Monday, October 26, 2009

Scientists discover link between older dads and genetic diseases

From The Times

October 26, 2009
Scientists discover link between older dads and genetic diseases
Mark Henderson");
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Scientists have moved a step closer to understanding why older fathers are more likely to have children with certain genetic diseases.
They have discovered a surprising genetic link between the formation of benign testicular tumours called spermocytic seminomas and several rare growth disorders, which are more common among the children of older fathers.
The abnormal testicular cells that form these rare tumours also produce sperm carrying mutant genes that cause serious inherited diseases, research at the University of Oxford and Copenhagen University Hospital in Denmark has shown.
The findings offer important new insights into the origin of several rare genetic disorders, including a cause of dwarfism called achondroplasia, and also promise to illuminate more common conditions such as autism, schizophrenia and breast cancer.

All three of these are known to be affected by genetics, and to be more prevalent among the children of older fathers, but few of the DNA mutations responsible have yet been identified. Scientists behind the research believe that abnormal testicular cells of the sort that develop into tumours could be partially responsible.
Professor Andrew Wilkie, of the University of Oxford, who led the research, said: “What we have seen so far may just be the tip of a large iceberg of mildly harmful mutations being introduced into our genome. 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.
“It may be that process we have identified might contribute to part of the excess risk for older fathers to have children with higher risks of, for example, breast cancer, schizophrenia, or autism. We have no direct evidence for this as yet.”
Details of the research are published in the journal Nature Genetics . Professor Wilkie’s team, which is funded by the Wellcome Trust, is now planning further research to investigate whether testicular abnormalities might be linked to conditions such as autism and schizophrenia.
Spermatocytic seminomas are rare tumours of the testes, almost always benign, which affect about one in 100,000 men. They are caused by the accumulation of genetic mutations in testicular cells, which can sometimes then divide to trigger tumours.
“We think most men develop these tiny clumps of mutant cells in their testicles as they age,” Professor Wilkie said. “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.”
The new study, has identified genetic mutations of the sort that cause achondroplasia and other rare inherited conditions in cells from spermatocytic seminomas. It appears that these mutations help the tumour cells to divide, but cause abnormal growth when transmitted to the offspring via sperm. “We call them ‘selfish’ because the mutations benefit the germ cell but are harmful to offspring,” Professor Wilkie said.
As the mutations cause the tumour cells to profilerate in the testes, they also increase the chances that a sperm that fertilises an egg will be abnormal.
The results will help doctors to explain to parents why children have developed these disorders, and to advise them about the risks of having further children. In most cases, these families will not have a high risk of having another affected child, though it will be higher than in the general population.
“The major implication is for older fathers,” Professor Wilkie said. “We already knew that men in their 50s have a risk of having children with various individually rare genetic disorders — achondroplasia is a well known one — about tenfold higher than men in their early 20s.
“Adding all these risks together, the total additional risk is still only a fraction of 1 per cent because each of these disorders is rare.”



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