Experiment
Linkage analysis using 70 polymorphic markers at an average spacing of 20 cM was performed on 57 males and 57 females from a (C57BL/6J x C57BR/cdJ)F1 x C57BL/6J backcross to identify QTLs associated with susceptibility to hepatocarcinogenesis. The genomescan covers approximately 85% of the mouse genome. Animals were injected with N,N-diethylnitrosamine (DEN) at 12 day of age and sacrificed for livers at 32 weeks for males and at 50 weeks for females. Female animals from parental strain C57BR/cdJ exhibit a 15-fold increase in hepatic tumor incidence compared to female animals from C57BL/5J, and male C57BR/cdJ animals exhibit a 5.8-fold increase in hepatic tumor incidence compared to C57BL/5J males.
Significant linkage to liver tumor susceptibility in both sexes mapped to 18 cM on mouse Chromosome 17 near D17Mit21 (LOD=3.55 for females, LOD=4.75 for males). This locus is named Hcif1 (hepatocarinogenesis in females 1). A second locus showing suggestive linkage mapped to 81 cM on mouse Chromosome 1 near D1Mit33 (LOD=2.29 in females) and D1Mit10 (LOD=3.69 in males). This locus was named Hcif2.
Mapping of a (C57BL/6J x C57BR/cdJ)F2 intercross population was used to verify Hcif1 and Hcif2. When data for the backcross and intercross populations are combined the LOD score of Hcif1 reaches 15.5 at D17Mit21 and the LOD score of Hcif2 reaches 6.7 at D1Mit33. The C57BR/cdJ allele confers increased liver tumor susceptibility at Hcif1. Interaction between Hcif1 and Hcif2 was observed. Animals heterozygous for C57BL/6Jand C57BR/cdJ alleles at both Hcif1 and Hcif2 display significantly increased liver tumor incidence compared to animals homozygous for C57BL/6J alleles at both loci.
Potential candidate genes for Hcif1 include C4a (18.83 cM), Cyp21a1 (18.77 cM), Rxrb (18.49), Hspa1b (18.9 cM, formerly Hsp70), Tnf (19.06 cM), Lta (19.059 cM, formerly Tnfb), Ltb (19.061 cM, formerly Tnfc), and the H2 locus. Potential candidate genes for Hcif2 are Abl2 (82.1 cM) and Rxrg (88.1 cM).
Analysis Tools