Juriloff D M
Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
J Craniofac Genet Dev Biol. 1995 Jan-Mar;15(1):1-12.
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.
A/WySn小鼠品系在胎儿或新生儿中出现颅面缺陷（唇裂伴或不伴腭裂，即CL(P)）的频率很高（20%）。先前的遗传学研究表明，CL(P)风险的遗传控制很复杂，但胚胎易感性的原因仅涉及一两个基因座。导致A/WySn小鼠出现CL(P)易感性的基因已通过12代选择性育种转移到正常品系背景AEJ/RkBc中，形成了一对同源品系。新的品系AEJ.A/Jur已被用于定位一个主要的CL(P)基因座clf1。对构建AEJ.A/Jur品系过程中的遗传数据进行分析表明，A/WySn小鼠中CL(P)的病因是两个隐性基因座clf1和clf2的联合作用，且存在不等位基因重复上位性。也就是说，clf1的正常等位基因是clf2隐性表型的显性抑制因子，而clf2的正常等位基因是clf1基因座隐性表型的半显性抑制因子。要出现CL(P)风险，胚胎必须是clf1突变的纯合子且至少是clf2突变的杂合子，如果两个基因座的突变均为纯合子，则风险更高。这种涉及与人类CL(P)相关区域具有连锁同源性且在两个物种中都有三个旁系同源区域的基因座clf1的上位性模型的描述，支持了以下观点：A/WySn小鼠品系的CL(P)是人类CL(P)的同源物；两个物种中CL(P)的遗传复杂性源于上位性，而非多基因修饰因子；人类连锁分析应明确CL(P)的上位性模型；旁系连锁群应被视为其他CL(P)基因座的候选区域。
