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 cancers.

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.