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in sperm DNA with age might underlie this study this September showed a similar but with sporadic forms of the disorder, meaning
observed association. less pronounced association of parental age they had no family history. The researchers’
“If this paternal age effect has something to with bipolar disorder (Arch. Gen. Psychiatry methods only pick up a fraction of mutations,
do with mutations, then that opens up all sorts 65,1034–1040; 2008). so the effect of sporadic mutations is probably
of interesting and sort of scary possibilities,” Spontaneous mutations can arise in both substantially larger, says Sebat.
says Jonathan Sebat, a human geneticist at Cold sperm and eggs. As women age, for example, Similar studies this year have shown that
Spring Harbor Laboratory in New York State. He they have an increased risk of delivering a child people with nonfamilial forms of schizophrenia
says it is conceivable that the trend of delaying with Down’s syndrome and other disorders also have a higher rate of spontaneous
fatherhood might contribute to an increased caused by large-scale chromosome problems duplications and deletions, and Sebat says his
incidence of mutations in the population that in eggs, such as trisomy. But unlike eggs, unpublished data show a similar association in
can give rise to neuropsychiatric disorders. sperm arise from stem cells that continuously bipolar disorder.
In a study of more than 100,000 people, divide—about 840 times by the time a man But whether the mutations that arise
along with records about their parents’ ages, is 50 years old (Cytogenet. Genome Res. 111, spontaneously in neuropsychiatric disorders
Avi Reichenberg at King’s College London 213–228; 2005). The theory is that the chances come mainly from mom or dad is still unclear,
and his colleagues found that 33 out of every of mutations increase with each round of DNA as is their association with parental age. Sebat
replication—a process that could underlie says larger studies underway should help clarify
estimates that the mutation rate in males is these questions.
about five times that in females (Nature 416, And researchers caution that they have
624–626; 2002). very little idea how the disrupted genes in
“Any mutation you can think of occurs eggs and sperm might potentially give rise to
more frequently in the sperm of older men,” neuropsychiatric disease. “It is not established,
says Sebat. and it can put a class of individuals in a negative
Meanwhile, recent genetic surveys of people light,” says Rita Cantor, a human geneticist at
with autism and other neuropsychiatric the University of California, Los Angeles.
disorders have bolstered this controversial— Moreover, other, even more tenuous
and still tenuous—hypothesis. The DNA explanations could underlie the parental age
studies have suggested that ‘spontaneous’ effect—such as the idea that fathers who delay
mutations contribute to schizophrenia and parenthood somehow have genes that affect
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autism. This type of mutation can arise in the their social behavior and make their offspring
sperm or egg of the parents. more prone to neuropsychiatric disorders. Says
Sebat and his colleagues, for instance, looked Cantor, “I think it’s a delicate subject.”
Time for fatherhood: Aging affects sperm at spontaneous deletions and duplications Charlotte Schubert, Washington, DC
Assisted reproduction includes a handful of expected by chance alone,” says Eamonn Maher,
procedures, many of which are based on in vitro a geneticist at the University of Birmingham, UK.
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fertilization (IVF) of the egg. In the US alone, Many cases of Beckwith-Wiedemann syndrome,
assisted reproduction accounted for slightly Maher says, stem from abnormalities in DNA
more than 1% of all births in 2005, according methylation—addition of a chemical tag called
The magic moment: Fertilization of the egg
to the country’s Centers for Disease Control and a methyl group—occurring in specific genes on
Prevention. The IVF process poses some minor chromosome 11.
