Age-related sperm DNA methylation changes are transmitted to offspring and associated with abnormal behavior and dysregulated gene expression

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Advanced paternal age (APA) has been shown to be a significant risk factor in the offspring for neurodevelopmental psychiatric disorders, such as schizophrenia and autism spectrum disorders. During aging, de novo mutations accumulate in the male germline and are frequently transmitted to the offspring with deleterious effects. In addition, DNA methylation during spermatogenesis is an active process, which is susceptible to errors that can be propagated to subsequent generations. Here we test the hypothesis that the integrity of germline DNA methylation is compromised during the aging process. A genome-wide DNA methylation screen comparing sperm from young and old mice revealed a significant loss of methylation in the older mice in regions associated with transcriptional regulation. The offspring of older fathers had reduced exploratory and startle behaviors and exhibited similar brain DNA methylation abnormalities as observed in the paternal sperm. Offspring from old fathers also had transcriptional dysregulation of developmental genes implicated in autism and schizophrenia. Our findings demonstrate that DNA methylation abnormalities arising in the sperm of old fathers are a plausible mechanism to explain some of the risks that APA poses to resulting offspring.

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We thank Dr Timothy Bestor for invaluable help with experimental design and helpful discussions; Jackie Tinsley, Prashant Donthamsetti, Heather El-Amamy and Matthew Gingrich for experimental help; Caitlin McOmish for helpful discussions. This research was supported by grants from the Simons Foundation and the National Institute of Mental Health (5R21MH073794) to JAG, the G Harold & Leila Y Mathers Foundation to DM and JAG; a NARSAD Young Investigator Award and Sackler Award to MHM.

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Correspondence to M H Milekic.

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