Older dads pass more gene mutations to kids

Thursday, 23 August 2012
AFP
A father's age is by far the biggest factor determining the rate of new, uninherited genetic mutations in his offspring. Older dads are more likely to pass on genetic mutations that may boost the risk of schizophrenia and autism, a new study has found. A father's age is by far the biggest factor determining the rate of new, uninherited genetic mutations in his offspring, say European scientists.
"The age of the father is the most important factor to determine the number of new mutations that happen when a child is conceived," says study co-author Kari Stefansson from Iceland 's DeCODE genetics company. From a man's peak reproductive years in adolescence, the rate of new or 'de novo' gene mutations triggered at conception in his children rises by about two per year, the researchers found.

The rate doubles every 16 years, meaning that the baby of a 36-year-old father would have twice as many new mutations than that of a 20-year-old. "Seeing an association between father's age and mutation rate is not surprising, but the estimated exponential effect of paternal mutations doubling every 16.5 years is striking," they write in this week's Nature.

Though de novo mutations are not necessarily harmful, it can take only one change in a key gene to cause some types of disease - and the more mutations the higher the risk. Previous research has shown a link between de novo mutations and autism and schizophrenia, and also a statistical link between the diseases and paternal age. "Our contention is that a part of the increase in the diagnosis of autism that is being made these days is accounted for by increase in the age of the father," says Stefansson. Further research is likely to show a similar link to other genetic illnesses, especially diseases of the brain, he adds.
 
Age of paternity The results from what is claimed to be the biggest-ever study of its kind suggest that disproportionate attention has been paid to the age at which women give birth. While men aged 20 contribute around 25 de novo mutations to their children, men aged 40 contribute around 65. But women contribute roughly 15 de novo mutations regardless of their age. "We have in a very unjust manner been pointing the finger at the old mother when we should have been careful when it comes to the old father. It is clearly dangerous to have an old father," says Stefansson.

Maternal age is linked to Down's syndrome and other chromosomal diseases that develop through a process that is different to the type of genetic mutation described in this study.

The mutations in the Nature report are caused by cell division during processes like sperm production.
Stefansson and a team in Iceland , Denmark and Britain sequenced the genomes of 78 parent-child trios, as well as hundreds of control subjects, looking for variants in the sequence of a child's genetic code that did not exist in the parents. They found that the rate of increase in de novo mutations could be ascribed to the tune of 97.1 per cent, "maybe entirely", to the age of the father- an outcome that "surprised" the researchers. The remaining 2.9 percent was ascribed to environmental factors and other random influences, Stefansson says, adding there was "no connection" between the mother and age-related increase in the rate of mutations.

Impact on health

The study is the most precise and definite we have so far, Alexey Kondrashov of the University of Michigan 's department of ecology and evolutionary biology writes in an accompanying commentary in Nature. In humans many as 10 per cent of point mutations are deleterious, but this study suggests that an average newborn carries 6 new deleterious mutuations, says Kondrashov. "Although most of these mutations will, on their own, have only mild effects, collectively they could have a substantial impact on health."

Kondrashov says the study suggests it might be a "wise individual decision" for young men to cold-store their sperm for later use.
The age of new fathers in the Western world has been climbing in recent decades, and the number of first-time dads over 40 is growing. Official statistics show that in Iceland, the average age of fathers at conception rose from 27.9 in 1980 to 33 in 2011.

Contrary to de novo mutations, which occur during cell division, inherited gene mutations are transferred at an equal rate by the father and mother, are more common and thus more commonly responsible for disease.
Scientists believe that both inherited and new mutations are responsible for diseases like autism and schizophrenia, but have not worked out the ratio of blame.
On the positive side, de novo gene mutations are a necessary element of human evolution, allowing us to adapt to our changing environment.