Experiment
Genome scan using 72 polymorphic markers was performed on 282 (C57BL/FaDk x RIII/FaDk)F2 animals to identify QTLs associated with susceptibility/resistance to prion disease. Animals were inoculated with mouse adapted scrapies strain C506-M3 and observed for scrapies symptoms up to time of death. Parental strain RIII/FaDk is more susceptible to prion disease compared to parental strain C57BL/FaDk.
Significant linkage to prion resistance mapped to an interval between 51 cM (D5Mit259) - 72 cM (D5Mit223) onmouse Chromosome 5 (Prnr1, LOD=4.7) and an interval between 2 cM (D7Mit76) - 18 cM (D7Mit228) on mouse Chromosome 7 (Prnr2, LOD=3.5). The peak of Prnr1 appears to occur near D5Mit95 (68 cM) and the peak of Prnr2 appears to occur near D7Mit246 (15 cM). Prnr1 on chromosome 5 affects female animals with RIII/FaDk-derived alleles conferring recessive prion disease resistance. This locus explains 13% of the variance. Potential candidate genes for Prnr1 are Ubc (64 cM) and Nos1 (65 cM). Prnr2 on chromosome 7 affects both sexes with C57BL/FaDk-derived alleles conferring dominant prion disease resistance. This locus explains 5% of the variance. Potential candidate genes for Prnr2 are Apoe (4 cM), Tgfb1 (6.5 cM), Ngfa (23.02 cM), and Ngfg (23.03 cM). There may be2 linked QTLs on mouse Chromosome 7, one near 6 cM (Prnr1) and another near 26 cM. The 26 cM peak reaches suggestive significance and is observed in males.
Several suggestive QTL intervals were identified: 34 cM - 64 cM on mouse Chromosome 4 (female specific, LOD=2.1), 25 cM - 67 cM on mouse Chromosome 6 (LOD=2.0), 22 cM - 64 cM on mouse Chromosome 8 (LOD=1.9), and on mouse Chromosome 17 at 7 cM - 21 cM (male specific, LOD=2.0) and 36 cM - 46 cM (female specific, LOD=2.5). Two of these intervals may be identical to prion incubation time QTLs (Pitm2- 42.5 cM Chr4, Pitm3-43 cM Chr8) identified by Manolakou et al., 2001 (J:70033).
Analysis Tools