Effect of methylation on genome mutability in cattle

Germline de novo mutations (DNMs) are rare events in mammals, typically occurring only a few dozen times per generation. These mutations are not entirely random; several factors are known to influence their rate, including DNA methylation. In this study, we leveraged the unique population structure of cattle with a few ancestors having a large contribution to the current gene pool, along with comprehensive genomic resources, to investigate mutational processes. We applied two complementary approaches: (1) identifying DNMs accumulated over generations in family trio segments (from identical-by-descent segments between descendants and direct ascendants spanning several generations) in Holstein and Montbéliarde breeds, and (2) detecting rare bi-allelic substitution variants (Minor Allele Frequency < 0.001) from a large panel of sequenced Holstein animals.

Overall, transitions were over-represented compared to transversions for both DNMs and rare substitutions. Considering the nucleotide context, a notable enrichment of C > T substitutions was observed within CpG sites (CpG > TpG). This enrichment was particularly pronounced in low CpG density regions and positively correlated with local methylation levels in both gametes and several somatic tissues. Additionally, several transposable elements exhibited higher mutation rates relative to the rest of the genome, particularly young SINE and LINE elements.

Together, these results provide insights into the mutational landscape in cattle and reinforce observations made in other mammalian species.