Edvin N Munk reports on the importance of single nucleotide polymorphisms (SNPs) to pharmaceutical industry and the work of The SNP Consortium made up by 13 leading pharmaceutical and information organisations.
The end of the sequencing efforts in the Human Genome Project is only the beginning of converting sequence data into meaningful and useful information. Human individuals share on average 99.7 to 99.9 genetic identity. Common variations in the DNA among individuals include repetitions, deletions and insertions as well as exchanges of single bases.
The latter are the most common mutations, called single nucleotide polymorphisms (SNPs), and are increasingly used by academic institutions and the pharmaceutical industry to explore the genetic basis of diseases and individual drug response.
Consortium
The importance of SNPs for the pharmaceutical industry is reflected by the foundation of The SNP Consortium by 13 leading pharmaceutical and information companies and the medical research charity The Wellcome Trust. Its goal is to create and make available a high-quality SNP map of the human genome with about 300 000 SNPs a number which is likely to exceed one million by 2001.
It is assumed that 3 to 10 million SNPs occur across the human genome at different densities, of which a maximum of 10 per cent directly affect gene function and gene expression because they are located in close proximity to or within genes.
Drug therapies today target less than 500 functionally fairly well characterised gene products, representing an estimated 2 to 10 per cent of the possible ones which can potentially be modulated by drug molecules.
In order to exploit the potential that gene-based medicine has to offer, academia and pharmaceutical companies need to draw correlations between individual genetic inheritance and medically important parameters such as disease and responsiveness to drugs, where thousands of SNPs are compared among thousands of individuals against a wide range of phenotypes and genetic markers.
Target genes
The whole process of drug development, from hunting for new target genes and the subsequent validation to the genetic profiling of study populations during clinical trials will require millions of genotypes for which complete solutions are required.
In order to cope with these formidable numbers, dedicated large scale SNP genotyping technologies should be able to provide computer based assay design, high flexibility in terms of varying assay and DNA sample amounts, parallel sample processing, high throughput, accurate data output, automated data interpretation tools, and cost effectiveness.
An important differentiator between the technologies which have become available in the recent years is the detection method used, since a genotyping result is influenced by the technical genotyping error rate, ie sensitivity and specificity of the detection method.
False negative results can occur, if a detection method is not sensitive enough to detect mismatch hybridisations or strongly imbalanced amplifications of heterozygous loci.
False positive results can occur for various reasons, and go unrecognised if indirect detection methods are used which infer the genotypes by means of surrogate markers like fluorescent, colourimetric or radioactive tags.
Methods that can detect alleles directly and unambiguously as a physical property of the molecular mass include MALDI-TOF mass spectrometry.
In the mass spectrometer the label free sample is exposed to laser energy, which causes structural decomposition of the irradiated crystal and generates a particle plume from which ions are extracted by an electric field. The ions accelerate and drift through a field-free path and hit a detector. Ion masses (mass-to-charge ratios, m/z) are calculated by measuring their time-of-flight which is directly correlated to the ion mass (Fig. 1). This technology (MassARRAY) has recently become available for dissecting SNPs as well as more complex genetic variants.
It seems that the more information about our genes becomes available, the higher the evidence that the overall contribution of genetics to drug response outweighs environmental and/or social influences.
This has led to a tremendous acceleration of pharmacogenomic and pharmacogenetic studies in both academic institutions, and genomic and pharmaceutical companies, which now look forward to enabling technologies and bioinformatics in order to keep pace with the race for information and knowledge in the post-genome era.
ENQUIRY No 71
Edvin N Munk is with Sequenom, Hamburg ,Germany. www.sequenom.com
