Monkeypox virus genomic accordion strategies.

Area of Science:

• Virology
• Genomics
• Evolutionary Biology

Background:

• The 2023 mpox epidemic was driven by a subclade IIb monkeypox virus (MPXV).
• Increased human-to-human transmission suggests potential genomic alterations in MPXV.
• Low-complexity regions (LCRs) are often overlooked but may harbor key genomic changes.

Purpose of the Study:

• To generate a high-quality MPXV genome sequence from the current epidemic.
• To accurately resolve LCRs and analyze their variability.
• To investigate the potential impact of LCRs on MPXV evolution and virulence.

Main Methods:

• High-sensitivity sequencing techniques to resolve MPXV genome, including LCRs.
• Analysis of short tandem repeat (STR) variation within LCRs.
• In silico analysis of MPXV orthologous poxvirus genes (OPGs) and their potential functional impact.

Main Results:

• A high-quality MPXV genome sequence with accurately resolved LCRs was obtained.
• Significant variation in STRs within MPXV LCRs was identified.
• LCR entropy in MPXV is higher than single-nucleotide polymorphisms (SNPs), and LCRs are non-randomly distributed.
• In silico analyses suggest LCR variability may influence MPXV gene expression, translation, stability, and function, consistent with "genomic accordion" evolution.

Conclusions:

• LCRs are a significant source of genomic variation in MPXV.
• LCR variability may play a crucial role in the evolutionary adaptation and increased transmissibility of MPXV.
• Future genomic studies of MPXV should incorporate detailed analysis of LCRs to understand phenotypic differences.