Genetic analysis of a quantitative trait in a mouse model of polycystic kidney disease.
The development of a variety of powerful tools for genome analysis has facilitated the ability to genetically map loci which contribute to the variation of a quantitative trait. However, the fact that these traits are often determined as a result of complex genetic interactions has made their analysis considerably more difficult then the molecular characterization of qualitative traits that are monogenic in origin. We have described the use of a novel method of chromosomal exclusion to map the recessive mutation juvenile cystic kidney (jck) to mouse chromosome 11 using an intercross between (C57BL/6J x DBA/2J) F1 jck/+ mice. The severity of polycystic kidney disease (PKD) in the intercross progeny, which could be quantitated as a function of kidney size, was significantly more variable than that found in the parental C57BL/6J strain, suggesting that a modifier locus or loci introduced from DBA/2J affects expression of jck. Two regions (one from DBA/2J on chromosome 10 and a second from C57BL/6J on chromosome 1) were found to be associated with inheritance of a more severe PKD phenotype. The finding of a highly significant association of inheritance of a C57BL/6J-related locus with disease severity was unexpected since the PKD phenotype in this inbred background is mild. This result suggests that inheritance in the affected F2 mice of loci from the two different parental backgrounds results in the more severe phenotype, presumably as a consequence of a direct or indirect interaction between their protein products. This type of effect, which is an example of genetic epistasis, will make the molecular characterization of loci that contribute to complex traits markedly more difficult than the analysis of monogenic disorders.
Iakoubova
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Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Dushkin
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Beier
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D000818:Animals; D002874:Chromosome Mapping / Q000379:methods*; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D008040:Genetic Linkage; D005838:Genotype; D007668:Kidney; D008126:Lod Score; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009929:Organ Size / Q000235:genetics; D007690:Polycystic Kidney Diseases / Q000235:genetics*; D019655:Quantitative Trait, Heritable