While women have long been told that fertility drops off as they age, men may have a biological clock as well. The offspring of older male mice have several copy number mutations in gene regions associated with developmental disorders, according to a new study publishing today (August 30) in Translational Psychiatry. The findings could explain why the children of older men have higher rates of schizophrenia and autism than those with younger fathers.
“This study is so important,” said Dolores Malaspina, a translational neuroscientist at the New York University Langone Medical Center, who was not involved in the study. Researchers have been reluctant to believe that mutations in sperm from older men could lead to developmental disorders, she said, and studies like this could go a long way towards convincing skeptics.
In 2006, Malaspina and her colleagues studying an Israeli cohort found children of men over the age of 40 were almost 6 times more likely to have autism than those with fathers younger than 30. Other studies have shown that people suffering from schizophrenia and autism had a more copy number mutations, where a stretch of DNA is missing or replicated, than those without the disorders. But it wasn’t clear whether advancing paternal age led to these mutations, or if the mutations were the cause of the disorders, said John McGrath, a psychiatrist and epidemiologist at the Queensland Brain Institute, at the University of Queensland in Australia.
To see whether age in itself could cause copy number mutations to spontaneously form, McGrath and his colleagues mated youthful, 3-month-old female mice with either similarly-aged male partners or middle-aged males (around 12 to 16 months old). Sure enough, the offspring of older dads had six new copy number mutations, including several in genes previously associated with autism, schizophrenia, and brain development.
“We’ve known for many years that in older mothers the offspring has a slightly increased risk of various adverse health outcomes, like Down syndrome. But epidemiology and animal models are suggesting the fertility clock ticks for men also.” he said.
It’s not surprising that men, as they age, may be prone to these heritable spontaneous mutations: male germ line cells, which produce sperm, divide every 16 days over a man’s lifetime, giving older men hundreds of opportunities to rack up mutations in their sperm.
But copy number mutations may not be the only reason that older fathers have children with higher rates of developmental disorders. It’s possible that epigenetic changes or point mutations also play a role, Malaspina said.
Follow-up work should look at some of the genes affected by mutations in mice to see if they are found more frequently in the children of older dads, McGrath said.
T. Flatscher-Bader, et. al, “Increased de novo copy number variants in the offspring of older males,” Translational Psychiatry, doi:10.1038/tp.2011.30, 2011.