Mutation detection and SNP analysis

Single nucleotide polymorphisms (SNPs) are the commonest source of mutation in man and can be used as markers in whole genome linkage analysis of families or in association studies of individuals in a population. The human genome project, and associated efforts to identify SNPs, will give rise to hundreds of thousands of potentially informative, mapped polymorphic sites. Mutation analysis, allied with basic biological studies to link mutation with phenotype in man and model organisms, is one of the fundamental goals of global intiatives in functional genomics. The requirement in population screening is for cheap and effective means to detect previously-identified mutations.

Microarrays are being applied increasingly to mutation analysis by minisequencing. In one format, fluorescent chain-terminating nucleotides are incorporated at the site of mutation to indicate the alleles present. In another, differential hybridisation of fluorescence-labelled PCR products to immobilised oligonucleotides is used to indicate sequence at the site of mutation (Affymetrix). However, currently there is a lack of a fully effective DNA diagnostic technology with high throughput and accuracy at a reasonable cost. Delivery of the new paradigm in healthcare - the right drug for the right person at the right dose - depends upon the application of accurate, rapid and cheap mutation analysis to large numbers of people. The result will be the rescue of otherwise unusable drugs, which are fully effective for defined sectors of the population, as well as a substantial reduction in side-effects and noncompliance.

Data capture and analysis, and information management, are clearly critical issues at all levels, from SNP harvesting and detection to population studies. Thus the participation of bioinformaticians will be crucial. Standardisation between different approaches, and in different European DNA laboratories is a further very important issue, and an aim will be to set up benchmarking activities and quality control criteria between European labs.