[Paleopsych] WSJ: Imprinted Genes Offer: Key to Some Diseases-- And to Possible Cures

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Imprinted Genes Offer: Key to Some Diseases-- And to Possible Cures
June 24, 2005; Page B1

According to the old joke, the homely but brilliant male scientist
married the gorgeous but dim model figuring their children would have
her looks and his brains. He was crushed when they had her brains and
his looks.

The scientist was clearly not among those studying a booming new area
of genetics. If he had been, he would have known that whether a
child's traits are shaped by mom's genes or dad's genes isn't a
simple matter of recessiveness or dominance, let alone of pure luck,
as the textbook wisdom says. Instead, some genes come with molecular
tags saying (in biochemical-ese), "I come from mom; ignore me," or
"You got me from dad; pretend I'm not here."

Such genes are called imprinted. Unlike recessive or dominant genes
(such as for black or blond hair), which are composed of different
molecules, these genes are identical except for the silencer tag
sitting atop them.

The result is that if the active gene is defective, there is no
working backup; a healthy but silenced gene from the other parent
can't step into the breach. In the joke, mom's beauty genes and dad's
brainy genes were silenced, leaving mom's dimwitted genes and dad's
homely ones to call the shots.

No one has reliably identified genes for beauty or for brains, let
alone figured out whether mom's or dad's count (or whether this
explains male-pattern baldness). But real imprinted genes are hitting
the big time. Imprinting may be one reason people seem to inherit
conditions such as autism, diabetes, Alzheimer's disease, male sexual
orientation, obesity and schizophrenia from only one side of the
family. At least one biotechnology company is planning to scan the
entire human genome for imprinted genes (detectable with a
biochemical test), hoping to use the data to diagnose incipient

Almost all imprinting happens automatically, long before birth, but
in some cases it can result from outside interference. Toxic
chemicals, for instance, may eliminate the silencer tag, causing
potentially harmful effects that can be transmitted to future
generations. (Two points to readers who say, "Lamarck lives!")

The number of human genes where the parent-of-origin matters keeps
rising. According to a new computer algorithm, about 600 mouse genes
are likely to be imprinted, scientists at Duke University report in
Genome Research. If that 2.5% rate holds for humans -- and virtually
every mouse gene has a human counterpart -- then we have hundreds of
imprinted genes, too.

Among the genes where the parent of origin matters are three on
chromosome 10. Only the copies from mom, studies suggest, are turned
on. One, expressed in the brain, is linked to late-onset Alzheimer's
disease. Another is linked to male sexual orientation, and a third to
obesity. With dad's contribution silenced, if there is anything
unusual in the copy from mom, that will determine the child's trait.
"For Alzheimer's, if the mutation is in dad's gene you'll never see
an effect, but if it's in mom's you're at risk for the disease," says
Duke's Randy Jirtle.

A gene on chromosome 9, linked to autism, seems to count only if it
came from dad. One on chromosome 2 and one on 22 are associated with
schizophrenia; only the copies from dad count. Having a family tree
mostly free of these diseases is therefore no assurance of good
health. If the disease runs on dad's side, his gene may be defective,
and that is the one that matters.

As they discover more imprinted genes, scientists are seeing that the
silencing tag can be knocked off, with dire consequences. An animal
study published this month suggests how. When fetal rats were exposed
to two toxic chemicals -- a fungicide called vinclozolin commonly
used in vineyards and a pesticide called methoxychlor -- they grew up
to have slower- and fewer-than-normal sperm, Michael Skinner of
Washington State University and colleagues report in the journal
Science. The abnormalities were inherited by the rats' sons,
grandsons and great-grandsons.

"That environmental toxins can induce a transgenerational genetic
change is a phenomenon we never knew existed," Prof. Skinner says.
How does it occur? Probably not through harmful mutations, which
become rarer with each generation. But imprinting changes, of which
Prof. Skinner's group has detected 50 and counting, persist through
the generations.

The ink is barely dry on the human genome project, but already
researchers are onto the "second genetic code," or the pattern of
silencers on our DNA. Using a technology called MethylScope ("methyl"
is the DNA silencer), "we will map this second genetic code to see
which genes are imprinted and identify any differences between normal
and cancerous cells," says Nathan Lakey, chief executive of Orion
Genomics, a closely held biotechnology concern.

Those differences may become the foundation for molecular diagnostic
tests within three years, perhaps starting with colon cancer.
Normally, the copy of a gene called IGF2 that you get from dad is
active, the copy from mom silenced. In 10% of us, though, mom's copy
has thrown off the silencer, leading to a greater risk of colorectal
cancer. Detecting that unsilencing could provide an early warning of
the disease.

* You can e-mail me at sciencejournal at wsj.com2.

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