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Testicular timebomb turns sperm selfish
Testicular time bomb In every man’s testicles, there’s a runaway cancer‑like process churning out mutant sperm. What are the consequences, asks Michael Le Page
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 46 | NewScientist | 22 February 2014
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? >
Emiliano Ponzi
22 February 2014 | NewScientist | 47
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.
Is it bad to be an older dad? As men get older, the risk of them fathering children with various disorders, including autism and schizophrenia, rises significantly. This paternal age effect was thought to be due to the slow accumulation of mutations in the stem cells that produce sperm, but the selfish sperm effect (see main story) may play a role too. So should men be encouraged to have children in their 20s rather than waiting until their 30s or 40s. Probably not. Although there is a big increase in risk for many disorders, it’s a big increase in a very small risk. A 40-year-old is about 50 per cent more likely to father an autistic child than a 20-year-old is, for instance, but the overall risk is only about 1 per cent to start with. Having older parents may also be beneficial – giving their children a more stable home environment, for example. From a society-wide perspective, however, a doubling in the number of people with disorders such as autism and schizophrenia is significant. A few women already freeze their eggs while they are still young to ensure they can have children in later life. In theory, young men could be offered the chance to freeze their sperm and undergo IVF later. But this would be controversial and costly. “Do we really want to go this way?” asks Anne Goriely at the University of Oxford. “I don’t know.”
48 | NewScientist | 22 February 2014
This still did not explain the relative commonness of Apert syndrome. But there was something odd about the results that provided another clue. Cells have two copies of most genes, only one of which is passed on in sperm. New mutations should be equally likely in both copies. But when Goriely looked at sperm from Apert and non-Apert dads, she got a shock: the mutations were nearly always in the same copy of the FGFR2 gene. This is what made her think the samples were contaminated on that night back in 2003. As Goriely agonised over the results, she had a brainwave. “I rushed into Andrew’s office and said, ‘There’s more to it. We have selection here’,” she says. Natural selection occurs when individuals with a particular trait are more likely to reproduce than those without it, making a trait more common in a population. Goriely realised a similar process might be selecting for sperm with the Apert mutation. Men produce more than 100 million sperm every day. The sperm arise from stem cells called spermatogonia that line the tubules inside the testes. When these stem cells divide, one of the cells turns into sperm while the other stays a spermatogonium (see diagram, below). Sperm can therefore be produced throughout a man’s life while keeping the overall number of stem cells constant. Every now and then, a spermatogonium will mutate. Sometimes the cell dies but most mutations have no obvious effect, meaning the mutant stem cells will continue to divide and pass on the new mutation to the sperm and stem cell they create. Over the course of a man’s lifetime, the number
with mutations will go up – but the rise should be slow and steady. But what if some mutations give the stem cells a selective advantage by making them divide abnormally and produce more than one daughter spermatogonium each? One such “selfish spermatogonium” arising in the testicles of a young man could give rise to thousands of these mutant stem cells after a decade or two, each carrying a copy of the mutated gene. The proportion of mutant sperm would increase at an exponential rate, rather than linearly.
