Emergence and diversity of monkeypox virus Clade IIb sub-lineages in Nigeria (1971–2023) and its role in the 2022 global outbreak

The exact role played by Nigeria in the global monkeypox virus (MPXV) outbreak of 2022 remains unclear, despite exported cases to Singapore, the United Kingdom (UK), the United States of America (USA), and Israel from 2018 to 2022. We sought to resolve the origin of the 2022 MPXV global outbreak. All MPXV whole genomes deposited in the EpiPox™ database were aligned using Nextclade v3.13.3 against the reference genome (NC_063383.1). Multiple sequence alignments were performed using MAFFT version 7, followed by the neighbor-joining and maximum likelihood trees were constructed and visualised in iTOL viewer. We quantified total C → T substitutions as APOBEC3-related mutations and clade distributions. Seven clades or sub-lineages, namely: A (2017–2023), A.1 (2018 and 2019), A.2 and A.3 (2019), A.2.2 (2022), A.2.3 (2022 and 2023), and B.1 (2022) were observed. There was a gradual buildup of total substitution events (APOBEC3 related mutations) from 1978 to 2023, with a slight decline in 2020 but most pronounced in 2019, 2021, and 2022. Furthermore, total substitutions events were widespread across both variable and core regions of the MPXV genome. The B.1 and A.3 maximum likelihood trees points to Nigerian ancestral roots, supporting our hypothesis that the B.1 sub-lineage originated in Nigeria. Our phylodynamics analyses showed peak distributions for the A,3 clade around, while that of B.1 showed rapid spread of the virus in May 2022. The evolution rates of the for A.3 and B.1 were 6.94 × 10 −5 and ~ 3.091 × 10 −4 substitutions/site/year, while their molecular clock signal were moderate with respective values of R 2 = 0.56 and = 0.56. Overall, our findings indicate that the B.1 sub-lineage, which triggered the 2022 outbreak, potentially evolved from A.3, with both lineages having their ancestral roots in Nigeria. • Investigated the origin and evolution of the 2022 global monkeypox (MPXV) outbreak using whole genome sequences. • Identified seven MPXV clades/sub-lineages between 2017 and 2023, with emphasis on A.3 and B.1. • Observed a progressive accumulation of APOBEC3-related mutations across MPXV genomes, especially in 2019, 2021, and 2022. • Phylogenetic analyses confirmed that the B.1 sub-lineage, responsible for the 2022 outbreak, evolved from the A.3 sub-lineage. • Evidence suggests Nigeria as the likely origin of the B.1 sub-lineage and a central node in MPXV global spread.