Genetic mapping of novel modifiers for Apc Min induced intestinal polyps’ development using the genetic architecture power of the collaborative cross mice

Alexandra Dorman, Ilona Binenbaum, Hanifa J. Abu-Toamih Atamni, Aristotelis Chatziioannou, Ian Tomlinson, Richard Mott, Fuad A. Iraqi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Background: Familial adenomatous polyposis is an inherited genetic disease, characterized by colorectal polyps. It is caused by inactivating mutations in the Adenomatous polyposis coli (Apc) gene. Mice carrying a nonsense mutation in the Apc gene at R850, which is designated ApcMin/+ (Multiple intestinal neoplasia), develop intestinal adenomas. Several genetic modifier loci of Min (Mom) were previously mapped, but so far, most of the underlying genes have not been identified. To identify novel modifier loci associated with ApcMin/+, we performed quantitative trait loci (QTL) analysis for polyp development using 49 F1 crosses between different Collaborative Cross (CC) lines and C57BL/6 J-ApcMin/+mice. The CC population is a genetic reference panel of recombinant inbred lines, each line independently descended from eight genetically diverse founder strains. C57BL/6 J-ApcMin/+ males were mated with females from 49 CC lines. F1 offspring were terminated at 23 weeks and polyp counts from three sub-regions (SB1–3) of small intestinal and colon were recorded. Results: The number of polyps in all these sub-regions and colon varied significantly between the different CC lines. At 95% genome-wide significance, we mapped nine novel QTL for variation in polyp number, with distinct QTL associated with each intestinal sub-region. QTL confidence intervals varied in width between 2.63–17.79 Mb. We extracted all genes in the mapped QTL at 90 and 95% CI levels using the BioInfoMiner online platform to extract, significantly enriched pathways and key linker genes, that act as regulatory and orchestrators of the phenotypic landscape associated with the ApcMin/+ mutation. Conclusions: Genomic structure of the CC lines has allowed us to identify novel modifiers and confirmed some of the previously mapped modifiers. Key genes involved mainly in metabolic and immunological processes were identified. Future steps in this analysis will be to identify regulatory elements – and possible epistatic effects – located in the mapped QTL.

Original languageEnglish
Article number566
JournalBMC Genomics
Issue number1
StatePublished - Dec 2021


FundersFunder number
Cancer Biology Research Center
Israel Cancer Research Fund
United States - Israel Binational Science Foundation
Wellcome Trust083573/Z/07/Z, 075491/Z/04, 090532/Z/09/Z, 085906/Z/08/Z
State Scholarships Foundation
Israel Science Foundation429/09, 961/15, 1085/18
Tel Aviv University
Cancer Biology Research Center, Tel Aviv University
State Scholarship Foundation in Greece


    • Apc
    • Candidate genes
    • Collaborative cross
    • Colorectal cancer
    • Familial adenomatous polyposis
    • Genetic modifier
    • Moms
    • Phenotyping
    • QTL mapping
    • Recombinant inbred lines


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