“Most men live their entire lives not realising their family jewels are becoming tarnished” The mutant stem cells have effectively taken a step towards becoming cancerous, although further mutations would be needed for a tumour to form. Yet unless they fathered a child with Apert syndrome, most men would go to their graves without realising that their family jewels were slowly becoming tarnished. This kind of sperm selection would neatly explain the result that had Goriely tearing her hair out: if Apert syndrome is relatively common because a single mutant gene in a single cell becomes amplified by cell division, the mutation would always be in the same copy of the gene. The hard part was proving it. “There was quite a lot of controversy over whether this was a real phenomenon
The selfish generation Why some kinds of mutation are surprisingly common in sperm Sperm are produced when stem cells called spermatogonia divide, to produce sperm and one stem cell
NORMAL STEM CELL
But certain mutations make stem cells divide abnormally, meaning they sometimes produce two stem cells
Over time, the numbers of mutant, or “selfish”, stem cells and sperm increase exponentially
MUTANT STEM CELL
HEALTHY SPERM
DAUGHTER STEM CELLS MUTANT SPERM
TESTICLE
From stem cells to sperm – healthy production in action
Ed Reschke/getty
or not,” says Wilkie. “Then little by little we built up evidence.” One key piece came from Norman Arnheim at the University of Southern California, Los Angeles. He had been studying achondroplasia, or dwarfism, whose odds are also considerably higher than you would expect, given that almost all cases involve a mutation in a single DNA letter. After reading Goriely and Wilkie’s 2003 paper, Arnheim’s team turned its attention to Apert syndrome, looking to see where cells with FGFR2 mutations were physically located in the testes. They found them clustered together in distinct areas – exactly as you would expect if a single selfish spermatogonium was giving rise to lots of selfish daughter cells (PLoS Biology, vol 5, p e224). So far, researchers have found mutations in five genes that can turn spermatogonia selfish. The genes are all involved in a cellular signalling system called the RAS pathway, which helps control cell division. “For this small group of mutations, the evidence is incontrovertible,” says Wilkie. There are undoubtedly more mutations to discover. But how many more? And what conditions do they cause? “The remaining question is whether what we have discovered is the tip of an iceberg,” says Goriely. We have known for some time that the children of older fathers are more likely to suffer from a range of disorders. Most are rare, such as Apert syndrome, but the list also includes some that are fairly common, from certain cancers to autism and schizophrenia. Children born to fathers over 35 years old, for instance, can be three times as likely to develop schizophrenia. This paternal age effect is usually attributed to the slow accumulation of mutations in spermatogonia, but the selfish sperm effect might also be at work. Wilkie and Goriely are particularly intrigued by the connection to the RAS pathway. That’s because as well as affecting sperm cell division, it also helps control cell proliferation in the brain, and disruption to this pathway is emerging as a major factor in autism. “There is quite a striking overlap,” says Goriely. “It is possible it is just chance, but unlikely.” Autism is certainly not due to a single mutation, unlike Apert syndrome. But there is growing evidence that new mutations play a role (Nature, vol 485, p 237) and new mutations are also more common in the sperm of older men. Mutations affecting the RAS pathway might increase brain growth
in their offspring by causing neurons to proliferate as well as sperm. A study published this year found an association between RAS mutations and autistic traits (Journal of Medical Genetics, vol 51, p 10). We don’t yet know whether these mutations are more common than expected because of the selfish sperm effect. However, “it has been known for years that children with autism tend to have overgrown brains”, says geneticist Jonathan Sebat at the University of California, San Diego, whose team has identified many mutations associated with autism and schizophrenia. Sebat thinks selfish selection almost certainly contributes to the paternal age effect, though he suspects it plays only a small part (see “Is it bad to be an older dad?”,
“A rise in the age of new fathers would boost the selfish mutations of each generation” left). To confirm it, researchers need to look at specific mutations to see if any of them increase exponentially rather than at a linear rate as men age. Even though the selfish sperm effect may be of little concern to most people, it could have a very marked effect over successive generations. It may have played a big role in our evolution, and could yet shape our future. None of the mutations identified so far, such as those that cause Apert syndrome,
tend to spread in populations because they are serious enough to prevent people having children. The big question is whether mutations exist that boost spermatogonial division with only a mildly harmful effect on the individuals that carry them. Such mutations could spread and persist in a population. And this would have worrying implications. A rise in the average age of fathers would boost the number of selfish mutations entering the population in each successive generation, and thus lead to a growing burden of disease. “That’s certainly the logical conclusion,” says Wilkie, although he stresses that for now this remains speculation. In theory, the selfish sperm effect would also have increased in strength a few million years ago, as our ancestors split from apes and began to live longer lives. It’s fascinating to ponder the role this could have played in our evolution, says Sebat.“New mutations would have a clear bias to increased brain growth,” he suggests. There are all kinds of theories to explain why hominin brains began to expand about 2.5 million years ago, from a switch to a seafood diet to the invention of cooking. The idea that it may have been a side effect of a process taking place in the testicles is surely the most extraordinary yet. But then they do say men’s brains are ruled by their genitals. Perhaps this is true in a way we never imagined. n Michael Le Page is a features editor for New Scientist 22 February 2014 | NewScientist | 49
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 46 | NewScientist | 22 February 2014
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? >
Emiliano Ponzi
22 February 2014 | NewScientist | 47
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.
