Genetic mapping of Mom5, a novel modifier of ApcMin-induced intestinal tumorigenesis

Abstract

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 ApcMin 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 ApcMin/+ mice to obtain ApcMin/+ ER β-/-, ApcMin/+ ER β+/- and ApcMin/+ 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 ApcMin/+ 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. © The Author 2009. Published by Oxford University Press. All rights reserved.