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

Abstract

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 4 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.

DNA methylation in epigenetic inheritance of metabolic diseases through the male germ line

“…It is notable that male mice fed a HFD were also included in the follow-up study, and the results showed that neither a HFD nor a LPD had a major direct impact on the sperm DNA methylome under the experimentally given dietary conditions (Shea et al 2015). Another interesting finding from the study was the identification of large diversity in mice sperm DNA methylation patterns for tandem repeat regions and CGI shores between individuals.…”

“…A follow-up to this study that included more samples and additional novel extensive reduced representation bisulfite sequencing (RRBS) and bisulfite pyrosequencing experiments also failed to identify any major DNA methylation changes in the sperm (Shea et al 2015). It is notable that male mice fed a HFD were also included in the follow-up study, and the results showed that neither a HFD nor a LPD had a major direct impact on the sperm DNA methylome under the experimentally given dietary conditions (Shea et al 2015).…”

“…Another interesting finding from the study was the identification of large diversity in mice sperm DNA methylation patterns for tandem repeat regions and CGI shores between individuals. This methylation variation (due to genetics and unknown environmental effects) was much larger between non-littermates given the same diet than between littermates on different diet paradigms (Shea et al 2015).…”

“…The existence of DNA methylation changes in sperm related to defined paternal dietary exposures within windows of susceptibility 1 and 2 seems evident. However, the existence of DNA methylation changes in sperm related to dietary exposures in later stages of spermatogenesis can still be debated (Shea et al 2015). The presence of dietary-induced DNA methylation changes may arise from specific cellular signal transduction affecting the male germ cells during gametogenesis in response to a given environmental context.…”

Paternal epigenetic programming: evolving metabolic disease risk

“…Thus, in haploid sperm, mosaic methylation changes occur only in the respective proportion of sperm, which is incompatible with methylation underlying the very high penetrance of programming that is generally observed (Rando & Simmons 2015). Further, recent findings indicate that diet has little effect on broad methylation patterns in sperm, with the vast majority of methylation variation being due to genetic or sporadic variation (Shea et al 2015). Taken together with the fact that most functional genomic elements are extensively demethylated after fertilization (Wang et al 2014), it seems unlikely that aberrations in R164 Review s s j hur and others Paternal metabolic programming 58 3 : R164 Review cytosine methylation patterns are responsible for the transmission of programming from father to child.…”