Every man's sperm is fighting an evolutionary civil war – and over the years, it ups the risk of fathering a child with a genetic disorder
"I THOUGHT, 'Oh my god, I have mixed all the samples, I have made a massive mistake here'. And I tore my hair overnight." It was 2003, and Anne Goriely had just seen the results of a series of tests on sperm samples. She was looking at them to try to solve the riddle of a rare developmental disorder called Apert syndrome. At first sight, she thought that there had been some kind of contamination or mix-up.
But as Goriely tried to work out what had gone wrong, another explanation sprang to mind. "It just clicked: 'Maybe there is no contamination, maybe these are real data'," she recalls.
Goriely had stumbled upon a hitherto unknown process occuring in the testicles of every man. Like a slow form of cancer, these mutations cause stem cells in the testicles to divide abnormally, resulting in an increasing proportion of mutant sperm as men age and an ever growing chance of a mutant sperm fertilising an egg. "It is something that is happening to all men," says Goriely. "The effect is subtle but it is real."
These mutations have recently been tied to a handful of rare conditions but they may play a role in a range of far more common disorders, including autism and schizophrenia. It could explain why such disorders are so common – and why they might become commoner still in cultures in which men delay fatherhood until their thirties, forties or later.
And yet it's not all bad news. Similar mutations may also boost brain-cell division, so it's possible the same process played a key role in the evolution of our big brains.
Our story begins in the 1990s when Andrew Wilkie, a clinical geneticist at the University of Oxford, began investigating the causes of Apert syndrome. Normal development is disrupted in children with the syndrome, and they are born with a range of physical problems including fused toes and fingers, and abnormalities of the skull and face. "It's always a shock when it occurs," Wilkie says, because the parents are completely healthy.
Apert syndrome is, thankfully, a very rare disease, affecting just 1 in 60,000 people. But it should be far rarer. Unlike genetic diseases such as cystic fibrosis or sickle cell anaemia, which are the result of mutations passed down the generations, Apert syndrome is caused by new mutations that arise spontaneously during the development of sperm and egg cells.
New mutations are common. Every one of us is born with about 50 new mutations, though it is rare for them to have any noticeable effect. But the 3 billion DNA letters of our genome stretch a long way and mutations can appear anywhere along it. That means the odds of a random new mutation triggering a single specific disorder such as Apert syndrome should be far lower than 1 in 60,000.
So why is it relatively common? "It must be a big target," was Wilkie's first idea. Perhaps mutations occurring at any point along a vast chunk of DNA can trigger the disorder, making its appearance much more likely. In fact the opposite turned out to be true. Wilkie's team discovered that Apert syndrome is caused by mutations in one of just two specific sites in a gene called FGFR2 – a minuscule target (Nature Genetics, vol 9, p 165). It could be that these sites are especially vulnerable to mutation, and mutate at a far higher rate than elsewhere. Such "hotspots" do occur in other regions of the genome, although none of them is so localised. So what, Wilkie wondered, was special about these two sites in the FGFR2 gene?
Another piece of the jigsaw came from a study of parents of children with Apert syndrome, in which Wilkie discovered that the novel mutation was always in the sperm, rather than the egg (Nature Genetics, vol 13, p 48). Did that mean there was something special about these dads that made them produce mutant sperm, or were they just unlucky?
To find out, Goriely, who had recently joined Wilkie's team, decided to compare sperm samples from Apert dads and randomly chosen men. What she discovered will disturb any would-be parents: it turns out that almost all men produce sperm with these mutations, though usually in very small numbers. The highest level they found was 1 in 6000 sperm in one man – but any couple could have a child with Apert syndrome. It just comes down to how the genetic dice fall. "Every now and then you are going to have a dad who is unlucky," says Wilkie.
This still did not explain the relative commonness of Apert syndrome. But there was something odd about the results that provided another clue.
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