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 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 clade Ib [1]. 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 outside the African continent [2–6]. Currently, there is a lack of comparative genomic data with which to address potential zoonotic transmissibility and pathobiology of clade Ib. 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 subsequently examined isolates of clade Ib lack the gene pairOPG032andOPG033, which encode the complement control protein (a vaccinia ortholog associated with virulence), and a Kelch-like protein, respectively. The genomic rearrangement of MPXV suggests a functional evolution that might play an important role in the pathobiology of the novel clade Ib virus. Our results lay the groundwork to exploit the genomic of 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 zoonosis of MPXV.