Abstract
Recent evidence demonstrates a role for paternal aging on offspring disease susceptibility. It is well established that various neuropsychiatric disorders (schizophrenia, autism, etc.), trinucleotide expansion associated diseases (myotonic dystrophy, Huntington's, etc.) and even some forms of cancer have increased incidence in the offspring of older fathers. Despite strong epidemiological evidence that these alterations are more common in offspring sired by older fathers, in most cases the mechanisms that drive these processes are unclear. However, it is commonly believed that epigenetics, and specifically DNA methylation alterations, likely play a role. In this study we have investigated the impact of aging on DNA methylation in mature human sperm. Using a methylation array approach we evaluated changes to sperm DNA methylation patterns in 17 fertile donors by comparing the sperm methylome of 2 samples collected from each individual 9–19 years apart. With this design we have identified 139 regions that are significantly and consistently hypomethylated with age and 8 regions that are significantly hypermethylated with age. A representative subset of these alterations have been confirmed in an independent cohort. A total of 117 genes are associated with these regions of methylation alterations (promoter or gene body). Intriguingly, a portion of the age-related changes in sperm DNA methylation are located at genes previously associated with schizophrenia and bipolar disorder. While our data does not establish a causative relationship, it does raise the possibility that the age-associated methylation of the candidate genes that we observe in sperm might contribute to the increased incidence of neuropsychiatric and other disorders in the offspring of older males. However, further study is required to determine whether, and to what extent, a causative relationship exists.
Highlights
The effects of advanced paternal age have only recently become of interest to the scientific community as a whole
The concern has more frequently surrounded the effects of advanced maternal age, but recent evidence suggests negative effects of advanced paternal age as well
In this study we have investigated a commonly hypothesized mechanism for this effect, namely sperm DNA methylation alteration
Summary
The effects of advanced paternal age have only recently become of interest to the scientific community as a whole This interest has likely arisen as a result of recent studies that suggest an association with increased incidence of diseases and abnormalities in the offspring of older fathers. Offspring sired by older fathers have been shown to have increased incidence of neuropsychiatric disorders (autism, bipolar disorder, schizophrenia, etc.) [1,2,3], trinucleotide repeat associated diseases (myotonic dystrophy, spinocerebellar atixia, Huntington’s disease, etc.) [4,5,6,7], as well as some forms of cancer [8,9,10,11]. These data strongly support the hypothesis that the sperm epigenome is well suited to facilitate mature sperm function, but that it contributes to events beyond fertilization
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