Older fathers pass on more brand-new genetic mutations to their children… (NHGRI )
Scientists have pinpointed a likely source for many cases of autism and schizophrenia: Men who become fathers later in life pass on more brand-new genetic mutations to their offspring.
The finding buttresses observations from population studies that rates of these disorders are more prevalent in children born to older fathers, sometimes by a factor of 2 or more, experts said.
The research, published online Wednesday by the journal Nature, also should help correct an overemphasis on the riskiness of women giving birth at older ages, some researchers said.
Although older mothers are more likely to have children with chromosomal disorders such as Down syndrome because of problems with older eggs, the study found that practically all of the novel mutations detected in children came from the father's sperm.
And the older the father, the more mutations he passed on.
A man who was 29.7 years old at the time he fathered a child contributed 63 new mutations, on average, to his offspring, while a man who was 46.2 would contribute 126 mutations, the researchers calculated.
Many of these mutations will have no effect on the children, scientists noted. But some will — and that is significant because more older men have been fathering children in developed countries over the last few decades, said Dr. Kari Stefansson, the study's senior author.
Stefansson, a human geneticist and neurologist at the University of Iceland and chief executive of deCODE Genetics in Reykjavik, noted that the average age of Icelandic fathers at the time of a child's conception was 27.9 years in 1980 and 33 years in 2011.
"Similar changes have taken place all over the Western world," he said. "It's very likely to have made meaningful contributions to increased diagnoses of autism in our society. What percentage is due to that and what percentage is due to increased focus on diagnosis, I cannot tell you."
Stefansson and his team sequenced the entire genomes of 78 mother-father-child "trios" to detect cases in which a single "letter" in the DNA code had been altered. Of the children, 44 had received a diagnosis of autism spectrum disorder and 21 had schizophrenia.
The scientists were able to identify stretches of the children's DNA that came from the father or mother. But they also detected new mutations that did not exist in the genome of either parent.
The scientists calculated that the age of the father could account for 97% of the variation in these new mutations in children. They also found that the rate at which the father generated new mutations increased with age.
There's a good biological reason why older fathers contribute more new mutations than older mothers, the researchers said.
The types of mutations examined in the study tend to occur when DNA is being copied. If this happens in sperm and eggs or in the cells that give rise to them, they can be passed on to the child.
In the case of a woman, all her eggs are produced to near-readiness before she is even born. In contrast, a man produces sperm in great quantities throughout his adult life. That means DNA is being copied at ages when errors may be more frequent and the mechanisms to chemically correct them may not function as efficiently.
"It's been known that aged sperm has more mutations," said Dr. Daniel Geschwind, director of UCLA's Center for Autism Research and Treatment. What's striking about the new study, he added, is "the magnitude and extent of the effect."
With more than half of all genes being active in the brain, there's reason to believe that these mutations would be especially likely to result in brain disorders such as autism and schizophrenia, scientists said.
But though such disorders were the focus of the study, there is no reason why the effect should be limited to such conditions, Geschwind said. It's known, for example, that rates of non-familial cases of achondroplasia, a type of dwarfism, and a condition known as Alport syndrome that affects kidney function increase with the age of the father.
Autism is the focus of intensive research efforts, and several DNA-sequencing studies published this spring strongly implicated new mutations from fathers as the cause of some cases of the disorder that don't seem to run in families.
It's a powerful approach for identifying genes that may be involved in this spectrum of conditions, Geschwind said.
Indeed, the new study pinpointed several genes of interest, including one called neurexin 1, which helps nerve cells make connections with one another and had previously been linked to schizophrenia.
Two others were cullin 3 and EPH receptor B2; new mutations in these genes have already been found in a few children with autism.