Post-genomic approaches to exploring neuropeptide gene mis-expression in disease

In the past, a great deal of time and effort has been spent in the analysis of mutations and polymorphisms of gene coding sequence and their relationships to neurological disorders. Unfortunately, many studies of genes that have been strongly implicated in the development of neuronal conditions, have failed to identify any significant coding sequence alterations in affected individuals. It is only relatively recently that mutations affecting gene regulation have been seriously considered as factors in the initiation and exacerbation of neurological disease. In this review, we will examine evidence from our own and other labs demonstrating how mutational or polymorphic changes in the primary structure of non-coding DNA sequences implicated in the development of disease are able to affect the expression of neuronally expressed genes. In addition, we will describe freely available methods of rapidly and accurately identifying likely neuropeptide gene regulatory regions using computer analysis of newly available mouse, rat, human and pufferfish (Fugu) genomic sequence. We will also describe how, in the absence of suitable cell lines, these identified sequences can be analysed in vivo using transgenic analysis. In silico analysis of the available genome sequences of different vertebrates in combination with cell and transgenic analysis has the potential of significantly accelerating the identification and characterisation of conserved neuropeptide gene regulatory regions and the identification of the transcription factors (TFs) that bind to them. Only by taking full advantage of these technologies and combining them with the huge and valuable resource represented by human polymorphic linkage analysis and association studies will neurobiologists gain a better understanding of how inappropriate regulation of neuropeptide gene expression can contribute to the progression of neurological disease. (C) 2003 Elsevier Ltd. All rights reserved.