Epigenetics

Effect of DNA methylation on de novo mutations in cattle

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Abstract

In mammals, DNA methylation is known to be mutagenic, leading to C→T substitutions at CpG sites. This study investigated the extent of this phenomenon in cattle using complementary genomic approaches. In the first approach, we relied on the unique population structure of dairy cattle breeds, where a limited number of ancestors significantly contribute to the genome of current animals, and on the large number of whole genome sequences available, especially for these major ancestors. Using Holstein and Montbéliarde data, we leveraged pedigree information together with phased genotypes to identify genomic segments that were Identical-by-Descent (IBD) between contemporary animals and their sequenced ancestors several generations upstream. De novo mutations (DNMs) were investigated within genomic regions with both copies being IBD with that of an ancestor. In a second approach, we searched for rare substitutions (MAFvs. transversion) and their trinucleotide context. Subsequently, to relate mutation patterns to methylation, we analyzed publicly available Whole Genome Bisulfite Sequencing data from several tissues, characterizing methylation level of (1) all CpGs in the genome and (2) sites showing CpG >TpG substitutions. The IBD-based strategy identified 3,543 DNMs (1,670 in Holstein and 1,873 in Montbéliarde), while the rare-variant screen led to the selection of 1.8 million substitutions in the Holstein breed. In both approaches, C >T and T >C were the most prevalent substitutions. Accounting for trinucleotide composition of the bovine genome, the patterns of substitution exhibited a distinct bias, characterized by an enrichment of transitions and a depletion of transversions. The most significant enrichments were observed for *CpG >*TpG mutations, with odds ratios ranging from 10 to 26. Further investigation of these CpG >TpG substitutions revealed that, for most of the tissues studied, the local methylation context was higher for CpG >TpG mutations than for all CpGs. In sperm, 95% of CpG >TpG substitutions exhibited a local methylation level exceeding 50%, while the proportion observed for all CpGs (non-polymorphic) was lower (85%). Within CpG islands (i.e., CpG-dense regions), the enrichment of CpG >TpG mutations was reduced relative to the rest of the genome, consistent with their lower methylation rate, yet these sites still exhibited higher methylation levels than non-polymorphic CpGs in these regions. Together, these complementary approaches provide new insights into the relationship between DNA methylation and mutational processes in cattle.CF is recipient of a CIFRE PhD grant from ANRT and APIS-GENE. This work was part of the POLYPHEME project funded by ANR and APIS-GENE.

Keywords: 2026

How to Cite:

Fouéré, C., Costes, V., Hozé, C., Besnard, F., Costa Monteiro Moreira, G., Fritz, S., Kiefer, H., Sanchez, M., Boichard, D. & Boussaha, M., (2026) “Effect of DNA methylation on de novo mutations in cattle”, World Congress on Genetics Applied to Livestock Production Digital Archive 2026(1): 2285404. doi: https://doi.org/10.31274/wcgalp.23685

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