Iakoubova O A, Dushkin H, Beier D R
Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Am J Respir Crit Care Med. 1997 Oct;156(4 Pt 2):S72-7. doi: 10.1164/ajrccm.156.4.12-tac-0.
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.
多种强大的基因组分析工具的开发，促进了对影响数量性状变异的基因座进行遗传定位的能力。然而，这些性状往往是由复杂的基因相互作用决定的，这使得它们的分析比起源于单基因的质量性状的分子特征分析要困难得多。我们描述了一种使用染色体排除的新方法，通过（C57BL/6J×DBA/2J）F1 jck/+小鼠之间的杂交，将隐性突变幼年多囊肾（jck）定位到小鼠11号染色体上。杂交后代中多囊肾病（PKD）的严重程度可以根据肾脏大小进行定量，其变异性明显高于亲代C57BL/6J品系，这表明从DBA/2J引入的一个或多个修饰基因座影响了jck的表达。发现两个区域（一个来自10号染色体上的DBA/2J，另一个来自1号染色体上的C57BL/6J）与更严重的PKD表型的遗传相关。在这个近交背景中PKD表型较轻的情况下，发现与疾病严重程度高度相关的C57BL/6J相关基因座的遗传是出乎意料的。这一结果表明，来自两种不同亲代背景的基因座在受影响的F2小鼠中的遗传导致了更严重的表型，推测这是其蛋白质产物之间直接或间接相互作用的结果。这种效应是基因上位性的一个例子，它将使对影响复杂性状的基因座进行分子特征分析比单基因疾病的分析明显更困难。