Is it bad to be an older dad? As men get older, the risk of them fathering children with various disorders, including autism and schizophrenia, rises significantly. This paternal age effect was thought to be due to the slow accumulation of mutations in the stem cells that produce sperm, but the selfish sperm effect (see main story) may play a role too. So should men be encouraged to have children in their 20s rather than waiting until their 30s or 40s. Probably not. Although there is a big increase in risk for many disorders, it’s a big increase in a very small risk. A 40-year-old is about 50 per cent more likely to father an autistic child than a 20-year-old is, for instance, but the overall risk is only about 1 per cent to start with. Having older parents may also be beneficial – giving their children a more stable home environment, for example. From a society-wide perspective, however, a doubling in the number of people with disorders such as autism and schizophrenia is significant. A few women already freeze their eggs while they are still young to ensure they can have children in later life. In theory, young men could be offered the chance to freeze their sperm and undergo IVF later. But this would be controversial and costly. “Do we really want to go this way?” asks Anne Goriely at the University of Oxford. “I don’t know.”
48 | NewScientist | 22 February 2014
This still did not explain the relative commonness of Apert syndrome. But there was something odd about the results that provided another clue. Cells have two copies of most genes, only one of which is passed on in sperm. New mutations should be equally likely in both copies. But when Goriely looked at sperm from Apert and non-Apert dads, she got a shock: the mutations were nearly always in the same copy of the FGFR2 gene. This is what made her think the samples were contaminated on that night back in 2003. As Goriely agonised over the results, she had a brainwave. “I rushed into Andrew’s office and said, ‘There’s more to it. We have selection here’,” she says. Natural selection occurs when individuals with a particular trait are more likely to reproduce than those without it, making a trait more common in a population. Goriely realised a similar process might be selecting for sperm with the Apert mutation. Men produce more than 100 million sperm every day. The sperm arise from stem cells called spermatogonia that line the tubules inside the testes. When these stem cells divide, one of the cells turns into sperm while the other stays a spermatogonium (see diagram, below). Sperm can therefore be produced throughout a man’s life while keeping the overall number of stem cells constant. Every now and then, a spermatogonium will mutate. Sometimes the cell dies but most mutations have no obvious effect, meaning the mutant stem cells will continue to divide and pass on the new mutation to the sperm and stem cell they create. Over the course of a man’s lifetime, the number
with mutations will go up – but the rise should be slow and steady. But what if some mutations give the stem cells a selective advantage by making them divide abnormally and produce more than one daughter spermatogonium each? One such “selfish spermatogonium” arising in the testicles of a young man could give rise to thousands of these mutant stem cells after a decade or two, each carrying a copy of the mutated gene. The proportion of mutant sperm would increase at an exponential rate, rather than linearly.
