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

## TL;DR

This study shows that mutation patterns in eukaryotic genomes are largely shaped by methylation-related processes, especially at CpG sites, influencing genome evolution.

## Contribution

The study identifies CpG mutation rates and transition/transversion ratios as the main drivers of mutation spectrum variation across diverse eukaryotic species.

## Key findings

- CpG mutation rates and transition/transversion ratios explain most of the variation in mutation spectra across eukaryotes.
- Inferred CpG mutation rates strongly predict genomic CpG depletion but are not linked to genome-wide methylation levels.
- The study uses a Bayesian approach to analyze pentanucleotide mutation spectra in 108 species, revealing cytosine transition mutability as a key factor.

## Abstract

Mutation is the source of all genetic variation. Different types of mutations occur at different rates—the mutation spectrum—which varies across species, shaped by differences in DNA sequence context, damage, replication, and repair. Inferring mutation spectra from 108 eukaryotic species, we demonstrate variation in mutation rates at CpG sites (where a cytosine is followed by a guanine), and in transition/transversion ratio at other sites accounts for most variation in mutation spectra. We also find that CpG mutation rates almost entirely explain genomic CpG content, highlighting the importance of the mutation spectrum in genome evolution.

Mutation spectra vary across genetic and environmental contexts, leading to differences between and within species. Most research on mutation spectrum has focused on trinucleotide (3-mer) mutation types in mammals, limiting the breadth and depth of variation surveyed. In this study, we use whole-genome resequencing data across 108 eukaryotic species—including mammals, fish, plants, and invertebrates—to characterize pentanucleotide (5-mer) noncoding mutation spectra using a Bayesian approach. Our findings reveal cytosine transition mutability at CpG sites and other sources of variation in the transition/transversion ratio as the main drivers of variation in mutation spectra across eukaryotes. We find that inferred CpG mutation rates almost perfectly predict genomic CpG depletion but are not predicted by genome-wide average CpG methylation levels. Together, our results illustrate the pivotal role of mutagenesis in shaping genome composition across eukaryotes and highlight a gap in knowledge about the mechanisms governing mutation rates.