Fine mapping of quantitative trait loci (QTL) and identification of candidate genes for prion disease incubation in mice

Prion diseases are progressive neurodegenerative diseases which show characteristic prolonged incubation periods. Polymorphisms in the prion protein gene are known to influence incubation time but additional genetic loci have also been identified by quantitative trait locus mapping studies in mice. Genome-wide screening approaches using two-way crosses have identified broad regions of linkage with large confidence intervals on several mouse chromosomes. In order to reduce and fine map the regions, a genetically diverse heterogenous stock (HS) of mice has been utilized which provides a powerful tool for fine mapping at centimorgan (cM) intervals. Linkage analysis in the HS mice identified small (l-2cM), highly significant regions of linkage on chromosomes 8, 9 and 11. The predicted regulatory regions and entire mRNA transcript of candidate genes within these regions have been sequenced to identify polymorphisms between the parental strains of the cross. This variation may be indicative of genetic differences that influence prion disease incubation time. Linkage analysis was used to determine if identified polymorphisms correlated with the strain effects observed in the cross and resulting candidates were genotyped in the cross to assess association with incubation time. The expression of candidate genes was quantified in the parental strains of the cross to assess the regulatory control of polymorphisms identified. Attention on chromosome 11 has focused on Trans-acting Transcription Factor 6 (Sp6) and Monocyte Chemoattractant Protein 1 (Mcp-1), the latter having been assessed in a mouse model. A small group of genes on chromosome 8 have also been implicated as promising candidates. The identification of modifier genes influencing susceptibility to prion diseases will provide further insights into the pathogenesis of prion disease and identify ligands and pathways for the design of rational therapeutics