Monkeypox virus pangenomics reveals determinants of clade Ib

Mpox, formerly monkeypox, is a viral zoonotic disease caused by the monkeypox virus (MPXV). MPXV, which is taxonomically divided into clade 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 clade Ib. With a unique set of genomic mutations and sustained human-to human transmission, clade Ib has rapidly spread throughout the eastern Democratic Republic of the Congo as well as neighboring non-endemic regions. Limited epidemiological data suggests clade Ib is less virulent than other clade I and clade II viruses. There currently is a lack of quantitated comparative genomic analyses to address potential zoonotic transmissibility and pathobiology between the two clades. Here we show MPXV clades I and II share a core genome composed of 68 protein-coding genes which are common in the genomes of other poxviruses such as camelpox, cowpox, and vaccinia. The first documented and all subsequential queried isolates of clade Ib featured the deletion of the OPG032 gene, which was found present in all queried clade Ia genomes. OPG032 encodes a vaccinia ortholog which encodes the vaccinia complement protein, an important virulence protein. The schism event in the genomic structure highlighted by an entire gene deletion suggests it plays an important role in the pathobiology of the novel clade Ib. We anticipate our results lay the groundwork for exploiting the genomic of elements of MPXV as potential targets for therapeutics development/repurposing, vaccine design, and molecular diagnostic expansion as well to uncover the viral diversity and function of MPXV.