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The newspaper of The Johns Hopkins University September 29, 2003 | Vol. 33 No. 5
Genetic Mutations in Sperm Increase with Men's Age

By Joanna Downer
Johns Hopkins Medicine

There's a lot said about a woman's ticking biological clock, but male biology doesn't age as gracefully as men might like to think.

By analyzing sperm from men of various ages, scientists from the McKusick-Nathans Institute for Genetic Medicine at Johns Hopkins have discovered that older men's sperm is more likely to contain specific disease-causing genetic mutations. Furthermore, one of the mutations may be increasing the sperm's chances of fertilizing an egg, compared with the other mutation, the researchers suggest.

The findings, which appear in the advance online section of the American Journal of Human Genetics, emerged during efforts to explain why a rare genetic disease is more common in children born to older fathers. The disease, Apert syndrome, leads to webbed fingers and early fusion of the skull bones, which must be surgically corrected.

The researchers found that mutation rates in sperm increased as men aged, but not enough to fully account for the increased incidence of Apert syndrome in children born to older fathers, leading to the suspicion that at least one of the disease-causing mutations confer some benefit to the sperm, despite the mutations' effects on the resulting baby.

"Mutations causing this disease occur more frequently in the sperm of older men, but the mutation rate isn't quite as high as the incidence of Apert syndrome," said Ethylin Jabs, director of the Center for Craniofacial Development and Disorders at Johns Hopkins. "There's a lot of work left to determine additional contributors to this condition's paternal-age effect."

While Apert syndrome itself affects only one in 160,000 births, the scientists believe that a combination of increased mutation rate and "mutation advantage" also might be behind some of the 20 or so other genetic conditions linked to older fathers, including achondroplasia dwarfism. These disorders begin to increase rapidly with the father's age at about the same time as maternal risks increase--ages 33 to 35. Most of the evidence for paternal age effects has come from determining how many children with these conditions are born to fathers of various ages.

For the current study, the Hopkins scientists studied sperm from 148 men of various ages and looked for two genetic changes that are responsible for 99 percent of Apert syndrome cases. They found that men over 60 were, on average, three times as likely as men under 30 to have sperm with at least one of these changes. The mutations didn't appear in the men's blood.

"Men over age 52 are six times more likely than a 27-year-old to have a child with Apert syndrome, so the mutation rate alone can't account for the condition's link to paternal age," said first author Rivka Glaser, a graduate student in the Human Genetics and Molecular Biology program at Johns Hopkins.

Jabs, also a professor of pediatrics, added, "Literally hundreds of millions of sperm are made in each batch, so in most cases there are still many normal sperm available. Men in our study who had fathered a child with Apert syndrome, however, had a much higher rate of these mutations at a much younger age than other men."

The two genetic mutations that cause most cases of Apert syndrome affect a protein called fibroblast growth-factor receptor-2. The mutated versions don't bind to FGFR-2's usual targets with the same affinity, but it's not known what, if any, effect either mutation has on the sperm itself.

The scientists looked for the two FGFR2 mutations in sperm from two groups of men who did not have children with Apert syndrome. These controls--57 from a Johns Hopkins study and 76 from an ongoing study at Lawrence Livermore National Laboratory--were asked to provide sperm and blood samples and to complete a health survey. The researchers also analyzed sperm from 15 fathers of children with Apert syndrome.

The research was funded by the National Institutes of Health, the Environmental Protection Agency and the Department of Energy. Authors on the study are Glaser, Jabs and Rebecca Schulman of the Johns Hopkins School of Medicine; Karl Broman of the Johns Hopkins Bloomberg School of Public Health; Brenda Eskenazi of the University of California at Berkeley School of Public Health; and Andrew Wyrobek of Lawrence Livermore National Laboratory.

Related Web sites:
American Journal of Human Genetics (this paper is currently online and scheduled for the October print issue of AJHG)
Johns Hopkins Center for Craniofacial Development and Disorders


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