Expanding the 'central dogma': the regulatory role of nonprotein coding genes and implications for the genetic liability to schizophrenia

It is now evident that nonprotein coding RNA (ncRNA) plays a critical role in regulating the timing and rate of protein translation. The potential importance of ncRNAs 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 ncRNA genes, and that in the human genome only a small fraction (2-3%) of genetic transcripts are actually translated into proteins. In this review, we discuss several examples of known RNA mechanisms for the regulation of protein synthesis. We then discuss the possibility that ncRNA regulation of schizophrenia risk genes may underlie the diverse findings of genetic linkage studies including that protein-altering gene polymorphisms are not generally found in schizophrenia. Thus, inadequate or mistimed expression of a functional protein may occur either due to mutation or other dysfunction of the DNA coding base pair sequence, leading to a dysfunctional protein, or due to post-transcriptional events such as abnormal ncRNA regulation of a normal gene. One or more 'schizophrenia disease genes' 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 schizophrenia and other complex neuropsychiatric disorders might very well include consideration of RNA and epigenetic regulation of protein expression in addition to polymorphisms of the protein coding gene.