DURHAM, N.C. - Duke University Medical Center researchers report that an unusual gene-control mechanism called "imprinting" is at work on human chromosome 19. For imprinted genes, the gene copy that is turned on depends only on whether it came from the mother or father, rather than on the classic laws of Mendelian genetics, where genes are either dominant or recessive.
In the Jan. 1, 2001, issue of Genomics, the researchers report that a particular gene called PEG3, or paternally expressed gene 3, is imprinted in humans, just as it is in mice. Mouse studies have shown that only the copy of PEG3 that is inherited from the father is functional, and the Duke researchers now have confirmed that is true in humans as well.
"Just because you have an imprinted gene in the mouse doesn't mean it's going to be imprinted in humans," said principal investigator Randy Jirtle, professor of radiation oncology and member at the Duke Comprehensive Cancer Center. "This is also the first evidence of imprinting on human chromosome 19."
Imprinted genes usually occur in clusters, so the researchers are now looking for other imprinted genes in the region of chromosome 19 near PEG3, said Duke's Susan Murphy, lead author of the study, which was funded by the National Institutes of Health. To date, about 40 imprinted genes have been identified in humans, primarily on regions of chromosomes 7, 11 and 15.
Generally speaking, imprinting is not reversible - if the functional copy becomes faulty, the non-working copy can't be turned on. The region of chromosome 19 that contains PEG3 has already been linked to ovarian cancer and gliomas, a form of brain cancer.
"Imprinted genes are particularly susceptible to complete loss of function or inappropriate overexpression, and have been implicated in a number of diseases as well as neurobehavioral disorders, including autism," said Murphy, a research associate in radiation oncology whose older son's death from cancer and younger son's diagnosis of autism prompted her to enter imprinting research.
Earlier this year, other Duke researchers reported preliminary findings that suggest imprinted regions on chromosomes 7 and 15 are involved in autism.
In addition to being the first evidence of imprinting on chromosome 19, the PEG3 findings indicate the possibility that the similarities between the human and mouse versions of the gene might extend to behavior changes caused by loss of the gene's function in mice, the researchers said.
Cambridge researchers reported last year that female mice that inherited a faulty PEG3 gene from their fathers - leaving them without a functional copy of this gene - demonstrated severe nurturing deficiencies that resulted in the deaths of most of their offspring.
"We don't know if there are behavioral changes associated with loss of this gene in humans," emphasized Jirtle. "What we do know is that, in humans, PEG3 is imprinted in the tissues we tested and that it remains imprinted throughout development and adulthood."
The PEG3 gene codes for a protein believed to be involved in transcription, one of the steps in reading genetic material to make proteins. Scientists speculate the nurturing problems seen in mice without PEG3 might be caused by "downstream" effects - genes whose expression would normally be aided by the PEG3 protein - rather than by a lack of PEG3 itself.
While no behavioral impact has been established for the human PEG3 gene, Jirtle noted that advancing technologies make it easier to identify genes and clarify their functions.
"For a long period of time, it was believed that nurturing controlled behavior," he said. "In mice, it's been shown that genes can have a profound impact on behavior, even on what might be thought of as the most fundamental behavior of mother and offspring."
Co-author of the study is Andrew Wylie, a research associate funded by AstraZeneca Pharmaceuticals Ltd., Cheshire, UK.
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