Testicular tumours may explain why genetic diseases tend to be more common in children of older fathers
26 October 2009
The research, funded by the Wellcome Trust and the Danish Cancer Society, could explain why certain diseases are more common in the children of older fathers.
Mutations can occur in different cells of the body and at different times during life. Some, such as those that occur in 'germ cells' (which create sperm or eggs), cause changes affecting the individual's offspring; those that occur in other cells can lead to tumours, but are not inherited.
In work published today in 'Nature Genetics', researchers at the University of Oxford and Copenhagen University Hospital describe a surprising link between certain severe childhood genetic disorders and rare testicular tumours occurring in older men: the germ cells that make the mutant-gene-carrying sperm also seem to be the same cells that produce the tumour.
Although the original mutations occur only rarely in the sperm-producing cells, they encourage the mutant cells to divide and multiply. When such a cell divides, it copies the mutation to each daughter cell, and so the clump of mutant-sperm-producing cells expands over time. Hence, the number of sperm carrying this mutation also increases as men get older, raising the risk to older fathers of having affected children.
Professor Andrew Wilkie from the University of Oxford, who led the study, explains: "We think most men develop these tiny clumps of mutant cells in their testicles as they age. They are rather like moles in the skin, usually harmless in themselves. But by being located in the testicle, they also make sperm - causing children to be born with a variety of serious conditions. We call them 'selfish' because the mutations benefit the germ cell but are harmful to offspring."
The work helps to explain the origins of several serious conditions that affect childhood growth and development. These include achondroplasia and Apert, Noonan and Costello syndromes, as well as some conditions causing stillbirth. The research links these conditions to a single pathway controlling cell multiplication, and will be valuable to doctors explaining to parents why the disorder has arisen, and informing them about the risks of it occurring again: in most cases, future children are unlikely to be affected.
The findings may also help to explain one of the mysteries of genetics: why scientists have yet to account for much of the genetic component of common diseases. Common diseases tend to be caused by the interaction of many genes, but despite powerful genome-wide association scans to search for these genes, relatively few have been uncovered. Several of these diseases, including breast cancer, autism and schizophrenia, seem to be more frequent in the offspring of older fathers, but the reasons are unknown. Professor Wilkie suggests that similar - but milder - mutations might contribute to these diseases.
"What we have seen so far may just be the tip of a large iceberg of mildly harmful mutations being introduced into our genome," he explains. "These mutations would be too weak and too rare to be picked up by our current technology, but their sheer number would have a cumulative effect, leading to disease."
Further research is needed to find other genes that are affected by this process. However, DNA-sequencing technology has recently undergone a step change in capacity, enabling more sequence to be obtained in one day than was possible in a whole year just a decade ago. As the sequencing data emerge over the next decade, we should discover just how vulnerable we are to men’s selfish mutation factories.
Image: Newly engaged couple with achondroplasia. Credit: Wellcome Images
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Wellcome Trust
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Notes for editors
1. Goriely A et al. Activating mutations in FGFR3 and HRAS reveal a shared genetic origin for congenital disorders and testicular tumors. Nat Genet 2009 25 Oct [Epub in advance of print].
2. The Wellcome Trust is the largest charity in the UK. It funds innovative biomedical research, in the UK and internationally, spending over £600 million each year to support the brightest scientists with the best ideas. The Wellcome Trust supports public debate about biomedical research and its impact on health and wellbeing.
3. The University of Oxford’s Medical Sciences Division is one of the largest biomedical research centres in Europe. It represents almost one-third of the University of Oxford’s income and expenditure, and two-thirds of its external research income. Oxford’s world-renowned global health programme is a leader in the fight against infectious diseases (such as malaria, HIV/AIDS, tuberculosis and avian flu) and other prevalent diseases (such as cancer, stroke, heart disease and diabetes). Key to its success is a long-standing network of dedicated Wellcome Trust-funded research units in Asia (Thailand, Laos and Vietnam) and Kenya, and work at the MRC Unit in the Gambia. Long-term studies of patients around the world are supported by basic science at Oxford and have led to many exciting developments, including potential vaccines for tuberculosis, malaria and HIV, which are in clinical trials.