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 t he variation of a quantitative trait. However, the fact that these tra its are often determined as a result of complex genetic interactions h as made their analysis considerably more difficult then the molecular characterization of qualitative traits that are monogenic in origin. W e have described the use of a novel method of chromosomal exclusion to map the recessive mutation juvenile cystic kidney (jck) to mouse chro mosome 11 using an intercross between (C57BL/6J x DBA/2J) F1 jck/+ mic e. The severity of polycystic kidney disease (PKD) in the intercross p rogeny, which could be quantitated as a function of kidney size, was s ignificantly more variable than that found in the parental C57BL/6J st rain, 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 associ ated with inheritance of a more severe PKD phenotype. The finding of a highly significant association of inheritance of a C57BL/6J-related l ocus with disease severity was unexpected since the PKD phenotype in t his inbred background is mild. This result suggests that inheritance i n the affected F2 mice of loci from the two different parental backgro unds results in the more severe phenotype, presumably as a consequence of a direct or indirect interaction between their protein products. T his type of effect, which is an example of genetic epistasis, will mak e the molecular characterization of loci that contribute to complex tr aits markedly more difficult than the analysis of monogenic disorders.