A recent study on genome-wide mutation rates has produced several very important discoveries. Understand that mutations generate sequence diversity and provide a substrate for selection. The rate of de novo mutations (mutations from the beginning) is therefore of major importance to evolution. Here we conduct a study of genome-wide mutation rates by sequencing the entire genomes of 78 Icelandic parent–offspring trios at high coverage. We show that in our samples, with an average father’s age of 29.7, the average de novo mutation rate is 1.20 × 10−8 per nucleotide per generation. Most notably, the diversity in mutation rate of single nucleotide polymorphisms is dominated by the age of the father at conception of the child. The effect is an increase of about two mutations per year. An exponential model estimates paternal mutations doubling every 16.5 years. After accounting for random Poisson variation, father’s age is estimated to explain nearly all of the remaining variation in the de novo mutation counts. These observations shed light on the importance of the father’s age on the risk of diseases such as schizophrenia and autism.
In the 1930s, the pioneering geneticist J. B. S. Haldane noticed a peculiar inheritance pattern in families with long histories of haemophilia. The faulty mutation responsible for the blood-clotting disorder tended to arise on the X chromosomes that fathers passed to their daughters, rather than on those that mothers passed down. Haldane subsequently proposed1 that children inherit more mutations from their fathers than their mothers, although he acknowledged that “it is difficult to see how this could be proved or disproved for many years to come”.
That year has finally arrived: whole-genome sequencing of dozens of Icelandic families has at last provided the evidence that eluded Haldane. More¬over, a study published inNature findsthat the age at which a father sires children determines how many mutations those offspring inherit2. By starting families in their thirties, forties and beyond, men could be increasing the chances that their children will develop autism, schizophrenia and other diseases often linked to new mutations. “The older we are as fathers, the more likely we will pass on our mutations,” says lead author Kári Stefánsson, chief executive of deCODE Genetics in Reykjavik. “The more mutations we pass on, the more likely that one of them is going to be deleterious.”
Haldane, working years before the structure of DNA was determined, was also correct about why fathers pass on more mutations. Sperm is continually being generated by dividing precursor cells, which acquire new mutations with each division. By contrast, women are born with their lifelong complement of egg cells.
Stefánsson, whose company maintains genetic information on most Icelanders, compared the whole-genome sequences of 78 trios of a mother, father and child. The team searched for mutations in the child that were not present in either parent and that must therefore have arisen spontaneously in the egg, sperm or embryo. The paper reports the largest such study of nuclear families so far.
“The increasing age of the father has a much bigger impact on a child’s health in a general way. Women are off the hook and we men are on it.”
Dr Allan Pacey, Chairman of the British Fertility Society, said: “It is a surprise to find that men transmit a higher number of mutations to their children than do women.
“Whilst not wanting to scare the children of older fathers, information like this is important to understand and should remind us that nature designed us to have our children at a young age and if at all possible men and women should not delay parenthood if they are in a position not to.”
“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 organization.
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.