Genetic analysis of the construction of the AEJ.A congenic strain indicates that nonsyndromic CL(P) in the mouse is caused by two loci with epistatic interaction.
The A/WySn mouse strain has a high frequency (20%) of the craniofacial defect, cleft lip with or without cleft palate, CL(P), in fetuses or newborns. Previous genetic studies have indicated that the genetic control of the risk of CL(P) is complex, but the cause of the liability of the embryo involves only one or two loci. The genes that cause the liability to CL(P) in A/WySn have been transferred by 12 generations of selective breeding to a normal strain background, AEJ/RkBc, to form a congenic strain pair. The new strain, AEJ.A/Jur, has been used to map a major CL(P) locus, clf1. Analysis of the genetic data from the process of constructing the AEJ.A/Jur strain indicates that the cause of CL(P) in A/WySn mice is the joint action of two recessive loci, clf1 and clf2 with unequal duplicate epistasis. That is, the normal allele at clf1 is a dominant suppressor of the recessive phenotype at clf2, and the normal allele at clf2 is a semidominant suppressor of the recessive phenotype at the clf1 locus. To be at risk for CL(P), embryos must be homozygous for clf1 mutations and at least heterozygous for clf2 mutations, and the risk is higher if they are homozygous for mutations at both loci. The delineation of this epistatic model involving a locus, clf1, that has linkage homology with a region implicated in human CL(P), and that has three paralogous regions in both species, supports the following arguments: and that has three paralogous regions in both species, supports the following arguments: that the CL(P) of the A/WySn mouse strain is a homologue of human CL(P); that the genetic complexity of CL(P) in both species originates in epistasis, not in polygenic modifiers; that human linkage analyses should specify epistatic models for CL(P); that the paralogous linkage groups should be considered candidate regions for other CL(P) loci.
Juriloff
D M
DM
Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
D000818:Animals; D002971:Cleft Lip / Q000235:genetics*; D002972:Cleft Palate / Q000235:genetics*; D003433:Crosses, Genetic; D004843:Epistasis, Genetic; D005260:Female; D008040:Genetic Linkage; D006579:Heterozygote; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains / Q000235:genetics*