Genetic and Epigenetic Variation, but Not Diet, Shape the Sperm Methylome

Paternal diet can impact metabolic phenotypes in offspring, but mechanisms underlying such intergenerational information transfer remain obscure. Here, we interrogate cytosine methylation patterns in sperm obtained from mice consuming one of three diets, generating whole genome methylation maps for four pools of sperm samples and for 12 individual sperm samples, as well as 61 genome-scale methylation maps. We find that “epivariation,” either stochastic or due to unknown demographic or environmental factors, was a far stronger contributor to the sperm methylome than was the diet consumed. Variation in cytosine methylation was particularly dramatic over tandem repeat families, including ribosomal DNA (rDNA) repeats, but rDNA methylation was strongly correlated with genetic variation in rDNA copy number and was not influenced by paternal diet. These results identify loci of genetic and epigenetic lability in the mammalian genome but argue against a direct role for sperm cytosine methylation in dietary reprogramming of offspring metabolism. •Whole genome nucleotide resolution analyses of dietary effects on sperm methylation•No consistent effects of paternal diet on sperm cytosine methylation pattern•Epivariation between animals influences methylation pattern differences over diet•Identification of genetic and epigenetic variability over tandem repeats such as rDNAs Shea et al. characterize genome-wide cytosine methylation patterns in sperm obtained from mice on a variety of dietary paradigms. They show that epivariation between animals exerts far greater influence on cytosine methylation patterns than the diet consumed. Characterization of regions subject to epivariation shows dramatic variation over tandem repeat families.