Polymorphic DNA markers and mental disease.

The remarkable recent advances in molecular genetics are grounds for considerable optimism in psychiatry, where many diseases appear to have an hereditary component. Most notably, the discovery of restriction fragment-length polymorphisms (RFLPs) has greatly increased the number of markers available for linkage studies. Linkage analysis has two basic requirements. First, co-operative families must be ascertained in which several people are affected by the condition under study. Secondly appropriate genetic markers must be available. These should be reliably detected and polymorphic, that is to say, present in two or more common forms in the population. These are studied in the families, in the hope that one variant of the polymorphism will segregate with the illness in that family, i.e. be present in affected, but not unaffected, members more often than would be expected by chance. If this happens, it suggests that the locus coding for the marker and the pathological gene are close enough on the same chromosome to render separation during meiosis (recombination) unlikely. The frequency of recombination is, therefore, a measure of the distance separating the two loci. Until the discovery of RFLPs the applicability of this potentially powerful technique was limited by the fact that few suitable polymorphic markers were available. Restriction enzymes cut DNA (which can be obtained quite easily from peripheral blood leucocytes) where specific base sequences occur in the molecule and result in a number of small, easily manageable pieces. These can then be separated according to size by electrophoresis. The positions of the sites that are cut by a given restriction enzyme vary from one individual to another, apart from the special case of identical twins. Thus, the fragments produced from the digestion of one individual's DNA by a given restriction enzyme will differ from those produced by its action on DNA from someone else. These polymorphisms are inherited in a simple Mendelian fashion. Variations in length of specific restriction fragments (RFLPs), can be detected after electrophoresis by adding a quantity of small, identical pieces of single-stranded DNA that have been radio-labelled. Single-stranded DNA will hybridize, in other words combine to form a double strand, with another single strand composed of complementary base sequences. Such 'gene probes' therefore recognize and label complementary sequences, and their application to DNA that has been cut with a restriction enzyme and denatured to a single strand allows detection of any RFLPs that are close to the labelled DNA on the genome. 'Candidate genes' whose involvement in the disease is suspected a priori may be used as probes. For example, genes coding for various enzymes involved in the monoamine neurotransmitter systems might be relevant to psychiatric disorders. Another strategy is to concentrate attention upon probes that label a particular part of the genome, such as a single chromosome, when the disease gene is believed to be located in that area. Unknown pieces of DNA selected at random may also be used as probes and their identities and position in the human genome determined only if linkage is established. It was this technique that Gusella et al. (1983) employed successfully to locate the gene for Huntington's disease on chromosome 4. The excitement generated by findings in Huntington's disease was tempered for psychiatrists by the realization that none of the common psychiatric disorders show such a clear and unambiguous pattern of inheritance. However, recent work on both Alzheimer's disease and affective disorder has removed many of the doubts about the extent to which molecular genetics will be applicable to the study of mental illness.