Guided by these observations, we investigated whether the increased levels of ANA and anti-chromatin Ab observed in the Apcs −/− mice were caused by a gene(s) within the fixed 129 region surrounding the mutated Apcs gene, rather than caused by the mutated Apcs gene itself. We compared the levels of these auto-Abs between all (129 × C57BL/6)F2.Apcs −/− mice and a group of 33 wild-type mice that were selected for being homozygous 129 in the region of Chromosome 1 between microsatellites D1Mit105 and D1Mit 223 (80–106 cM) (Figure 6A–6D). In contrast to the results reported in Table 1, this comparison showed no significant differences between the two experimental groups. This result demonstrates that, most likely, the 129-derived region and not the lack of Apcs was mediating the production of ANA and anti-chromatin Ab. Consistent with this explanation, we found that the 129 mice have significantly higher levels of Apcs in circulation compared with the C57BL/6 mice (median, 83 mg/l; range, 25–208; n = 16 versus median, 5 mg/l; range, 4–9; n = 10, respectively; p < 0.0001). The C57BL/6 strain has previously been reported to be one of the murine strains defined as low Apcs producers (Pepys et al. 1979; Baltz et al. 1980). In addition, sequence analysis of the entire Apcs coding region in both strains failed to identify any coding sequence polymorphisms in the Apcs gene (data not shown), indicating that a structural variant of the protein is unlikely to be the explanation for our findings. This is consistent with a previous report by Drake et al. (1996) that showed no Apcs coding sequence differences amongst several autoimmune and nonautoimmune murine strains.