Scientists have been looking for genes that can explain behavioral disorders for 20 years without much success. According to L. Alison McInnes of Mt. Sinai School of Medicine, that may be because they have been concentrating their efforts in the wrong places in the genome.
Speaking on Dec. 8 at the annual meeting of the American College of Neuropsychopharmacology held in San Juan, Puerto Rico, McInnes advised that those interested in genetic links to behavior should start looking at places in the genome that produce special molecules called small non-messenger RNA (smnRNA) rather than concentrating on genes that code for proteins.
Current genetic screening techniques do not pick up these sequences because they are very small and not much is known about their structure. So McInnes and her colleagues at Mt. Sinai have created a computational and molecular screening technique designed specifically to look for smnRNA molecules produced by regions in the genome that have been associated with behavioral disorders. Furthermore, they have used this method to successfully identify such molecules in the first few genes that they investigated, she reported.
The existence of smnRNAs has been known for some time. Until recently, they have been generally dismissed as unimportant. New studies are finding that they are actually quite abundant and involved in a wide variety of biological processes. As a result, some scientists are beginning to speculate that they may represent an entirely new class of gene and type of gene activity.
McInnes cited the theoretical work of John Mattick and Michael Gagen at the University of Queensland in Brisbane. Last year they published a lengthy paper in Molecular Biology and Evolution in which they argued that, rather than being useless, smnRNAs and introns – the sequences in the genome between genes that code for proteins that have been called junk DNA – form a powerful network that can turn ordinary genes on and off at the proper times.
"It appears that smnRNA may be especially relevant for understanding behavioral differences," McInnes said, "because they appear to be particularly enriched in the brain. They represent a swift and energy efficient means of regulating gene expression and may be especially important for rapid regulatory events."
Lack of expression of an smnRNA has already been strongly associated with one neuropsychiatric disorder, Prader Willi syndrome, McInnes reported. Prader-Willi syndrome is characterized by abnormally poor muscle tone and feeding difficulties in early infancy, followed by excessive eating and gradual development of morbid obesity. It is also accompanied by cognitive impairment.
In the initial trial of their new screen, the Mt. Sinai researchers identified a possible smnRNA molecule produced by an intron of the human corticotrophin-releasing hormone gene. Corticotrophin releasing hormone (CRH) plays a key role in the response of humans and other mammals to external threats. It acts at a number of sites in the nervous system to control automatic, behavioral and immunological responses of stress. Alterations in CRH neural activity appear to contribute to a number of mental illnesses including depression, anxiety disorders and anorexia nervosa. In addition, the CRH smnRNA appears to form a complimentary match with a sequence in an untranslated region associated with a receptor, called the NMDA-glutamate receptor, which is widely implicated in schizophrenia and other degenerative neurological disorders.
The members of McInnes' research team are Esther Richler, Tara L. Lauriat, Eric Mesh and Gary Benson from the biomathematics department. Former team member Michael Inman also contributed to the research. The team also acknowledges the valuable input of Jerome Cavaille, a pioneer in the discovery of snmRNA molecules. The project was supported by the Seaver Center for Autism Research.
The American College of Neuropsychopharmacology (ACNP) is a professional organization of some 600 leading scientists that was founded in 1961. Members are selected primarily on the basis of their original research contributions to the field of neuropsychopharmacology, which involves the evaluation of the effects of natural and synthetic compounds on the brain, mind and human behavior. The principal functions of the College are research and education. ACNP's annual meeting is limited to participants from around the world who have made major research or clinical contributions in the field.
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