“Most men live their entire lives not realising their family jewels are becoming tarnished” The mutant stem cells have effectively taken a step towards becoming cancerous, although further mutations would be needed for a tumour to form. Yet unless they fathered a child with Apert syndrome, most men would go to their graves without realising that their family jewels were slowly becoming tarnished. This kind of sperm selection would neatly explain the result that had Goriely tearing her hair out: if Apert syndrome is relatively common because a single mutant gene in a single cell becomes amplified by cell division, the mutation would always be in the same copy of the gene. The hard part was proving it. “There was quite a lot of controversy over whether this was a real phenomenon
The selfish generation Why some kinds of mutation are surprisingly common in sperm Sperm are produced when stem cells called spermatogonia divide, to produce sperm and one stem cell
NORMAL STEM CELL
But certain mutations make stem cells divide abnormally, meaning they sometimes produce two stem cells
Over time, the numbers of mutant, or “selfish”, stem cells and sperm increase exponentially
MUTANT STEM CELL
HEALTHY SPERM
DAUGHTER STEM CELLS MUTANT SPERM
TESTICLE
From stem cells to sperm – healthy production in action
Ed Reschke/getty
or not,” says Wilkie. “Then little by little we built up evidence.” One key piece came from Norman Arnheim at the University of Southern California, Los Angeles. He had been studying achondroplasia, or dwarfism, whose odds are also considerably higher than you would expect, given that almost all cases involve a mutation in a single DNA letter. After reading Goriely and Wilkie’s 2003 paper, Arnheim’s team turned its attention to Apert syndrome, looking to see where cells with FGFR2 mutations were physically located in the testes. They found them clustered together in distinct areas – exactly as you would expect if a single selfish spermatogonium was giving rise to lots of selfish daughter cells (PLoS Biology, vol 5, p e224). So far, researchers have found mutations in five genes that can turn spermatogonia selfish. The genes are all involved in a cellular signalling system called the RAS pathway, which helps control cell division. “For this small group of mutations, the evidence is incontrovertible,” says Wilkie. There are undoubtedly more mutations to discover. But how many more? And what conditions do they cause? “The remaining question is whether what we have discovered is the tip of an iceberg,” says Goriely. We have known for some time that the children of older fathers are more likely to suffer from a range of disorders. Most are rare, such as Apert syndrome, but the list also includes some that are fairly common, from certain cancers to autism and schizophrenia. Children born to fathers over 35 years old, for instance, can be three times as likely to develop schizophrenia. This paternal age effect is usually attributed to the slow accumulation of mutations in spermatogonia, but the selfish sperm effect might also be at work. Wilkie and Goriely are particularly intrigued by the connection to the RAS pathway. That’s because as well as affecting sperm cell division, it also helps control cell proliferation in the brain, and disruption to this pathway is emerging as a major factor in autism. “There is quite a striking overlap,” says Goriely. “It is possible it is just chance, but unlikely.” Autism is certainly not due to a single mutation, unlike Apert syndrome. But there is growing evidence that new mutations play a role (Nature, vol 485, p 237) and new mutations are also more common in the sperm of older men. Mutations affecting the RAS pathway might increase brain growth
in their offspring by causing neurons to proliferate as well as sperm. A study published this year found an association between RAS mutations and autistic traits (Journal of Medical Genetics, vol 51, p 10). We don’t yet know whether these mutations are more common than expected because of the selfish sperm effect. However, “it has been known for years that children with autism tend to have overgrown brains”, says geneticist Jonathan Sebat at the University of California, San Diego, whose team has identified many mutations associated with autism and schizophrenia. Sebat thinks selfish selection almost certainly contributes to the paternal age effect, though he suspects it plays only a small part (see “Is it bad to be an older dad?”,
“A rise in the age of new fathers would boost the selfish mutations of each generation” left). To confirm it, researchers need to look at specific mutations to see if any of them increase exponentially rather than at a linear rate as men age. Even though the selfish sperm effect may be of little concern to most people, it could have a very marked effect over successive generations. It may have played a big role in our evolution, and could yet shape our future. None of the mutations identified so far, such as those that cause Apert syndrome,
tend to spread in populations because they are serious enough to prevent people having children. The big question is whether mutations exist that boost spermatogonial division with only a mildly harmful effect on the individuals that carry them. Such mutations could spread and persist in a population. And this would have worrying implications. A rise in the average age of fathers would boost the number of selfish mutations entering the population in each successive generation, and thus lead to a growing burden of disease. “That’s certainly the logical conclusion,” says Wilkie, although he stresses that for now this remains speculation. In theory, the selfish sperm effect would also have increased in strength a few million years ago, as our ancestors split from apes and began to live longer lives. It’s fascinating to ponder the role this could have played in our evolution, says Sebat.“New mutations would have a clear bias to increased brain growth,” he suggests. There are all kinds of theories to explain why hominin brains began to expand about 2.5 million years ago, from a switch to a seafood diet to the invention of cooking. The idea that it may have been a side effect of a process taking place in the testicles is surely the most extraordinary yet. But then they do say men’s brains are ruled by their genitals. Perhaps this is true in a way we never imagined. n Michael Le Page is a features editor for New Scientist 22 February 2014 | NewScientist | 49