Project description:The offspring of older fathers have an increased risk of neurodevelopmental disorders such as schizophrenia and autism. It has been proposed that de novo point mutations and copy number variants (CNVs) in the continually dividing spermatogonia underlie this association. In light of the evidence implicating CNVs with schizophrenia and autism, here we use a mouse model to test the hypothesis that the offspring of older males have an increased risk of de novo CNVs. Three-month-old and fourteen- to sixteen-month-old C57BL/6J sires were mated with three-month-old dams to create control offspring and offspring of old sires, respectively. Applying genome-wide microarray screening technology, seven distinct CNVs were identified in a discovery set of twelve offspring and their parents. Competitive quantitative PCR was employed to confirm the variants and establish their frequency in a replication set of 77 offspring and their parents. Six de novo CNVs were detected in the offspring of older sires, while none were detected in the control group. One of the de novo CNVs involved Auts2 (autism susceptibility candidate 2), and other CNVs included genes linked to schizophrenia, autism and brain development. Two of the CNVs were associated with behavioural and/or neuroanatomical phenotypic features. This is the first experimental demonstration that the offspring of older males have more de novo CNVs. The results suggest that offspring of older fathers may be at increased risk of neurodevelopmental disorders such as schizophrenia and autism via the generation of de novo CNV in the male germline. In light of the trends for delayed parenthood in many societies, and in light of the potential for these CNVs to accumulate over subsequent generations, the impact of these mechanisms on the health of future generations warrants closer scrutiny. 2 sires of advanced paternal age (12-16 months of age) and 2 control (3 months of age) sires were mated to dams (3 months of age) to create 6 offspring of advanced paternal age (APA) and 6 control offspring (C), respectively, with an even number of sexes within each group of offspring. A commerical aCGH and a custom CNV array (both supplied by Agilent) were used in combination to detect copy number variations in the genomes of the offspring and their parents. DNA from all male animals was hybridized against a male reference animal and that from all female animals against a female reference animal.

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Effect of Advanced Paternal Age on Copy Number Variation in Offspring (custom array)

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