Genetic mapping of Mom5, a novel modifier of Apc^Min-induced intestinal tumorigenesis

The initial purpose of this study was to assess the role of estrogen receptor β (ER β) in intestinal tumorigenesis by examining the effects of an ERβ knockout (ERβ^-/-) on Apc^Min mice. In order to accomplish this goal on a uniform genetic background, we were required to backcross the ERβ 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 N₅ backcross generation of the ERβ knockout strain were intercrossed with Apc^Min/+ mice to obtain Apc^Min/+ ER β^-/-, Apc^Min/+ ER β^+/- and Apc^Min/+ ER β^-/+ mice. Intestinal tumorigenesis in the N₅F₂ mice was evaluated at 14 weeks of age. The analysis of the impact of ER β in the N₅ cross was complicated by segregating 129P2-derived alleles that affected tumor number and were unlinked to ER β. Genetic linkage analysis of this cross permitted the localization of a single genetic modifier of tumor number in Apc^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.