Paternal age effects on spermFOXK1andKCNA7methylation and transmission into the next generation

Abstract

Children of older fathers carry an increased risk for developing autism and other disorders. To elucidate the underlying mechanisms, we investigated the correlation of sperm DNA methylation with paternal age and its impact on the epigenome of the offspring. Methylation levels of nine candidate genes and LINE-1 repeats were quantified by bisulfite pyrosequencing in sperm DNA of 162 donors and 191 cord blood samples of resulting children (conceived by IVF/ICSI with the same sperm samples). Four genes showed a significant negative correlation between sperm methylation and paternal age. For FOXK1 and KCNA7, the age effect on the sperm epigenome was replicated in an independent cohort of 188 sperm samples. For FOXK1, paternal age also significantly correlated with foetal cord blood (FCB) methylation. Deep bisulfite sequencing and allele-specific pyrosequencing allowed us to distinguish between maternal and paternal alleles in FCB samples with an informative SNP. FCB methylation of the paternal FOXK1 allele was negatively correlated with paternal age, whereas maternal allele was unaffected by maternal age. Since FOXK1 duplication has been associated with autism, we studied blood FOXK1 methylation in 74 children with autism and 41 age-matched controls. The FOXK1 promoter showed a trend for accelerated demethylation in the autism group. Dual luciferase reporter assay revealed that FOXK1 methylation influences gene expression. Collectively, our study demonstrates that age-related DNA methylation changes in sperm can be transmitted to the next generation and may contribute to the increased disease risk in offspring of older fathers.

Association between assisted reproductive technology and the risk of autism spectrum disorders in the offspring: a meta-analysis

“…It seemed that ART procedures together with etiological factors, including reduced fertility of the parents or the advanced maternal and paternal age, impact the epigenetic DNA methylation state. Recent studies has found epigenetic variability in the male or female germline, and occurrence of age-related DNA-methylation changes in a number of genes, and those changes may contribute to the increased ASD risk in offspring of older parents383940.…”

Exercise and epigenetic inheritance of disease risk

“…In humans, the sperm epigenome is modified by ageing and obesity . Interestingly, the age‐associated sperm DNA demethylation of the FOXK1 promoter is associated with offspring foetal cord blood methylation and accelerated gene demethylation in autistic youth …”

“…100 Interestingly, the age-associated sperm DNA demethylation of the FOXK1 promoter is associated with offspring foetal cord blood methylation and accelerated gene demethylation in autistic youth. 98 It is important to note the difference between transgenerational inheritance and environmental impacts leading to intergenerational or multi-generational inheritance (see Fig. 3).…”

The Age of the Father

“…To study epigenetic inheritance as a possible mechanism underlying the paternal age effect, Atsem et al [2016] selected DRD4 , NCOR2 , NKX2-5 , KCNA7 , GET4 , DMPK , PDE4C , TNXB , and FOXK1 from a set of genes with age-related changes in DNA methylation because of their association with neuropsychiatric and other disorders [Jenkins et al, 2014]. To calibrate their data, repetitive LINE-1 elements, comprising roughly 17% of the human genome, were used as a surrogate marker for global DNA methylation.…”

“…In hindsight, such transmitted factors may very well relate to aberrant methylation at specific genomic loci in the brain [Schneider et al, 2012[Schneider et al, , 2014[Schneider et al, , 2016Berko et al, 2014]. Another ramification of the study by Atsem et al [2016] may be possible phenotypic differences in patients with genetic and epigenetic mutations. In ASD patients with or without comorbid conditions, diverse subphenotypic manifestations of CNVs have been inferred and detected [Poot, 2013;Merikangas et al, 2015].…”