risks to women, including ovarian cysts, mood Methylation is one of an array of DNA Conclusive evidence for the possible adverse
changes and hot flashes. But a few rare risks to markers, called imprints, that guide normal effects of IVF is unavailable, owing to the dearth
the fetus have given some fertility researchers development of the embryo. For example, of long-term follow up of babies conceived
pause. imprinting seems crucial to proper brain growth, through the technology. One Canadian study
Tinkering with sex cells and embryos says Carmen Williams, a clinical investigator at reported at the Society for Maternal-Fetal
outside the body, scientists worry, might spur the US National Institute of Environmental Medicine’s conference in 2007 found that
genetic changes that manifest as congenital Health Sciences in North Carolina. “The concern babies conceived through IVF were nearly
birth defects. No direct evidence supports that is that while the embryo is being cultured in the 60% more likely to develop birth defects than
notion, but epidemiological studies have shored [IVF] lab, maybe the imprint marks are being naturally conceived ones. Most of the defects
up possible links between assisted reproduction changed. We know for sure that happens in were gastrointestinal, although some were bone,
and rare genetic syndromes in newborns, such mice,” she adds (Biol. Reprod. 62, 1526–1535; muscle or heart related. Another study, from the
as Beckwith-Wiedemann syndrome, a condition 2000). University of Iowa, found birth defects in about
marked by premature birth, an enlarged tongue Some studies have suggested a causal 6.2% of about 1,500 IVF-conceived children,
and heightened susceptibility to tumors, relationship between ICSI and abnormal in contrast to 4.4% among naturally conceived
respiratory and speech defects (Hum. Reprod. methylation patterns (Am. J. Hum. Genet. 71, ones (Fertil. Steril. 84, 1308–1315; 2005).
Update 10, 3-18; 2004). 162–164; 2002; Am. J. Hum. Genet. 72, 218–219; If future studies bear out these links, Williams
Fortunately, the syndrome is rare: it normally 2003). And Maher says the findings hint that suggests that one can perhaps decrease the risk to
affects about 1 out of every 12,000 newborns imprinting defects might trigger Beckwith- the child by avoiding certain invasive procedures
worldwide. But a study found that 3 out 65 US Wiedemann syndrome. that might not be necessary depending on
children afflicted with the syndrome had been But he also cautions that the absolute individual circumstances, such as biopsies
conceived through IVF (Am. J. Hum. Genet. risk of giving birth to a child with Beckwith- of implanted embryos, culturing embryos in
72, 156–160; 2003). In other studies, 6 out of Wiedemann syndrome is low. the lab longer than the minimal time period
149 children in British and French medical “The disease is so rare that it’s difficult to and using ICSI in the absence of male fertility
registries of the syndrome were found to have counsel an infertile couple not to go forth with problems.
been conceived through IVF or through a ART,” Williams says. Prashant Nair, Chapel Hill, North Carolina
A more experimental option is to remove last method also holds the greatest promise do ovulate after chemotherapy, but their egg
strips of ovarian tissue, freeze them, and for children. “You’re not going to do embryo reserve is diminished, and they go into early
transplant them back into the woman after freezing with a ten-year-old,” notes Oktay. menopause. It’s too early to say whether this
treatment. Although researchers are still trying In the pipeline are also several drugs that might also happen with the participants in
to figure out how to reconnect the tissues to promise to protect ovaries from the effects of the Australian trial. Stern says her team is set
the blood supply, at least four women have chemotherapy. In one trial, Kate Stern of the to launch a randomized clinical trial to test
given birth after an ovarian transplant. This Royal Women’s Hospital in Melbourne and her cetrorelix further.
colleagues gave 18 women, with an average Other candidate treatments, such as the
age of 25, a drug called cetrorelix. The drug compound sphingosine-1-phosphate, prevent
blocks gonadotropin-releasing hormone, the eggs from self-destructing in response to
Anatomical Travelogue / Photo
effectively sending ovaries into a prepubertal radiation, but research on those candidates
state. One year after treatment, 94% of has for the most part been limited to animal
the women were ovulating normally, the models. Pending further studies on these
Researchers, Inc.
researchers reported at a conference in July. compounds, experts say the best option for
However, because it was a proof-of-concept preserving fertility in women is still to freeze
study, the trial did not include a control group. embryos or eggs.
Precious commodity: The human egg In their mid-20s, notes Oktay, many women
Apoorva Mandavilli, New York