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Imprinted Genes Offer Key to Some Diseases and to Possible Cures

By Sharon Begley, Wall Street Journal

23 June 2005: 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.