Key Takeaways & Executive Findings
- •• Positive selection signal identified in OPG027, specifically in Clade I lineage of MPXV. • Accelerated protein sequence evolution observed in 2022 outbreak variants. • Strong epistasis between amino acid substitutions in different genes. • Codon usage deoptimization correlates with reduced fatality rates, though causality remains unclear.
Abstract
The monkeypox virus (mpox virus, MPXV) epidemic in 2022 has posed a significant public health risk. Yet, the evolutionary principles of MPXV remain largely unknown. Here, we examined the evolutionary patterns of protein sequences and codon usage in MPXV. We first demonstrated the signal of positive selection in OPG027, specifically in the Clade I lineage of MPXV. Subsequently, we discovered accelerated protein sequence evolution over time in the variants responsible for the 2022 outbreak. Furthermore, we showed strong epistasis between amino acid substitutions located in different genes. The codon adaptation index (CAI) analysis revealed that MPXV genes tended to use more non-preferred codons compared to human genes, and the CAI decreased over time and diverged between clades, with Clade I > IIa and IIb-A > IIb-B. While the decrease in fatality rate among the three groups aligned with the CAI pattern, it remains unclear whether this correlation was coincidental or if the deoptimization of codon usage in MPXV led to a reduction in fatality rates. This study sheds new light on the mechanisms that govern the evolution of MPXV in human populations.
1. Introduction
The monkeypox virus (mpox virus, MPXV) epidemic in 2022 has caused substantial public health risks. MPXV is a linear double-stranded DNA virus that belongs to the Poxviridae family, Chordopoxvirinae subfamily, and Orthopoxvirus genus [1]. The genome of MPXV is approximately 197 kb in length and encodes around 200 genes [2]. MPXV can infect various animal species, including humans, non-human primates, and rodents [3–6]. Similar to variola virus (VARV) and vaccinia virus (VACV) in the Orthopoxvirus genus, MPXV can lead to human disease and death.
MPXV was initially discovered in a Danish animal facility in 1958 [6], and it was first isolated from a human case in the Democratic Republic of the Congo in 1970 [7]. Prior to 2022, MPXV was predominantly endemic in Central and Western African countries, with sporadically reported instances in other regions resulting from importations [8–13]. The first human case of the 2022 MPXV outbreak was reported in the United Kingdom on May 7th, 2022 [14]. The global outbreak of MPXV was declared an international public health emergency on July 23rd, 2022. According to the World Health Organization, as of September 11th, 2023, a total of 90,439 confirmed cases from 115 countries and regions had been reported during the 2022–2023 outbreak.
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Ke-Jia Shan, Changcheng Wu, Xiaolu Tang, Roujian Lu, Yaling Hu, Wenjie Tan, Jian Lu (2026). Molecular Evolution of Protein Sequences and Codon Usage in Monkeypox Viruses. Genomics, Proteomics & Bioinformatics. https://doi.org/10.1093/gpbjnl/qzad003
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Frequently Asked Questions
What is the main finding of the study on monkeypox virus evolution?
The study identified positive selection in the OPG027 gene, accelerated protein evolution in 2022 outbreak variants, and strong epistasis between amino acid substitutions. It also found that codon usage deoptimization in MPXV correlates with reduced fatality rates, though causality remains unclear.
How does codon usage in monkeypox virus compare to human genes?
MPXV genes tend to use more non-preferred codons compared to human genes, and the codon adaptation index (CAI) decreased over time and diverged between clades, with Clade I > IIa and IIb-A > IIb-B.
What is the significance of the OPG027 gene in monkeypox virus?
OPG027 shows signals of positive selection, specifically in the Clade I lineage of MPXV, suggesting it may play a role in viral adaptation and evolution.
What is the role of APOBEC3 enzymes in monkeypox virus evolution?
APOBEC3 enzymes are hypothesized to cause the increased substitution rate observed in 2022 MPXV genomes, leading to C>T and G>A mutations, which may drive accelerated evolution.
What are the implications of this study for public health?
Understanding the evolutionary mechanisms of MPXV, including codon usage deoptimization and positive selection, can inform surveillance and intervention strategies, potentially explaining changes in fatality rates.
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