Older maternal age has been known to be associated with increased risk of several congenital disorders such as trisomy 21, which results in Down’s syndrome. Female fertility is also affected by increasing age with the chances of conception dropping significantly after the age of 35 years. Researchers, lead by Dr. John McGrath, have provided evidence that suggests that increasing paternal age also influences the health of children. The results of their research were published online in the journal Translational Psychiatry. Increasing paternal age has been shown to be associated with greater copy number variants in the male germline. Copy number variants are structural alterations in the genomic DNA where one section may be duplicated or deleted. Copy number variants have been associated with the development of autism, schizophrenia, idiopathic learning disability, and other neuropsychiatric disorders. The researchers used a mouse model to test the hypothesis that offspring of older males have increased risk of de novo copy number variants. To test the hypothesis, male mice that were 3, 12, and 16 months old were mated to 3 month old female mice. The investigators used applied genome wide microarray screening to identify distinct copy number variants in the offspring of older male mice. The occurrence of these copy number variants was confirmed by competitive quantitative PCR techniques. The researchers showed that 6 de novo copy number variants were detected in the offspring of older male mice while none of the copy number variants were detected in the offspring of younger control male mice. One of the de novo copy number variants involved Auts2, also known as autism susceptibility candidate 2, and other copy number variants involved genes associated with the development of schizophrenia, autism, and central nervous system development. The authors wrote, “This is the first experimental demonstration that the offspring of older males have an increased risk of de novo [copy number variants]. Our results support the hypothesis that the offspring of older fathers have an increased risk of neurodevelopmental disorders such as schizophrenia and autism by generation of de novo [copy number variants] in the male germline”. The researchers concluded that increased copy number variants which occur in male spermatogenesis over time may be the biological mechanism that contributes to the epidemiologic observation that children of older males have increased risk of neuropsychiatric disorders.
T Flatscher-Bader et al. “Increased de novo copy number variants in the offspring of older males” Translational Psychiatry published online ahead of print August 30, 2011 doi:10.1038/tp.2011.30