Identification of potentially functional SNPs at ABC transporters and development of novel assays to genotype these SNPs

Abstract

<P>THIS THESIS DEMONSTRATES THE FEASIBILITY OF UTILIZING AN IN SILICO APPROACH BASED ON NATURAL SELECTION, KNOWN AS RECENT POSITIVE SELECTION (RPS), TO IDENTIFY SNPS WITHIN 18 ABC TRANSPORTERS GENE LOCI THAT MAY CONFER A FUNCTIONAL ADVANTAGE, PRIOR TO TESTING THEIR ROLES IN INDIVIDUAL/POPULATION DRUG RESPONSE VARIATION OR IN COMPLEX DISEASE SUSCEPTIBILITY. AT LEAST ONE SNP IN EACH OF THESE GENES AND A TOTAL OF 32 SNPS DISPLAYED THE EVIDENCE OF RPS IN AT LEAST ONE POPULATION. TO FACILITATE THE VALIDATION OF THESE SNPS AS USEFUL MARKERS FOR DRUG RESPONSE IN ASSOCIATION STUDIES, THIS THESIS THEN REPORTS THE DEVELOPMENT OF NOVEL GENOTYPING ASSAYS BASED ON PROOF-READING POLYMERASE IN BOTH LIQUID AND SOLID-PHASE FORMATS. THE EASE AND COST-EFFECTIVENESS OF THESE METHODS MAKES THEM POTENTIALLY USEFUL FOR LARGE-SCALE GENOTYPING AND ROUTINE CLINICAL TESTING. </P>