Identification of five novel modifier loci of ApcMin harbored in the BXH14 recombinant inbred strain

Nnadi, Stephanie C.; Watson, Rayneisha; Innocent, Julie; Gonye, Gregory E.; Buchberg, Arthur M.; Siracusa, Linda D.

doi:10.1093/carcin/bgs185

Cited by 12 publications

(15 citation statements)

References 55 publications

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“…Another modifier, Mom 2, is an Atp5a1 mutation that acts by suppressing loss of heterozygosity through cell lethality [ 14 , 27 , 28 ]. Other Mom loci have been mapped, but no other genes been cloned [ 29 ]. The most comprehensive modifier screen to date in a population of female BXH recombinant inbred mice backcrossed to C57BL/6- Min males [ 29 ] identified five modifier loci.…”

Section: Introductionmentioning

confidence: 99%

Genetic analysis of intestinal polyp development in Collaborative Cross mice carrying the Apc Min/+ mutation

Dorman¹,

Baer²,

Tomlinson³

et al. 2016

BMC Genet

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BackgroundColorectal cancer is an abnormal tissue development in the colon or rectum. Most of CRCs develop due to somatic mutations, while only a small proportion is caused by inherited mutations. Familial adenomatous polyposis is an inherited genetic disease, which is characterized by colorectal polyps. It is caused by inactivating mutations in the Adenomatous polyposis coli gene. Mice carrying and non-sense mutation in Adenomatous polyposis coli gene at site R850, which designated ApcR850X/+ (Min), develop intestinal adenomas, while the bulk of the disease is in the small intestine. A number of genetic modifier loci of Min have been mapped, but so far most of the underlying genes have not been identified. In our previous studies, we have shown that Collaborative Cross mice are a powerful tool for mapping loci responsible for phenotypic variation. As a first step towards identification of novel modifiers of Min, we assessed the phenotypic variation between 27 F1 crosses between different Collaborative cross mice and C57BL/6-Min lines.ResultsHere, C57BL/6-Min male mice were mated with females from 27 Collaborative cross lines. F1 offspring were terminated at 23 weeks old and multiple phenotypes were collected: polyp counts, intestine length, intestine weight, packed cell volume and spleen weight. Additionally, in eight selected F1 Collaborative cross-C57BL/6-Min lines, body weight was monitored and compared to control mice carry wildtype Adenomatous polyposis coli gene. We found significant (p < 0.05) phenotypic variation between the 27 F1 Collaborative cross-C57BL/6-Min lines for all the tested phenotypes, and sex differences with traits; Colon, body weight and intestine length phenotypes, only. Heritability calculation showed that these phenotypes are mainly controlled by genetic factors.ConclusionsVariation in polyp development is controlled, an appreciable extent, by genetic factors segregating in the Collaborative cross population and suggests that it is suited for identifying modifier genes associated with ApcMin/+ mutation, after assessing sufficient number of lines for quantitative trait loci analysis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-016-0349-6) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Genetic analysis of intestinal polyp development in Collaborative Cross mice carrying the Apc Min/+ mutation

Dorman¹,

Baer²,

Tomlinson³

et al. 2016

BMC Genet

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“…The identification of genetic interactions is more straightforward in mice due the high degree of homogeneity among inbred mouse strains and the long stretches of linkage disequilibrium in the mouse crosses used for linkage mapping. Approximately 20 quantitative trait loci for CRC susceptibility have been mapped by crossing mouse strains resistant to and susceptible to chemically induced colon cancer or by looking for modifiers of transgenic mutations such as Apc Min which cause spontaneous development of intestinal adenomas . Mouse models of chemically induced CRC follow a similar multistage disease progression and develop tumors with many of the same mutations observed in human CIN tumors .…”

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confidence: 99%

“…Approximately 20 quantitative trait loci for CRC susceptibility have been mapped by crossing mouse strains resistant to and susceptible to chemically induced colon cancer or by looking for modifiers of transgenic mutations such as Apc Min which cause spontaneous development of intestinal adenomas. [14][15][16][17][18][19][20][21][22][23] Mouse models of chemically induced CRC follow a similar multistage disease progression and develop tumors with many of the same mutations observed in human CIN tumors. 24 This similarity suggests that the genes controlling cancer susceptibility in mice will be relevant to humans.…”

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confidence: 99%

Allele‐specific imbalance mapping at human orthologs of mouse susceptibility to colon cancer (Scc) loci

