Men who have kids later in life may pass on more new genetic mutations to their offspring, possibly raising their child's risk of disorders such as autism and schizophrenia, new research suggests.
New mutations arise in the sperm cells of men near the time of conception instead of being passed down through generations. They have been associated with relatively rare cases of non-hereditary autism.
Researchers in Iceland searched the genomes of 78 families for new mutations as they first appeared and looked at how the number of these mutations in children was related to the age of their parents. In most of the families, the child had either non-hereditary autism or schizophrenia.
How the study was done
The study, which was published in the journal Nature, found that every year a man ages, he is predicted to pass on more than two additional new (or "de novo") mutations. More than 97% of these new mutations in children were explained by having an older dad.
"The father is an incredibly important contributor to mutations, and even if de novo mutations happen randomly, the more mutations you have, the more likely you will have one in a gene that matters," said study author Dr Kari Stefansson, CEO of deCODE Genetics, a genome analysis company based in Reykjavik, Iceland.
Previous research has linked higher rates of spontaneous mutations to older dads based on the sequence of select regions of the genome; this study is the first to make the connection based on data from the entire genome of parents and their children, Stefansson said.
"This study further establishes that paternal age is a risk factor for [non-hereditary] autism," said Daniel Smith, senior director of discovery neuroscience at Autism Speaks, an autism research and advocacy organisation.
Although it is not known how many cases are autism are non-hereditary, it is so far only thought to be less than 1 percent of autism cases, Smith said.
The rate of autism spectrum disorder in the United States has been steadily climbing and is now estimated to affect one in 88 children, according to the US Centers for Disease Control and Prevention.
"Whether [paternal age] accounts for the increased prevalence of autism by itself is very unlikely," Smith said. "It's definitely in the mix as an important risk factor."
The current study of 78 families in Iceland included 44 children with an autism spectrum disorder and 21 children with schizophrenia. In most cases, the parents were not affected by these disorders.
Stefansson and his colleagues analysed the entire genomes of the parent-child sets for a specific type of mutation called single nucleotide polymorphisms (SNP), which essentially are typos that affect a single letter in the DNA code.
What the study showed
The team found that the number of new mutations was strongly associated with the age of the father, whereas the relationship between mutation rate and maternal age was not statistically significant.
In addition, the data suggest that the age of the father is linked to a steady increase in mutations, instead of reaching a "tipping point" age after which mutations were more likely, Stefansson said.
Men are probably more likely to transmit new mutations to their offspring as they age because their reproductive cells divide and produce sperm throughout their lifetime, and every cell division is an opportunity for genetic errors to be made. In contrast, women are born with their full set of eggs.
The team uncovered new mutations in several genes that have been implicated in autism and schizophrenia, as well as nervous system development and behavioural changes.
The role of new mutations in disease risk is not limited to autism and schizophrenia, and they could contribute to other diseases that have non-hereditary cases, such as epilepsy, Stefansson noted. "It is beginning to look like there is a fairly large number of diseases where the contribution of de novo mutations is going to be significant," he said.
In addition to spontaneous mutations, environmental factors could play a part in non-hereditary autism cases, Smith said, explaining that unknown environmental factors, which older men have had more time to be exposed to, could promote genetic errors during sperm production.
Even though the rate of new mutations increases in children with age of the father, this should not be an argument for older men to avoid procreating or for younger men to freeze their sperm, Stefansson said.
"We don't know how large a percentage of cases of autism and schizophrenia are caused by de novo mutations," he explained. "The risk is not huge."
"On a grander scale, in the context of our species, the increasing mutation rate increases diversity when we are evolving," Stefansson said. "Getting rid of extra mutations might make us as a species less fit to survive the next natural disaster."
"This study should not be used as guidance for parents," Smith said. "Many cases of autism are from parents in their 20s."
Signs and symptoms of autism
For more about the signs and symptoms of autism, visit Autism Speaks.
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