MPXV RNA-seq data provide evidence for protection of viral transcripts from APOBEC3 editing

Area of Science:

• Virology
• Molecular Biology
• Genetics

Background:

• The 2022 monkeypox virus (MPXV) outbreak exhibited a high mutation rate, particularly C→T and G→A substitutions.
• These mutations are consistent with APOBEC3 cytidine deaminase activity, known to affect DNA.
• The impact of APOBEC3 on MPXV RNA transcripts was previously unclear.

Purpose of the Study:

• To investigate whether APOBEC3 enzymes actively edit MPXV RNA transcripts.
• To differentiate between RNA editing and DNA-level mutagenesis as the source of observed substitutions.

Main Methods:

• Analysis of RNA sequencing (RNA-seq) data from MPXV-infected samples.
• Examination of substitution patterns, including G→A mutations and their distribution.
• Assessment of substitution impact on protein-coding sequences and correlation with transcriptional features.

Main Results:

• Enrichment of APOBEC signature substitutions was observed.
• Evidence strongly supports DNA-level mutagenesis over RNA editing, including a significant number of G→A substitutions.
• Substitutions had a largely neutral effect on protein sequences and lacked correlation with RNA secondary structures or transcriptional hotspots.

Conclusions:

• APOBEC3A or APOBEC3B likely drove the observed DNA-level mutagenesis in MPXV.
• The apparent APOBEC-like changes in RNA are attributed to fixed DNA mutations, not active RNA editing.
• APOBEC3's role in shaping MPXV evolution primarily occurs at the DNA level.