DMMC Course POPULATION GENETICS & SNP ANALYSIS

Durkan Lecture Theatre, Institute of Molecular Medicine, TCD, St James's Hospital

1330-1400 Wednesday 6 June 2007

Introduction to SNPs
Prof David Croke (Molecular & Cellular Therapeutics and RCSI Research Institute, The Royal College of Surgeons in Ireland, St Stephen’s Green, Dublin 2)

The phenomenon of polymorphism within natural populations is the basis of genetics and provides essential tools for gene mapping, including the identification of predispositional alleles in human disease. Single Nucleotide Polymorphisms (SNPs), formally the substitution of a single base for another at discrete points in a DNA sequence, are the most abundant and widespread class of polymorphism with an estimated 10 – 20 million in the human genome. The utility of SNPs in human gene mapping results from associations that have persisted over time in the population between particular SNPs and allelic variants contributing to disease liability, modified to greater or lesser extents by genetic (recombination, selection) and demographic factors (genetic drift, population growth, stratification). Such associations, quantified as Linkage Disequilibrium (LD), form the basis of linkage approaches that have been applied with great success to the identification in families of rare single gene variants contributing the bulk of the genetic liability to disease (eg: the deltaF508 mutation in Cystic Fibrosis). The availability of SNP maps of the human genome at higher levels of resolution has allowed the development of LD mapping approaches that can identify predispositional alleles in common ‘complex’ disorders (such as diabetes and cardiovascular disease), and in ‘quantitative’ traits (such as blood pressure as related to hypertension) where multiple alleles contribute to the overall disease/trait liability. Because the human population is relatively young (< 5,000 generations), areas of extended LD exist within the genome referred to as ‘haplotype blocks’. This LD ‘structure’ within the genome can be exploited, as in the HapMap project, to optimise the efficiency of LD studies through the use of haplotype tagging SNPs. SNPs can yield valuable information also on human population history through investigations of genetic diversity within and between human regional populations. Being biallelic ‘markers’ SNPs are less informative than tandem repeat polymorphisms such as microsatellites (STRs), but the fact that they are easier to genotype and more economical (both in terms of unit cost per assay and DNA consumption) more than compensates for this.