Hydroxymethylated cytosines are associated with elevated C to G transversion rates

Area of Science:

• Genomics
• Epigenetics
• Molecular Biology

Background:

• Cytosine modifications, including 5-methylcytosine and 5-hydroxymethylcytosine, are crucial in mammalian genomes.
• Methylated cytosines are known mutational hotspots, but the evolutionary impact of hydroxymethylation is unclear.

Purpose of the Study:

• To investigate the distinct evolutionary patterns and mutation rates associated with hydroxymethylated and methylated cytosines.
• To determine the relationship between hydroxymethylation and C to G transversion rates across different genomic contexts and in cancer.

Main Methods:

• Integrated base-resolution maps of methyl- and hydroxymethylcytosine in human and mouse.
• Analysis of population genomic, divergence, and somatic mutation data.
• Statistical control for potential confounding factors.

Main Results:

• Hydroxymethylated sites show distinct variation and evolution patterns compared to methylated sites.
• Hydroxymethylated sites are consistently associated with elevated C to G transversion rates (1.43-fold in humans, 1.22-fold in mice).
• Increased C to G rates correlate with Tet enzyme expression and mismatch repair pathway components (MSH2, MSH6, MBD4) in cancer genomes.

Conclusions:

• Hydroxymethylation is associated with a unique mutational burden, specifically increased C to G transversions.
• The mismatch repair pathway appears implicated in driving elevated transversion rates at hydroxymethylated cytosine sites.