International Mammalian Genome Society

The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

E18 The Complex Genetics of Cleft Lip in Mice and Mapping the Second Epistatic Locus, CLF2

Diana M. Juriloff, Muriel J. Harris, Department of Medical Genetics, University of British Columbia, Vancouver, B.C., Canada

Cleft lip (formerly "hare-lip") is almost never seen in most inbred strains of mice, but occurs commonly (5-30% of newborns) in the "A/-" strains (e.g., A/J, A/HeJ, A/WySnJ) and in strains with A/- strain ancestry (e.g., CL/Fr, AXB-6/Pgn). Cleft lip is a developmental threshold trait involving quantitative variation in the size of the embryonic maxillary prominence; consequently, not all individuals with the genetic liability express the trait, which is lethal soon after birth in mice. The genetic cause of liability to cleft lip in the A/- strains is complex, involving epistatic interaction between genes functioning in the embryo, and modification of risk by the genotype of the mother. It serves as a model of genetically complex birth defects, including human "multifactorial" CL(P).

Our primary interest is in the genetic reasons underlying the complexity of inheritance of some common birth defects. We study the genetics and embryopathogenesis of cleft lip in the A/- strains as a model system for developing strategies to identify the genes involved and the nature of their interaction to create genotypes at risk.

Focussing on the difference between C57BL/6J (normal) and A/- strains, we previously demonstrated a bimodality of first backcross breeding values for cleft lip risk that indicated that one or two recessive loci were essential to the cause of risk of cleft lip. In the next step, we created a congenic strain for a recessive causative gene, clf1, and used it to map clf1 to Chr 11 near D11Mit10. Analysis of testcrosses of the congenic strain showed that clf1 is necessary but not sufficient to cause A/- strain levels of risk of cleft lip.

In the present study, the 35 cleft lip embryos (2.7%) obtained among 1299 first backcross segregants in A/WySnJ mothers, after a cross between A/WySnJ and C57BL/6J strains, were used in a genome screen to map a second locus, clf2 on Chr 13, that interacts epistatically with clf1 to cause risk of cleft lip. The observed 2.7% is significantly lower than the 5% expected for segregation of two epistatic loci, suggesting involvement of other loci. Candidate regions for a third locus, clf3, were suggested by the genome screen.

Testcrosses of various strains of the AXB/BXA RI set (derived from A/J and C57BL/6J), with known genotypes in the clf1 and clf2 regions, were used to further confirm the fully recessive essential role of clf1 and the epistatic, essential, mostly recessive role of clf2 in causing cleft lip risk (i.e., "duplicate epistasis"). Haplotypes of the AXB/BXA RI strains that produced high frequencies (20%) of cleft lip in testcrosses, AXB-6/Pgn and BXA-8/Pgn, were used to narrow the candidate region for clf2 to a 4 cM region between D13Mit13 and D13Mit231. The presence of "A" alleles in one of the candidate regions for the third locus, clf3, in these two strains suggests that clf3 is on mouse Chr 7.

clf1 is linked to Neurod2. clf2 is linked to Neurod3. clf1 and clf2 seem to interact with duplicate epistasis. This suggests that clf1 and clf2 may be paralogous duplicates of a single ancestral gene and that genetic redundancy may be part of the basis of the complex inheritance of risk of cleft lip.

(Research funded by the Medical Research Council of Canada.)


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