Exploring the key genomic variation in monkeypox virus during the 2022 outbreak

Abstract

Background: In 2022, a global outbreak of monkeypox occurred with a significant shift in its epidemiological characteristics. The monkeypox virus (MPXV) belongs to the B.1 lineage, and its genomic variations that were linked to the outbreak were investigated in this study. Previous studies have suggested that viral genomic variation plays a crucial role in the pathogenicity and transmissibility of viruses. Therefore, understanding the genomic variation of MPXV is crucial for controlling future outbreaks.

Methods: This study employed bioinformatics and phylogenetic approaches to evaluate the key genomic variation in the B.1 lineage of MPXV. A total of 979 MPXV strains were screened, and 212 representative strains were analyzed to identify specific substitutions in the viral genome. Reference sequences were constructed for each of the 10 lineages based on the most common nucleotide at each site. A total of 49 substitutions were identified, with 23 non-synonymous substitutions. Class I variants, which had significant effects on protein conformation likely to affect viral characteristics, were classified among the non-synonymous substitutions.

Results: The phylogenetic analysis revealed 10 relatively monophyletic branches. The study identified 49 substitutions specific to the B.1 lineage, with 23 non-synonymous substitutions that were classified into Class I, II, and III variants. The Class I variants were likely responsible for the observed changes in the characteristics of circulating MPXV in 2022. These key mutations, particularly Class I variants, played a crucial role in the pathogenicity and transmissibility of MPXV.

Conclusion: This study provides an understanding of the genomic variation of MPXV in the B.1 lineage linked to the recent outbreak of monkeypox. The identification of key mutations, particularly Class I variants, sheds light on the molecular mechanisms underlying the observed changes in the characteristics of circulating MPXV. Further studies can focus on functional domains affected by these mutations, enabling the development of effective control strategies against future monkeypox outbreaks.

Keywords: Genomic variation; Monkeypox virus; Phylogenetic tree; Protein structure prediction; Reference sequence.

Fig. 1

Flow chart of data acquisition, screening, and analysis

Fig. 2

Phylogenetic tree of isolates and RSs. SNP are used as the length scale. A, Phylogenetic tree of all 212 isolates (isolates of A.2 (RS7) and B.1 (RS9, RS10) lineages were folded; colors represent the RSs to which the isolates belong); B, Phylogenetic tree based on 10 RSs (colors represent three clade classifications); lineages corresponding to the RSs in clade IIb are marked

Fig. 3

Phylogenetic trees of RS7 (A), RS9 (B), and RS10 (C); sequences of EPI ISL_15022589 and EPI ISL_14952916 in RS7 had too many ‘N’ bases and are not shown

Fig. 4

Homology based on the constructed RSs. The total number of sites and the proportion of mutant sites with HR > 20% for three substitution types: SNPs (both overall P < 0.0001) (A), insertions (both overall P < 0.0001) (B), and deletions (overall P < 0.0001 and P < 0.001) (C)

Fig. 5

Protein conformation differences in the key ORFs of RS9. RS1 (green), RS5 (purple), RS8 (red), and RS9 (yellow) were compared. A, Compared with the conformation of J2L, the local structure of S54F RS9 mutant differed substantially. B, Compared with the conformation of C9L, the downstream structure of the R48C mutant differed significantly. C, The predicted protein conformation of C15L showed that RS9 was locally separated near P78S. D, Compared with the protein conformation of A47R, the difference of RS9 near H221Y was significant. E, The AA sequence of A45L was the identical for all RSs and served as a control