Older fathers pass on more genetic mutations, study shows

According to scientists, rates of conditions such as autism and schizophrenia could be a result of the rising age of fatherhood

The rising age of fatherhood could be a factor in increased rates of conditions such as schizophrenia and autism, scientists say, after new research suggesting that older fathers pass on more genetic mutations to their children.

A child will normally have 60 new mutations in its genetic sequence (out of a total of more than 3bn DNA letters) passed on from its parents. Despite being a tiny fraction of the sequence, these differences are the root of much of the diversity in the human genomes and, over long periods of time, amount to a significant force in human evolution.

"Most of these mutations are probably neutral," said Kari Stefansson, chief executive of deCODE Genetics in Iceland, who led the latest work, published on Wednesday in Nature.

"Occasionally, they will be deleterious, they will lead to a disease. Once in a blue moon, you will get a mutation that confers a selective advantage. We showed that some of these mutations are in genes that have been indicated in diseases like autism and schizophrenia."

A single-letter mutation in a gene called APP can confer protection against Alzheimer's disease and help people live longer, for example, while a single-letter mutation in the CFTR gene causes cystic fibrosis. Similar single-letter mutations in genes are behind sickle cell anaemia and even colour blindness.

Stefansson said a 40-year-old father was approximately twice as likely to conceive a child that developed autism as a 20-year-old father, although the overall risk remained low. The increase in risk factor for schizophrenia went up by a similar amount. "It's incredibly important to recognise that, even though there is a doubling in risk of a 40-year-old father conceiving a child that develops schizophrenia compared to a 20-year-old, the overall risk is still not above 1%," he said.

Stefansson urged fathers not to worry about having children at an older age. "This has been a fact of life for centuries – nothing has changed with this. This is only giving us an opportunity to quantify the changes that are happening in genomes," he said.

He hoped that the work would, however, shift some of the focus from the increasing age of the mother to the increasing age of the father when it came to concerns about developmental disorders in children.

Alexey Kondrashov of the department of ecology and evolutionary biology at the University of Michigan, in an accompanying analysis for Nature, said: "In humans, as many as 10% of point mutations are deleterious, so [Stefansson's] findings suggest that an average newborn carries six new deleterious mutations. Although most of these mutations will, on their own, have only mild effects, collectively they could have a substantial impact on health."

Stefansson's team studied the mutation rates in 78 Icelandic parent-offspring trios and found that a 20-year-old father transmits, on average, around 25 mutations to his child, whereas a 40-year-old father transmits around 65.

Every additional year of the father's age meant an average of two extra mutations in the child. In comparison, the number of new mutations passed on by the mother was always around 15, regardless of her age.

In Iceland, where the study was carried out, the age of fathers at conception had risen from an average of 27.9 years in 1980 to 33 years in 2011, mainly owing to increased education and the higher use of contraception.

In the UK, the average age of fathers in 2008 was 32.4, up from 31.5 a decade earlier.

Autism spectrum disorders are known to have some genetic triggers and increased rate of mutations from older fathers might be a factor.

Kondrashov said it was unsurprising that disorders of brain function, such as autism, schizophrenia, dyslexia and reduced intelligence, seemed particularly affected by the age of the father. "This is consistent with the fact that more genes are expressed in the brain than in any other organ, meaning that the fraction of new mutations that will affect its functions is the highest."

He added that the reason that older fathers passed on more mutations was easily explained by the fact that "in mammals, male germ cells (sperm) are continually produced, so they go through many more cell divisions over the course of a generation than do female germ cells (eggs), which are not actively dividing in individuals of reproductive age".

Darren Griffin, professor of genetics at the University of Kent, said that, though the effect observed by Stefansson was significant, it should not necessarily cause great worry among prospective older fathers. "This study only considered single DNA letter changes. However, overall DNA damage in the sperm as well as more gross genomic [chromosomal] age-related changes on the egg should be considered. The maternal age effect on chromosomal abnormalities is far more potent and measurable."

Allan Pacey, an andrologist at the University of Sheffield and chairman of the British Fertility Society, said it was a surprise to find that men transmitted a higher number of mutations to their children than women.

Contributor

Alok Jha, science correspondent

The GuardianTramp

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