Although considerable efforts have been made to identify the genes responsible for the development of the disease, with the exception of the lpr mutation, none of the genetic contributions to disease in the three well-documented murine SLE strains have yet been fully resolved at the molecular or protein level. Thus, targeted genetic disruption of candidate genes encoding proteins of the immune system has been extensively used to examine their role in immune regulation. However, the most surprising result of this powerful approach has been the high frequency with which such mutations have been associated with an autoimmune phenotype. In this regard, it is of note that hybrid strains between 129 and C57BL/6 mice, widely used in the generation of gene-targeted mice, are spontaneously predisposed to development of humoral autoimmunity with low levels of glomerulonephritis (Obata et al. 1979; Botto et al. 1998; Bickerstaff et al. 1999; Santiago-Raber et al. 2001). Furthermore, the genetic background markedly influences the autoimmune phenotype in gene-targeted mice (Bolland and Ravetch 2000; Santiago-Raber et al. 2001; Mitchell et al. 2002). These observations led to the hypothesis that the autoimmune phenotype described in some gene-targeted mice might be due primarily to combinations of as-yet-uncharacterised background genes, originating from 129 and C57BL/6 mice strains, interacting or not with the mutated allele. To test this, we conducted a genome-wide scan analysis of two large cohorts of (129 × C57BL/6)F2 mice, one of which carried a mutation in the serum amyloid P component gene (Apcs). The Apcs-deficient mice (Apcs −/−) were chosen as an example of a gene-targeted strain previously reported to develop a lupus-like disease on the hybrid genetic background (129 × C57BL/6); autoimmunity in Apcs −/− mice persists even after backcrossing the mutated gene onto C57BL/6 (Bickerstaff et al. 1999). We chose this targeted gene in particular to study since the Apcs gene is located on Chromosome 1, approximately 94 cM from the centromere, within a region where several lupus-susceptibility loci, designated Sle1 (Morel et al. 2001), Nba2 (Drake et al. 1995; Vyse et al. 1997), and Bxs3 (Hogarth et al. 1998; Haywood et al. 2000), have been mapped in NZW, NZB, and BXSB lupus-prone strains, respectively. This region contains several genes, including those encoding FcγRII, the complement receptor CR1/2 (CD35/CD21), and the decay-accelerating factor CD55 (Prodeus et al. 1998; Bolland and Ravetch 2000; Miwa et al. 2002; Wu et al. 2002), which have each been implicated in the causation of SLE when inactivated by gene-targeting in 129 embryonic stem cells.