Published online 28 August 2007 | Nature | doi:10.1038/news070827-1

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Clumps of mutant sperm-making cells help to explain Apert syndrome.

An Apert syndrome mutation is seen in sperm 100-1,000 times more frequently than would be expected. Getty

Researchers have delved into the human testis to help explain why fathers are so likely to pass a disease-causing mutation to their children.

Apert syndrome, which causes an abnormal formation of the skull, fingers and toes, affects roughly 1 in 150,000 live births. Affected men are unlikely to go on to have children, so the vast majority of cases aren't inherited; instead, they arise from spontaneous mutations.

It has been a puzzling mystery to scientists why one particular mutation that causes Apert syndrome – a tiny change in the DNA sequence of a gene involved in bone development — is seen in sperm 100-1,000 times more frequently than would be expected if it were the result of random mutation.

Geneticists have offered two different explanations for why this unusually common error, called C755G, crops up so often: either the C755G site is unusually prone to errors when DNA is copied (the 'mutation hotspot' theory); or this mistake gives cells a growth advantage, so if it happens by chance in a sperm-making cell, the mutant cell out-competes other cells and starts to take over sperm production (the 'selfish sperm' model).

In 2003, Andrew Wilkie at the University of Oxford and colleagues tracked how older men were more likely than young ones to pass on the mutation. This seemed to support the 'selfish sperm' model, because continually expanding mutant sperm factories within the testes would increase as a man ages1.

Now, researchers working with Norman Arnheim at the University of Southern California, Los Angeles, say they have definitely crossed the 'hotspot' theory off the list by using used a novel approach — chopping up human testes into nearly 200 pieces.

Sperm map

Despite sounding crude, not to mention messy, careful analysis of the DNA in these tiny portions of tissue enabled the biologists to construct a three-dimensional map of where in the testes of two men the sperm-making cells with the C755G mutation were situated.

Instead of being scattered throughout the organ, as would be expected if the mutation occurred randomly, the C755G cells were knotted together in clusters, the researchers report in PLoS Biology2. Computer modelling confirmed that this wouldn't happen if the gene site was simply prone to mutation. "We have rejected the mutation hotspot model," says Arnheim.

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Instead it fits nicely with the 'selfish sperm' theory — if C755G gives a sperm progenitor cell a boost to copy itself, a group of mutants will start to grow and churn out thousands of Apert-causing sperm.

Wilkie says the new study "adds another dimension" to the evidence supporting the idea of 'selfish' cells expanding in the testis. He adds that what is happening in the testis seems to have parallels with cancer, where critical mutations cause cells to multiply unchecked. In fact the C755G mutation has recently been spotted in endometrial tumours in the uterus, though what it is doing there is not yet known.

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