'NEW POINT MUTATIONS IN HUMANS ARE INTRODUCED THROUGH THE MALE LINE" THE NUMBER OF MUTATIONS IN SPERM INCREASE AS MEN AGE

Paul D. Thacker


Genetic Defects Linked to Sperm of Older Fathers
McGillivray, Katrina katrina at beststart.org
Wed Apr 14 10:00:40 EDT 2004

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Biological Clock Ticks for Men, Too
Genetic Defects Linked to Sperm of Older Fathers
Paul D. Thacker

JAMA. 2004;291:1683-1685.

Women approaching middle age have long been aware that the consequences of a
ticking biological clock include not only decreased fertility but also a
sharp increase in the odds of delivering a child with Down syndrome. Older
men, seemingly untouched by such biological constraints, felt free to father
children as they entered middle, and even old, age.

But now it is becoming increasingly clear that the biological clock ticks
for men as well as women, as researchers turn up evidence that as would-be
fathers get older, they have an increased chance of passing on genetic
defects to their children.

"New point mutations in humans are introduced through the male line," says
Dolores Malaspina, MD, professor of clinical psychiatry at Columbia
University and the New York State Psychiatric Institute. Furthermore, she
adds, the number of mutations in sperm increases as men age.

"This has been known since the 50s," said Malaspina. "What is intriguing is
why society chooses to ignore this."

Society is starting to pay attention. With many couples now deferring
childbearing until they are older, the issue of paternal age and increased
risk for birth defects is gaining a higher profile. It is also possible, say
some experts, that if current trends of older fatherhood continue, it could
someday become a public health problem as well as a personal one.

According to the latest birth statistics released in December by the Centers
for Disease Control and Prevention (CDC), the average age of motherhood is
at an all-time high of 25.1 years compared with 21.4 years in 1971. Although
some of this increase can be explained by the drop in teen births, another
reason was an increase in older women having children. Women in two age
groups-35 to 39 years and 40 to 45 years-now have children at the highest
levels in 3 decades. Statisticians find that women tend to marry men of
similar ages, so it can be surmised that the ages of fathers have also
increased.

Interestingly, while news reports on the CDC figures by various news outlets
mentioned the link between increased female age and disease risk to infants,
none reported the vulnerabilities posed by aging fathers that researchers
have turned up in recent years, such as the association between increased
paternal age and genetic diseases such as Apert syndrome (a disorder
characterized by craniofacial and limb abnormalities) and achondroplasia (a
skeletal disorder that causes dwarfism). Furthermore, studies show that 2%
of children born to men 50 years or older will have schizophrenia, three
times the incidence of schizophrenia in offspring born to fathers in their
early 20s.

Some experts in this field speculate that as the mean age of fathers
increases, the accumulation of mutations in the human gene pool could
heighten the risk of some recessive genetic disorders in future generations.


Malaspina notes that some European countries now ban men from becoming sperm
donors after reaching certain ages.

"I wouldn't discourage a man from having a child because the risk for many
of these diseases is quite small for an individual," she says. "But it's
quite meaningful at the population level." The Human Fertilisation and
Embryology Authority in the United Kingdom revised the upper age of sperm
donors downwards from 50 to 45 in 2000, based on the evidence that older men
are more likely to pass on genetic defects to offspring.


EARLY HINTS

The first hint of a link between paternal age and incidence of birth defects
was noted in 1912 by Wilhelm Weinberg, MD, who found that achondroplasia, an
inherited skeletal disorder occurred more often in younger siblings than
older ones, suggesting that as parents aged, the likelihood of the disorder
increased. Decades later, L. S. Penrose, MD, discovered that only the
father's age that correlated with de novo incidence of the autosomal
dominant disorder.

There are now approximately 20 different disorders that are correlated with
paternal age. The effect is quite prominent for de novo diseases such as
Apert, Crouzon, and Pfeiffer syndromes, for which frequency increases
rapidly with paternal age. Fathers of children with these syndromes are, on
average, 5 years older than the mean age of fathers in the population or
those of similarly affected children with familial forms of the same
diseases.

The increase in such genetic disorders probably has multiple causes,
including differences in how sperm are produced as well as environmental
factors. In 1955, Penrose hypothesized that mutations in sperm cause
disease. The copy-error hypothesis posits that mutations arise
disproportionately in the male germ line, because these cells undergo many
more replications than do the germ cells that give rise to eggs. Also,
because the number of replications leading to sperm formation increases as
men age, there are more possibilities for genetic mistakes.

Abnormal expression of paternally imprinted genes is another possible
mechanism linking advancing paternal age and offspring health, suggests
Malaspina. Imprinting is a phenomenon affecting certain genes that causes
such genes to be expressed differently in offspring, depending on whether
they are inherited from the mother or the father.

DNA DAMAGE IN SPERM
Men thus add more mutations to the gene pool than women simply because their
germ cells pass through more mitotic replications. Women have only about 24
divisions in the cells that give rise to their eggs, and these divisions all
occur before birth. In men, germ line cells have already passed through 30
rounds of mitosis before puberty, and then continue to divide every 16
days-a total of 23 replications per year.

