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More than 150 ‘Silenced’ Genes Identified For the First Time — Some Implicated in Neurologic Disorders

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They are called imprinted genes and they defy Mendelian genetics. Mom and dad each pass along a copy of their genes, but in the process, one is silenced by molecular instructions from one of the parents, leaving the other gene to do all the work. The first one was described in 1992. Since then, about 40 imprinted human genes have been identified.

Now, scientists at Duke University, led by Alexander J. Hartemink, PhD, Randy L. Jirtle, PhD, and Philippe P. Luedi, PhD, have used a computer model to scour the entire human genome, providing the first map of 156 imprinted genes.

Figure

Imprinted genes are providing a new way of looking at genetically linked neurologic conditions.

Imprinted genes are on chromosomes in regions that have been linked to human diseases — such as some forms of neurofibromatosis and Prader-Willi and Angelman syndromes.

The Duke researchers said that many of the novel imprinted genes popped up in regions associated with Alzheimer disease and schizophrenia. They are hoping that others take on the search to discover whether these imprinted genes are involved in these conditions, and if so, how.

These imprinted genes are providing a new way of looking at genetically linked conditions, say researchers who commented on the Dec. 3, 2007, study in Genome Research.

“This is the beginning of a major piece of the puzzle of what goes into creating a disease within an individual — even within the same family,” said M. Elizabeth Ross, MD, PhD, professor and head of the laboratory of neurogenetics and development at Weill Cornell Medical College in New York City. “We will certainly see a lot more research on imprinted genes in the coming years.”

Dr. Ross, who was not involved with the current study, said that scientists have known for a long time that inheriting a genetic mutation isn't a guarantee that someone will get a disease. “We are trying to understand what factors are involved in this process,” she added. “It seems to require some event in the environment that tips the genetic scale.” Dr. Ross's lab is focusing on gene changes in response to environmental events.

In the current study, Dr. Hartemink, a computer scientist, teamed up with geneticists interested in identifying the characteristics of the already known imprinted genes. They wanted to determine what features they had in common with genes that were not imprinted (meaning that both copies are functional). They asked the computer to scan through every gene, comparing the 40 known imprinted genes to 52 non-imprinted genes and 500 random genes. With an identification method in place, they scanned the rest of the genome and found 156 novel imprinted genes.

To prove that they had imprinted genes in hand, they selected two on chromosome 8 for further testing, because no imprinted genes had been identified on that chromosome. One of the genes, dubbed KCNK9, is a potassium channel gene expressed in the brain that has been associated with a risk for bipolar disorder and epilepsy. The other one, called DLGAP2, is believed to be a bladder cancer suppressor.

Dr. Hartemink explained that the silencing of genes occurs through epigenetic modification, which involves modifications to genes that do not entail changes in the DNA sequence. These modifications include the addition of molecules, like methyl groups, to the DNA backbone. Adding these groups can change the appearance and structure of DNA, altering how a gene interacts with important transcribing molecules in the cell's nucleus. Because they change how genes can interact with the cell's transcribing machinery, epigenetic modifications generally turn genes on or off, allowing or preventing the gene from being used to make a protein.

The Duke scientists found, for example, that many of the imprinted genes have one copy of a gene that is methylated and another that is not. “We don't understand the mechanisms for silencing all these imprinted genes,” said Dr. Hartemink. Most commonly, the one that is silenced has extra methylation, he added.

Epigenetics provides the potential to understand how environmental influences can combine with genetics to influence outcomes, Dr. Hartemink said. That was reflected in an experiment conducted by one of the investigators. Dr. Jirtle worked with Agouti mice, which are born with a yellow coat, are obese, and are prone to cancer. He fed the pregnant mothers a diet that included genistein, an isoflavone found in soy products, and lo and behold, the mice were born with a dark coat, slim, and with no extra risk for cancer.

Now, back in the lab, they are trying to figure out just how imprinting works, and whether there might be ways to turn on an improperly silenced gene without negative consequences.

References

• Leudi PP, Dietrich FS, Hartenmik AJ, et al. Computational and experimental identification of novel human imprinted genes. Genome Res 2007;17(12):1723–1730.