February 03, 2006
Implicating Noncoding RNAs in the Genetics of Mental Disorders
NAMHC Concept Clearance
Steven O. Moldin, Ph.D.
Director, Office of Human Genetics & Genomic Resources
Associate Director, Division of Neuroscience & Basic Behavioral Science
Noncoding RNAs are surprisingly prevalent in the human genome and may play a critical role in the regulation of gene expression. The potential importance of noncoding RNAs is suggested by the observation that the complexity of an organism is poorly correlated with its number of protein coding genes, yet highly correlated with its number of noncoding RNA genes, and that in the human genome only a small fraction (2?3%) of genetic transcripts are actually translated into proteins. A systematic analysis of transcription observed about 10 times more transcriptional activity than can be accounted for by predicted protein-coding genes. Much of this activity was subsequently shown to be regulated. Large-scale cDNA analysis and genome annotations predict thousands of noncoding RNAs and computational analyses suggests that over 20% of human genes are regulated by noncoding RNAs known as microRNAs. These are about 20 nucleotides in length and are believed to regulate genes expression either through messenger RNA cleavage or by translational repression. These and other findings support the notion that microRNAs have a central role in the regulation of protein translation throughout the human genome. The biological functions of most micro RNAs are unknown, but some have already been found to be of relevance to understanding the genetics of mental disorders. For example, in Fragile X syndrome the dFmr1 protein regulates the translation of its mRNA via microRNA interaction. This initiative will focus on whole-genome wide approaches to characterize the role that microRNAs and other noncoding RNAs play in the etiology of mental disorders.
Possible activities under this initiative include determination of the expression of computationally predicted microRNAs by high-throughput microRNA microarray analysis and validation of the sequence of predicted microRNAs that give high signals on the microarray using state-of-the-art sequence-directed cloning and sequencing methods. A particular focus of this initiative will be the characterization of inadequate, spatially aberrant or mistimed expression of a functional protein as modulated by noncoding RNAs. Alterations in protein expression attributable to these novel mechanisms are expected to play a significant role in the etiology of mental disorders. One or more susceptibility genes for mental disorders may turn out to include abnormal transcriptional units that code for RNA regulators of protein coding gene expression or to be proximal to such units, rather than to be abnormalities in the protein coding gene itself. Understanding the genetics of mental disorders might very well include consideration of RNA and epigenetic regulation of protein expression.