Methylation-associated mutagenesis underlies variation in the mutation spectrum across eukaryotes

Area of Science:

• Genomics
• Evolutionary Biology
• Molecular Biology

Background:

• Mutation spectra differ across species and environments.
• Previous studies focused on trinucleotide (3-mer) mutation types in mammals, limiting scope.
• Eukaryotic mutation variation remains incompletely understood.

Purpose of the Study:

• To characterize pentanucleotide (5-mer) non-coding mutation spectra across diverse eukaryotes.
• To identify key drivers of mutation spectrum variation.
• To investigate the relationship between methylation and mutation rates.

Main Methods:

• Whole-genome resequencing data from 108 eukaryotic species.
• Bayesian analysis of pentanucleotide (5-mer) mutation spectra.
• Correlation analysis with genomic CpG and CHG depletion and methylation levels.

Main Results:

• Cytosine transition mutability at CpG and CHG sites are major drivers of eukaryotic mutation spectra variation.
• Strong correlation observed between mutation spectra and genomic CpG/CHG depletion.
• Genome-wide methylation levels do not consistently predict transition rates at CpG and CHG sites.

Conclusions:

• Mutagenesis plays a crucial role in shaping eukaryotic genome composition.
• Unknown genetic or environmental factors influence mutation rates at methylated cytosines.
• Further research is needed to elucidate mechanisms governing mutation rates at methylated sites.