Genetic mapping of Mom5, a novel modifier of Apc super(Min)-induced intestinal tumorigenesis

The initial purpose of this study was to assess the role of estrogen receptor b (ERb) in intestinal tumorigenesis by examining the effects of an ERb knockout (ERb super(-/-)) on Apc super(Min) mice. In order to accomplish this goal on a uniform genetic background, we were required to backcross the ERb knockout from the 129P2 genetic background to the B6 genetic background for 10 generations. Midway through this process, we performed a test cross in which mice from the N sub(5) backcross generation of the ERb knockout strain were intercrossed with Apc super(Min/+) mice to obtain Apc super(Min/+) ERb super(+/+), Apc super(Min/+) ERb super(+/-) and Apc super(Min/+) ERb super(-/-) mice. Intestinal tumorigenesis in the N sub(5)F sub(2) mice was evaluated at 14 weeks of age. The analysis of the impact of ERb in the N sub(5) cross was complicated by segregating 129P2-derived alleles that affected tumor number and were unlinked to ERb. Genetic linkage analysis of this cross permitted the localization of a single genetic modifier of tumor number in Apc super(Min/+) mice. This locus, Modifier of Min 5 (Mom5), maps to proximal mouse chromosome 5; the 129P2 allele of this locus is associated with a 50% reduction in mean intestinal tumor number. Through in silico analysis and confirmatory sequencing, we have identified the Rad50-interacting protein-1 gene as a strong candidate for Mom5.