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.
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