Gerber

Hampel

Zhou

et al. 2015

Intl Journal of Cancer

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Colorectal cancer (CRC) can be classified into different types. Chromosomal instable (CIN) colon cancers are thought to be the most common type of colon cancer. The risk of developing a CIN-related CRC is due in part to inherited risk factors. Genomewide association studies have yielded over 40 single nucleotide polymorphisms (SNPs) associated with CRC risk, but these only account for a subset of risk alleles. Some of this missing heritability may be due to gene-gene interactions. We developed a strategy to identify interacting candidate genes/loci for CRC risk that utilizes both linkage and RNA-seq data from mouse models in combination with allele-specific imbalance (ASI) studies in human tumors. We applied our strategy to three previously identified CRC susceptibility loci in the mouse that show evidence of genetic interaction: Scc4, Scc5 and Scc13. 525 SNPs from genes showing differential expression in the mouse and/or a previous role in cancer from the literature were evaluated for allele-specific imbalance in 194 paired human normal/tumor DNAs from CIN-related CRCs. One hundred three SNPs showing suggestive evidence of ASI (31 variants with uncorrected p values < 0.05) were genotyped in a validation set of 296 paired DNAs. Two variants in SNX10 (SCC13) showed significant evidence of allelic selection after multiple comparisons testing. Future studies will evaluate the role of these variants in combination with interacting genetic partners in colon cancer risk in mouse and humans.Colorectal cancer (CRC) is the third leading cause of cancerrelated death in the United States.1 Genetic alterations drive the transformation of normal colon epithelium into adenomas and ultimately malignant adenocarcinomas.2 Pathways such as chromosomal instability (CIN), microsatellite instability, and CpG island methylator phenotype lead to genomic alterations and thus promote tumorigenesis.3 Estimates suggest that as many as 80% to 85% of sporadic colorectal cancers demonstrate CIN, which is marked by an accelerated rate of gains or losses of whole or partial chromosomes.3 In CRC, CIN is typically coupled with mutational activation of proto-oncogenes like KRAS, inactivation of tumor suppressor genes like APC and TP53, and loss of heterozygosity at 18q. One mechanism by which CIN leads to activation and inactivation of oncogenes and tumor suppressor genes, respectively, is by altering gene dosage as a result of copy number alterations.Array comparative genomic hybridization (aCGH) studies can be used to identify refined regions of somatic copy number alterations in human colorectal tumors. Such studies have led to the identification of oncogenes and tumor suppressor

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“…Indeed, 18 such polymorphic modifier loci of the Apc Min tumor multiplicity phenotype have been reported to date (Eversley et al 2012; Nnadi et al 2012). The requirement for quantitative precision in this genetic strategy led us to move beyond the initial, informative outcross design and to develop an “isogenic design” (Figure 1B).…”

Section: Resultsmentioning

confidence: 99%

A Strategy to Identify Dominant Point Mutant Modifiers of a Quantitative Trait

Dove

Shedlovsky

Clipson

et al. 2014

G3 Genes|Genomes|Genetics

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A central goal in the analysis of complex traits is to identify genes that modify a phenotype. Modifiers of a cancer phenotype may act either intrinsically or extrinsically on the salient cell lineage. Germline point mutagenesis by ethylnitrosourea can provide alleles for a gene of interest that include loss-, gain-, or alteration-of-function. Unlike strain polymorphisms, point mutations with heterozygous quantitative phenotypes are detectable in both essential and nonessential genes and are unlinked from other variants that might confound their identification and analysis. This report analyzes strategies seeking quantitative mutational modifiers of ApcMin in the mouse. To identify a quantitative modifier of a phenotype of interest, a cluster of test progeny is needed. The cluster size can be increased as necessary for statistical significance if the founder is a male whose sperm is cryopreserved. A second critical element in this identification is a mapping panel free of polymorphic modifiers of the phenotype, to enable low-resolution mapping followed by targeted resequencing to identify the causative mutation. Here, we describe the development of a panel of six “isogenic mapping partner lines” for C57BL/6J, carrying single-nucleotide markers introduced by mutagenesis. One such derivative, B6.SNVg, shown to be phenotypically neutral in combination with ApcMin, is an appropriate mapping partner to locate induced mutant modifiers of the ApcMin phenotype. The evolved strategy can complement four current major initiatives in the genetic analysis of complex systems: the Genome-wide Association Study; the Collaborative Cross; the Knockout Mouse Project; and The Cancer Genome Atlas.

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Identification of five novel modifier loci of ApcMin harbored in the BXH14 recombinant inbred strain

Cited by 12 publications

References 55 publications

Genetic analysis of intestinal polyp development in Collaborative Cross mice carrying the Apc Min/+ mutation

Genetic analysis of intestinal polyp development in Collaborative Cross mice carrying the Apc Min/+ mutation

Allele‐specific imbalance mapping at human orthologs of mouse susceptibility to colon cancer (Scc) loci

A Strategy to Identify Dominant Point Mutant Modifiers of a Quantitative Trait

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