Danciger Michael, Yang Haidong, Handschumacher Lisa, LaVail Matthew M
Department of Biology, Loyola Marymount University, Los Angeles, CA 90045-2659, USA.
Mol Vis. 2005 May 27;11:374-9.
In a previous constant light-induced retinal damage (CLD) quantitative genetics study between the albino C57BL/6J-c2J (B6al) and BALB/c mouse strains, we identified a very strong and highly significant quantitative trait locus (QTL) on distal Chr 3 that we associated with a variant of the Rpe65 gene. The B6al strain carries the MET450 variant of RPE65 and is resistant to CLD while the BALB/c strain carries the LEU450 variant and is sensitive. Since then, we have discovered that the NZW/LacJ (NZW) albino mouse strain is sensitive to CLD but carries the MET450 variant of RPE65. The purpose of this study was to determine if the NZW mouse disproves the hypothesis that the MET450 variant of RPE65 protects the mouse retina against constant light-induced retinal damage.
F2 progeny were bred from an intercross between the NZW/LacJ and B6al mouse strains. After a prolonged exposure to moderate constant light, F2 mice were phenotyped for retinal outer nuclear layer thickness as the quantitative trait. A subset of 156 of the 201 F2 mice was genotyped for a set of markers spanning the genome, and any marker with a significant association with the quantitative trait was genotyped in the remaining 45 F2s. Data were analyzed for QTL by the Map Manager QTX software.
No QTL was identified at distal Chr 3, although several QTL on Chrs 1 (two), 10, 13, 14, 16, and X were detected. One QTL on middle Chr 1 (LOD 5.22) mapped to the same location of a QTL (LOD 6.8) in a previous intense, short exposure light-induced retinal damage study conducted with an intercross between the 129S1/SvImJ and BALB/c strains. QTL on Chrs 1 (distal), 10, and 14 also appeared in other retinal damage quantitative genetics studies. Three pairs of genes exhibited significant epistatic effects. Two of the pairs involved synergistic interactions between NZW and B6al alleles, and the third between two B6al alleles.
If another gene besides Rpe65 was responsible for the QTL in the original BALB/c x B6al study, and the NZW mouse carried a light sensitive allele of this gene, a QTL should have been present in this study. Since a QTL on Chr 3 was not found, the hypothesis that RPE65-MET450 protects the retina from constant light-induced damage is left intact. The explanation for the NZW mouse being sensitive to constant light while carrying the RPE65-MET450 variant is that other light sensitive QTL (gene alleles) negate the protective effect.
在先前对白化病C57BL/6J-c2J（B6al）和BALB/c小鼠品系进行的持续光照诱导视网膜损伤（CLD）定量遗传学研究中，我们在3号染色体远端鉴定出一个非常强且高度显著的数量性状基因座（QTL），我们将其与Rpe65基因的一个变体相关联。B6al品系携带RPE65的MET450变体，对CLD具有抗性，而BALB/c品系携带LEU450变体，对CLD敏感。从那时起，我们发现NZW/LacJ（NZW）白化病小鼠品系对CLD敏感，但携带RPE65的MET450变体。本研究的目的是确定NZW小鼠是否反驳了RPE65的MET450变体可保护小鼠视网膜免受持续光照诱导的视网膜损伤这一假设。
F2后代由NZW/LacJ和B6al小鼠品系杂交产生。在长时间暴露于中度持续光照后，对F2小鼠的视网膜外核层厚度进行表型分析，将其作为数量性状。在201只F2小鼠中，对156只小鼠的一个子集进行全基因组标记的基因分型，并对其余45只F2小鼠中与数量性状有显著关联的任何标记进行基因分型。通过Map Manager QTX软件对数据进行QTL分析。
在3号染色体远端未鉴定到QTL，尽管在1号染色体（两个）、10号、13号、14号、16号和X染色体上检测到了几个QTL。在先前对129S1/SvImJ和BALB/c品系杂交进行的强烈、短时间暴露光照诱导视网膜损伤研究中，1号染色体中部的一个QTL（LOD 5.22）映射到一个QTL（LOD 6.8）的相同位置。1号染色体（远端）、10号和14号染色体上的QTL也出现在其他视网膜损伤定量遗传学研究中。三对基因表现出显著的上位效应。其中两对涉及NZW和B6al等位基因之间的协同相互作用，第三对涉及两个B6al等位基因之间的协同相互作用。
如果除Rpe65之外的另一个基因负责原始BALB/c×B6al研究中的QTL，并且NZW小鼠携带该基因的光敏感等位基因，那么本研究中应该存在一个QTL。由于在3号染色体上未发现QTL，RPE65 - MET450可保护视网膜免受持续光照诱导损伤的假设仍然成立。NZW小鼠携带RPE65 - MET450变体却对持续光照敏感的解释是，其他光敏感QTL（基因等位基因）抵消了这种保护作用。
