Phylogenomic characterization and signs of microevolution in the 2022 multi-country outbreak of monkeypox virus

Abstract

The largest monkeypox virus (MPXV) outbreak described so far in non-endemic countries was identified in May 2022 (refs. ^1-6). In this study, shotgun metagenomics allowed the rapid reconstruction and phylogenomic characterization of the first MPXV outbreak genome sequences, showing that this MPXV belongs to clade 3 and that the outbreak most likely has a single origin. Although 2022 MPXV (lineage B.1) clustered with 2018-2019 cases linked to an endemic country, it segregates in a divergent phylogenetic branch, likely reflecting continuous accelerated evolution. An in-depth mutational analysis suggests the action of host APOBEC3 in viral evolution as well as signs of potential MPXV human adaptation in ongoing microevolution. Our findings also indicate that genome sequencing may provide resolution to track the spread and transmission of this presumably slow-evolving double-stranded DNA virus.

Fig. 1. Phylogenetic analysis of MPXV viral sequences associated with the 2022 worldwide outbreak.

a, MPXV global phylogeny showing that the 2022 outbreak cluster (lineage B.1) belongs to clade 3. Clade and lineage are designated according to the nomenclature proposed by Happi et al.. b, Genetic diversity within the outbreak cluster, including the 15 sequences analyzed in this study (released in the NCBI before 27 May 2022). The deletion symbol (Δ) denotes a large deletion (11,335–12,247 in the MPXV-UK_P2-010 gene) shared by sequences segregating in a small subcluster. c, Outbreak phylogenetic tree updated with sequences available in the NCBI as of 15 June 2022 (provided during revision for more updated contextualization). The list of the sequences used in these phylogenetic analyses is detailed in Supplementary Table 2, and the alignments are provided as Supplementary Data.

Fig. 2. SNPs characterizing the 2022 MPXV outbreak variant.

Light-colored mutations represent the SNPs separating the MPXV 2022 outbreak cluster from the MPXV_UK_P2 (MT903344.1) reference sequence (Supplementary Table 3). Dark-colored mutations represent the genetic diversity within the outbreak cluster (Supplementary Table 4).