By the time a man reaches age 30, the cells that create sperm will have
passed through 380 mitotic divisions. At age 40, the number has climbed to
610, and at age 50, it reaches 840 rounds of replication. Each round of
division creates another opportunity for an error to enter into the germ
line.

"When I worked in industry before [going to] medical school, women were
closely watched for their exposure to toxins in case they were pregnant,"
says Malaspina. Such an approach ignores the fact that men, with their
dividing germ cells, also should be protected from benzenes and other
chemicals, as well as radiation.

Multiple studies have examined aging's effect on sperm DNA. Narendra Singh,
MBBS, of the bioengineering department at the University of Washington, in
Seattle, and colleagues found in a study of 66 men aged 20 to 57 years,
there were significantly more breaks in the DNA of sperm from older men (="
src="/math/ge.gif" border=036 years) than from younger men (Fertil Steril.
2003;80:1420-1430).

"There is a gradual increase in DNA damage with age," Singh says. "But the
change was most remarkable at age 35."

Older stem cells might simply be creating more damaged sperm. Another
possibility is that protection from free radicals, which damage DNA, might
decrease with age. The researchers also found that both motility and the
rate of apoptosis, or programmed cell death, in sperm also fell. Apoptosis
is one mechanism to keep damaged sperm from fertilizing an egg.

"This is the first study showing that apoptosis goes down as a function of
age," notes Singh. "This finding is troubling because it shows that aging
predisposes the offspring for transmission of damaged DNA." Future research
might uncover strategies for either selecting healthy sperm or helping the
body to cull the sperm with damaged DNA, he says.

Other studies have found high rates of point mutations in the genes
associated with disease in offspring. Ethylin Jabs, MD, a professor of
pediatric genetics at Johns Hopkins University, in Baltimore, found that 99%
of the Apert syndrome cases were caused by mutations from the male germ line
(Am J Hum Genet. 2003;73:939-947). The incidence of these mutations
increases as men age, but the higher predicted incidence of Apert syndrome
in society suggests that some other process may be at work.

"It's more complex than just the number of mutations in the sperm," said
Jabs. "There may be some sort of selection process for sperm with mutations
that we can't yet explain."

A similar trend has been found by Norman Arnheim, PhD, professor of
molecular and computational biology at the University of Southern
California, Los Angeles. Achondroplasia closely correlates with male age,
but its incidence is higher than can be accounted for by the frequency of
mutated sperm (Proc Natl Acad Sci U S A. 2002;99:14952-14957). He has
posited a number of theories to explain why sperm selection might be
occurring.

"There's a big field on sperm competition and we know that it happens in a
number of animals," he says. Some scientists suggest, for example, that it
is possible that a mutation that increases the odds of a birth defect will
also allow the particular sperm possessing that mutation to outcompete other
sperm to fertilize the egg. "Some think it might have to do with the
mitochondria that power the sperm's flagella. I don't know if that's the
right hypothesis, but it's one that's out there."

A PUBLIC HEALTH THREAT?
Although researchers have attempted to conduct epidemiological studies to
look for correlations of disease with paternal age, such studies can be
difficult to perform. For one thing, data sets often lack information about
paternal age. Statistics from the CDC, for example, indicate that 13.4% of
birth certificates from 2002 did not list the father's age.

This lack of information makes it difficult to ask questions about paternal
age and birth defects, says Mathias Forrester, a data consultant for the
Hawaii Birth Defects Program. "We've looked at maternal age, but we've never
even asked the question about paternal age because it's difficult to get
good denominators out of birth certificates."

Even when information about the father's age is provided on a birth
certificate, birth defects might be missed; they are often underreported
because they are sometimes identified after the birth certificate is filled
out, notes Thomas Mathews, a CDC demographer. In some cases, conditions with
a genetic component have a late onset, which further complicates linking
paternal age to a disorder in offspring.

To overcome this problem in a study that found a strong association between
paternal age and risk of developing schizophrenia, Malaspina anonymously
linked data from a population-based birth cohort to the records of the
Israeli Psychiatric Registry (Arch Gen Psychiatry. 2001;58:361-367).
"Ours was the first study to show this," she says. "The problem is that
people never asked about paternal age."

CULTURAL RESISTANCE
There are many reason why paternal contribution to birth defects has a low
profile. James F. Crow, PhD, emeritus professor of genetics and medical
genetics at the University of Wisconsin in Madison, mentions that most of
these defects occur at low levels, on the order of 1 in tens of thousands.
In contrast, the odds of having a child with Down syndrome are about 1 in
350 when the mother is age 35 years and 1 in 100 at age 40 years. However,
some scientists hint that society may not be ready to hear that older men,
like older women, run the risk of passing on birth defects.

But the risk of having a child who later develops schizophrenia, Malaspina
notes, is about 1 in 110 when the father is age 40-similar to a 40-year-old
woman's risk of having a child with Down syndrome.

Malaspina says she believes her findings met resistance because of a
reluctance by men to accept that fathering children later in life poses
increased health risks to their children.

"Despite the fact that our paper received excellent reviews it was rejected
by two medical journals," she said, noting that the study results now have
been replicated five times with similar results. "And these biases really
hold us back from scientific advances."