Older men are more likely than younger ones to have children with autism or schizophrenia, and a new genetic study points to why: compared with younger dads, older fathers pass on significantly more random genetic mutations to their offspring that increase the risk for these conditions.
And when compared to the genetic contributions of the mother, older fathers are responsible for nearly all of a child’s random genetic mutations: a father’s age at conception may account for 97% of the new, or de novo, mutations found in his offspring, according to the new study led by Augustine Kong at deCODE Genetics in Iceland.
The findings may partly explain the rise in autism diagnoses in recent decades — the rate has reached 1 in 88 children in the U.S. — and they shore up previous studies finding that children born to older dads are more likely to have developmental and psychiatric disorders. The study also counters the common assumption that it is a mother’s advanced age that contributes to these problems. While older mothers are more likely to have children with chromosomal abnormalities, such as Down syndrome, the new study finds that it is the father’s age that accounts for virtually all of the genetic risk of autism and schizophrenia attributable to de novo mutations.
“Our data indicate there is probably much more reason to be concerned with the age of the father,” says Dr. Kari Stefansson, CEO of deCODE and senior author of the paper, published in Nature.
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De novo mutations are changes in DNA that arise spontaneously in egg or sperm cells around conception. Most people are born with many such mutations, and most of these changes are harmless. However, some of these mutations have been associated with increased autism risk in previous studies, with that risk rising along with the age of the father.
That makes sense since sperm, unlike women’s eggs, are made constantly throughout a man’s life. With each cell division, the entire genome is copied — and with three billion base pairs packed into 23 pairs of chromosomes, errors can occur in replication. The older men are, the more times his reproductive cells have continuously divided, generating new genetic material — sometimes under environmental exposures such as radiation or other chemical influences that can affect the accuracy with which DNA is replicated. In contrast, a woman’s egg cells don’t divide until they mature in the ovaries.
The study found that a 20-year-old dad passes on an average of 25 new genetic mutations to his child, while a 40-year-old passes 65. For each additional year in the father’s age, children gained two new mutations in their DNA, resulting in a doubling of the de novo mutation rate for every 16.5 years of paternal age. A mother transmits about 15 new mutations, regardless of age.
“It’s not surprising, and makes sense that it is this way,” says Stefansson.
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The study involved the sequencing of the full genomes of 78 trios of mother, father and child, in which the children were affected by either autism or schizophrenia but their parents had no mental disorder. The deCODE scientists were thus able to identify new mutations in children’s DNA that didn’t exist in the genetic material of the parents. The researchers also decoded the genomes of 1,859 unrelated Icelanders for comparison, in order to determine which mutations were meaningful and which were background noise.
The analysis showed that while paternal age had a statistically significant effect on mutation rates in children, maternal age did not. The deCODE scientists looked specifically at families affected by autism and schizophrenia because these conditions are caused by a range of mutations, and the researchers were more likely to detect an effect of father’s age with these conditions than with others; brain disorders are likely to be most affected by de novo mutations because more of our active genes play a role in the development of the brain than elsewhere in the body
But while new genetic mutations associated with a father’s age may account for 15% or more of cases of autism, that’s not the full story; at least half of the risk is believed to be due to inherited genes, along with other possible environmental exposures.
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The findings also give us insight into how our gene pool is changing, and what, in modern times, is driving the genetic diversity that is critical to the survival of our species. Every difference in our DNA that distinguishes each of us as individuals, or that separates Homo sapiens from other species, arguably got its start as a mutation. Some of these alterations in DNA occur by chance, during cell division, others are triggered by exposure to environmental factors, while still others are selected for when they happen to confer some survival advantage, such as an ability to ward off disease. “It’s extraordinarily important to determine the mutation rate and determine the factors that influence the mutation rate,” says Stefansson. “Mutations are the things that underpin the future diversity of our species.”
The age at which fathers decide to have children may be the driving force behind modern mutation rates, Stefansson and his colleagues found. Indeed, in Iceland, the researchers estimated that children born in 2011 would have 17% more de novo mutations than those born in 1980 (70 mutations versus 60). Over that time period, the average age of fathers rose from 28 to 33.
“It’s basically a compelling connection between the rise in mutation rate and the rise in prevalence of these diseases, [such as autism and schizophrenia],” Stefansson says.
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If the findings hold up and the paternal-age effect on the de novo mutation rate is found to affect children’s health broadly, “then collecting the sperm of young adult men and cold-storing it for later use could be a wise individual decision,” wrote Alexey Kondrashov of the University of Michigan in an editorial accompanying the new study.
But other experts say that may not be necessary. Not all such mutations are deleterious, and even the ones that are must occur in the right combinations to generate disease. “The observed effect is a significant one but not one necessarily to cause great worry among prospective older fathers,” Darren Griffin, a professor of genetics at University of Kent, wrote in a comment on the results. “There are three billion of letters in the DNA code of humans and the numbers of mutations detected in this study are in the dozens…and not realistically likely to deter more mature fathers from having children.” It might, however, give them pause before putting off fatherhood for too long.
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