Researchers’ Findings May Lead
Evidence supporting a controversial theory on the genetic origin of autism – an imprinted gene on the paternal X chromosome in mice – has been uncovered by Michael J. O’Neill, assistant professor of molecular and cell biology, and a Ph.D. student in his research group, Adam Raefski.
Their findings were published in the June issue of Nature Genetics, one of the premier science journals.
The research represents a potential breakthrough in the understanding of autism, addressing what O’Neill calls an “enduring genetic mystery,” the 4:1 prevalence of autism in males.
Their work supports a controversial theory by a British behavioral scientist and psychiatrist, Dr. David Skuse. In 1997, Skuse hypothesized that the reason autism is four times more common in males than in females might be due to the presence of imprinted genes on the X chromosome.
The theory has been controversial because imprinted genes had never been found on the X chromosome, a sex chromosome, and some scientists thought it was unlikely they would be.
Imprinted genes do not follow Mendel’s laws of genetic inheritance, in which one copy of each gene is inherited from both parents and both copies are active. In an imprinted gene, the copy from one parent is “silenced,” or not expressed.
O’Neill began studying gene imprinting in 1997. Gene imprinting was not found in humans until the 1990’s. Of the 24,000 or so known human genes, less than 1 percent have been shown to be imprinted, and they have been found only on autosomes, or non-sex chromosomes.
O’Neill and Raefski’s findings, which they confirmed through other experiments, are the first to locate an imprinted gene on the X chromosome of mutant laboratory mice – females with only one X chromosome.
Mice and humans have a similar genetic structure, and the mouse models will enable researchers to obtain a better understanding of the human X chromosome, O’Neill says. Almost all imprinted genes that have been found in humans were first identified in mice.
Since imprinted genes tend to exist in clusters on a chromosome, O’Neill and Raefski are following up the discovery of one by looking for more.
“We’re basically just brushing the surface of what’s likely to be a large cluster,” says O’Neill.
This basic research may have applications in diagnosing autism. If researchers find that the human X chromosome also has imprinted genes, it may be possible to determine whether a person carries a gene that is predisposed to autism. This could eventually lead to earlier diagnosis and treatment of the developmental disorder, which affects a person’s ability to communicate with others and respond appropriately. Currently autism is often not recognized until a child is two years old.
Much of the experimental work leading to the Nature Genetics paper was done at a laboratory in the new Center for Applied Genetics and Technology in Beach Hall, using a sophisticated gene chip system.
Imprinted genes are hard to identify, because the material from both parents is present, but only the gene from one is expressed in RNA transcription. That means imprinted genes have to be seen in their “expression profile.” To do this, Raefski extracted messenger RNA from the brain tissue of embryonic mice, hybridized it to the gene chips, and through a fluorescent signal given off by a biochemical label, was able to tell if a gene was inactive.
O’Neill and Raefski have been studying since 2001 the problem posed by Skuse’s hypothesis that imprinted genes could be present on the X chromosome. Skuse studied patients with Turner’s Syndrome, in which females have only one X chromosome instead of two.
Skuse’s hypothesis has been controversial because of a genetic phenomenon known as “dosage compensation.” This describes a molecular mechanism that evolved to compensate for females having two X chromosomes and males having only one X, along with one Y. In mammals, one of the two X’s in females is, in effect, turned off in the early days of embryonic development.
Those disputing Skuse’s theory have argued that if the X inherited from the father was turned off, and a critical gene from the maternal X was silenced by imprinting, the resulting cell would lack any expression of that gene and would not survive.
Finding an imprinted gene on the paternal X chromosome is a modification of Skuse’s hypothesis, O’Neill said. It could mean that an impairment results not from a lack of expression of a maternal gene, but from over-expression of it.