Originally published as Genetics Published Articles Ahead of Print on August 24, 2008.

Genetics, Vol. 180, 601-609, September 2008, Copyright © 2008
doi:10.1534/genetics.108.091967

The Pleiotropic Phenotype of Apc Mutations in the Mouse: Allele Specificity and Effects of the Genetic Background

Richard B. Halberg*, Xiaodi Chen*, James M. Amos-Landgraf*, Alanna White*, Kristin Rasmussen*, Linda Clipson*, Cheri Pasch*, Ruth Sullivan{dagger}, Henry C. Pitot* and William F. Dove*,{ddagger},1

* McArdle Laboratory for Cancer Research, {dagger} Research Animal Resources Center and Comprehensive Cancer Center and {ddagger} Laboratory of Genetics, University of Wisconsin, Madison, Wisconsin 53706

1 Corresponding author: University of Wisconsin, 1400 University Ave., Madison, WI 53706.
E-mail: dove{at}oncology.wisc.edu

Familial adenomatous polyposis (FAP) is a human cancer syndrome characterized by the development of hundreds to thousands of colonic polyps and extracolonic lesions including desmoid fibromas, osteomas, epidermoid cysts, and congenital hypertrophy of the pigmented retinal epithelium. Afflicted individuals are heterozygous for mutations in the APC gene. Detailed investigations of mice heterozygous for mutations in the ortholog Apc have shown that other genetic factors strongly influence the phenotype. Here we report qualitative and quantitative modifications of the phenotype of Apc mutants as a function of three genetic variables: Apc allele, p53 allele, and genetic background. We have found major differences between the Apc alleles Min and 1638N in multiplicity and regionality of intestinal tumors, as well as in incidence of extracolonic lesions. By contrast, Min mice homozygous for either of two different knockout alleles of p53 show similar phenotypic effects. These studies illustrate the classic principle that functional genetics is enriched by assessing penetrance and expressivity with allelic series. The mouse permits study of an allelic gene series on multiple genetic backgrounds, thereby leading to a better understanding of gene action in a range of biological processes.