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The application of differential cloning techniques in post-mortem studies of neuropsychiatric disorders: a way ahead

Despite much research, we still have no clear understanding of the exact causes and molecular biology of psychotic illness. Perhaps the clearest contributor to liability to illness is heredity, yet the mode of inheritance and number of genes involved remain undefined. In theory, genetic susceptibility loci may be detected using linkage analysis in multiply affected pedigrees, though uncertainties in diagnosis and genetic parameters make this difficult. Such factors must have contributed to the current disappointments in molecular genetic analysis of psychotic illness, with reports of susceptibility loci either remaining unconfirmed in other pedigrees or being withdrawn by the original authors (Kelsoe et al. 1989; Watt & Edwards, 1991; Baron el al. 1993). The ultimate reward from genetic studies is at present difficult to predict (Owen, 1992), but is likely to fall well short of the initial expectation that causal genes would be first detectable and then identifiable by pure reverse genetic techniques. In cases where the genetic component of an illness is complex, it is arguably more rewarding to study the underlying molecular biology of the cell, as this provides a description of the cellular processes occurring during the illness and may also indicate the underlying genetic systems involved. Such an approach has the attraction that it may ultimately provide ways of devising therapeutic management based on cell biological principles. Gene expression can be studied by the quantitative comparison of mRNA populations in different states. Such an approach can allow the isolation of coordinately controlled genes, and hence may be of great benefit in the psychiatric disorders, which are likely to have a complex genetic basis. In the case of the psychoses a comparison of mRNA extracted from affected brain with that obtained from control, normal brain would allow the identification of genes whose expressions were altered between the two states. More generally, fundamental analysis of gene expression in the brain during development may also be used to determine the molecular mechanisms underlying cell differentiation and organogenesis; such information can provide a ' normal' baseline against which 'affected/diseased' data can be compared in illness states. As with linkage studies, two approaches are possible for mRNA analysis the use of candidate genes and the random search for genes whose expressions are changed in the illness. While providing valuable information on the cell biology of illness, candidate gene strategies rarely provide information beyond the researcher's own preconceptions, and have tended to concentrate on a pharmacological description of the illness (e.g. Collinge & Curtis, 1992). Random search methods, in contrast, are not susceptible to assumptions other than the idea that gene expression may be altered in the neuropsychiatric disorders. Such an approach relies on the identification of genes whose expression is altered in the affected state compared to normal control. This editorial attempts to explain the basis and prospects for the application of differential and subtractive cloning and screening methodologies in research into the underlying molecular basis of psychotic illness.