Experiment
QTL associated with susceptibility to radiation-induced adenomatous polyposis were mapped using 142 BALB/cByJ x (BALB/xByJ x C57BL/6J-ApcMin)F1 backcross animals irradiated with 2 Gy x-irradiation and genotyped for 112 polymorphic markers at an averageresolution of 15 cM. A separate population of 111 sham-irradiated backcross animals was also analyzed. All backcross animals carried at least one BALB/cByJ-derived Pla2g2aMom1-R allele. Parental strain C57BL/6J-ApcMin displays susceptibility to intestinal adenomas compared toparental strain BALB/cByJ. The upper small intestine of C57BL/6J-ApcMin animals appears more sensitive to radiation-induced adenoma development than the lower small intestine.
Significant linkage to adenoma susceptibility in the upper small intestine after 2Gy irradiation mapped to 55.7 cM on mouse Chromosome 2 near D2Mit395 (P<0.0001). This locus explains 9% of the phenotypic variance and is named Mrip1 (Mom radiation-induced polyposis 1). The confidence interval for Mrip1 spans 40 cM to 70 cM. Ptprj (49.5 cM) and Scc2 (28 cM) are loci associated with colon cancer that map near Mrip1. Potential candidate genes for Mrip1 include Duox2, Bubr1, Mertk, Dll4, Casc5 and Bub1 (73 cM).
Highly significant linkage to adenoma susceptibility inthe upper small intestine after 2Gy irradiation mapped to 28.4 cM on mouse Chromosome 5 near D5Mit201 (P<0.0001). This locus explains 15% of the phenotypic variance and is named Mrip2 (Mom radiation-induced polyposis 2). The Mrip2 confidence interval spans approximately 13.4 cM to 43.4 cM. Rfc1 (formerly Recc1; 39 cM) is a potential candidate gene for Mrip2. A separate locus also exhibiting linkage to upper small intestine adenoma susceptibility after 2Gy irradiation mapped to 59 cM near D5Mit139 (P<0.0001) and is named Mrip3 (Mom radiation-induced polyposis 3). Mrip3 explains 19% of the phenotypic variance and the confidence interval spans approximately 44 cM to 74 cM. Arap2 (formerly Centd1) and Cxcl5 (53 cM) are potential candidate genes for Mrip3.Mrip2and Mrip3 were both detected using interval mapping (IM) and composite interval mapping (CIM) methods.
Susceptibility to upper small intestine adenoma formation after 2Gy irradiation mapped to two locations on mouse Chromosome 16. Mrip4 (Mom radiation-induced polyposis 4) mapped to 9.2 cM near Prkdc, which is also the most likely candidate gene. The confidence interval for Mrip4 spans approximately 0 cM to 25 cM and the QTL explains 11% of the phenotypic variance. A previously identified QTL for radiation induced thymic lymphoma susceptibility (Ritls; 9.61 cM) overlaps with Mrip4. Mrip5 (Mom radiation-induced polyposis 5) mapped to 40.1 cM near D16Mit189. The Mrip5 confidence interval spans approximately 25 cM to 55 cM. This locus explains 14% of the variance. Itgb2l was named a potential candidate gene for Mrip5. Mrip4 and Mrip5 were both detected using interval mapping (IM) and composite interval mapping (CIM) methods.
Suggestive linkage to radiation-induced adenoma formation in the upper small intestine of 2Gy irradiated backcross animals mapped to 25.1 cM on mouse Chromosome 17 near D17Mit180 (P<0.005). Suggestive linkage to radiation-induced adenoma formation in the lower small intestine of 2Gy irradiated backcross animals mapped to 110.4 cM on chromosome1 near D1Mit17, 51.4 cM on chromosome 6 near D6Mit194, 0 cM on chromosome 7 near D7Mit178, 5.3 cM on chromosome 8 near D8Mit211 and 14.2 cM on chromosome 11 near D11Mit216.
Suggestive linkage to adenoma susceptibility in the small upper intestine in sham-irradiatedbackcross animals mapped to 63.4 cM on mouse Chromosome 3 near D3Mit352 and 15.3 cM on mouse Chromosome 13 near D13Mit179. Suggestive linkage to adenoma susceptibility in the lower small intestine of sham-irradiated backcross animals mapped to 3.3 cM on mouse Chromosome 6 near D6Mit83.
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