the Congo as well as neighboring non-endemic regions and outside the African continent. Currently, there is a lack of comparative genomic data with which to address the potential zoonotic transmissibility and pathobiology of subclade Ib. Here we report 105 protein-coding genes that are shared by all the queried MPXV subclade Ia, Ib, and IIb genomes. Our comparative genomic analysis identified that the core Clade I gene pair, OPG032 and OPG033, is now a critical branching element for subclade Ia/Ib due to their loss in subclade Ib. These genes encode the complement control protein (a vaccinia virus ortholog associated with virulence), and a Kelch-like protein associated with pathogenesis, respectively, suggesting a functional evolution that might play an important role in the pathobiology of the new MPXV subclade Ib. Our results lay the groundwork to exploit the genomic elements of MPXV as potential targets for therapeutics development/repurposing, vaccine design, and molecular diagnostic expansion, as well as to uncover the viral diversity, and human-to-human transmission of MPXV.