Introduction to bioinformatics lecture 11 SNP by Ms.Shumaila Azam

Human Genome and SNPs Now that the human genome is (mostly) sequenced, attention turning to the evaluation of variation Alterations in DNA involving a single base pair are called single nucleotide polymorphisms, or SNPs Map of ~1.4 million SNPs It is estimated that ~60,000 SNPs occur within exons;

Goals of SNP Initiatives Immediate goals: The hundreds of thousands of SNPs estimated to be present in the human genome Interest also in other organisms, e.g. potatoes(!) Establishment of SNP Database(s)

Longer term goals: Areas of SNP Application Gene discovery and mapping Diagnostics/risk profiling Response prediction Gene function identification

Polymorphism Technical definition: most common variant (allele) occurs with less than 99% frequency in the population Also used as a general term for variation Many types of DNA polymorphisms, including RFLPs, VNTRs, microsatellites ‘Highly polymorphic’ = many variants

Use of Polymorphism in Gene Mapping 1980s – RFLP marker maps 1990s – microsatellite marker maps

Gene Discovery and Mapping Linkage Analysis Within-family associations between marker Linkage Disequilibrium (LD) Across-family associations

Crossing over and Recombination

Disease-Marker Association A marker locus is associated with a disease if the distribution of genotypes at the marker locus in disease-affected individuals differs from the distribution in the general population A specific allele may be positively associated (over-represented in affecteds) or negatively associated (under-represented)

Examples: Alzheimer’s E4 present E4 absent Patients 58 33 Controls 16 55 The E4 allele appears to be positively associated with Alzheimer’s disease: Odds Ratio = (58/16)/(33/55) = 6

Linkage Mutation occurs Allele D is created Nearby marker Allele M was nearby D and M subsequently transmitted together

Candidate Polymorphism Testing Large SNP collections may allow testing for direct, physiologically relevant associations with trait

Diagnostics/Risk Profiling Identified SNP associations can potentially be used to develop diagnostic tools

Response Prediction Pharmaceutical companies especially interested in this: Aim to identify those likely to respond Predict toxicity reactions in susceptible individuals Response to any kind of substance; creation of ‘functional foods’

Gene Function Identification Alternative to other experimental procedures (e.g. knock-outs, which cannot be used in humans) Studies to compare individuals with and without naturally occurring disease predisposing genetic profiles