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) on mouse 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), Klk1b4 (23.02 cM), and Klk1b3 (23.03 cM). There may be 2 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 intervalsmay be identical to prion incubation time QTLs (Pitm2- 42.5 cM Chr4, Pitm3-43 cM Chr8) identified by Manolakou et al., 2001 (J:70033).