Danciger M, Yang H, Ralston R, Liu Y, Matthes M T, Peirce J, Lavail M M
Department of Biology, Loyola Marymount University, Los Angeles, CA 90045-2659, USA.
Mol Vis. 2007 Jan 25;13:79-85.
Previously, several quantitative trait loci (QTL) that influence age-related retinal degeneration (ageRD) were demonstrated in a cross between the C57BL/6J-c(2J) and BALB/cByJ strains (B x C). In this study, as a complementary approach to ongoing recombinant progeny testing for the purpose of identifying candidate quantitative trait genes (QTG), a second test cross using the A/J and the pigmented C57BL/6J strains (A x B) was carried out. The albino A/J strain was selected because it had the most amount of ageRD among several inbred strains tested, and the pigmented C57BL/6J strain was selected because along with its coisogenic counterpart C57BL/6J-c(2J) it had the least amount of ageRD. Thus, the effect of pigment on ageRD could be tested at the same time that the C57BL/6 genetic background was kept in common between the crosses from the two studies for the purpose of comparison.
A non-reciprocal F1 intercross between the A/J and C57BL/6J strains produced 170 F2 progeny. At 8 months of age after being maintained in relatively dim light, F2 mice, control mice and mice of other strains were evaluated for retinal degeneration by measurement of the thickness of the outer nuclear layer of the retina. The F2 mice were genotyped with dinucleotide repeat markers spanning the genome. Correlation of genotype with phenotype was made with Map Manager QTX software.
Comparison of several strains of mice including the pigmented strains 129S1/SvImJ and C57BL/6J and the albino strains A/J, NZW/LacJ, BALB/cByJ and C57BL/6J-c(2J), showed significant differences in ageRD. The greatest difference was between the albino A/J strain and the pigmented C57BL/6J strain. However, there was no significant difference between the pigmented C57BL/6J and its albino coisogenic counterpart C57BL/6J-c(2J). Neither was there significant difference between the pigmented and albino F2 mice from the A x B cross. On the other hand, F2 males had a small but significantly lower amount of ageRD than females. Several QTL were identified in the A x B cross but surprisingly none of the 3 major QTL present in the original B x C cross (Chrs 6, 10, and 16) was present. There were minor QTL on proximal Chr 12 and proximal Chr 14 in common between the two crosses, and the proximal Chr 12 QTL was present in a previous light damage study involving the B and C strains. At least one sex-limited QTL was present on the X chromosome with a peak in a different location from that of a sex-limited QTL in the previous B x C study. In addition, the protective X allele was from the BALB/cByJ strain in the B x C cross and from C57BL/6J in the A x B cross. In both crosses, the C57BL/6J X-chromosome allele was recessive.
Significant differences were observed in ageRD among several inbred strains of mice maintained in relatively dim light. AgeRD was not influenced by pigment but was influenced by gender, albeit to a small degree. The presence of the same QTL in one light-induced and two ageRD studies suggests at least partial commonality in retinal degeneration pathways of different primary cause. However, the three main QTL present in the B x C cross were absent from the A x B cross. This suggests that the genetic determinants responsible for the greater sensitivity to ageRD of BALB/cByJ and A/J relative to C57BL/6J are not the same. This is supported by the presence of sex-limited X-chromosome QTL in the two crosses in which the C57BL/6J allele is protective relative to the A allele and sensitive relative to the C allele. The findings in the two studies of differing allelic relationships of QTG, and differing QTL aid the identification of candidate genes mapping to critical QTL. Identifying natural modifying genes that influence retinal degeneration resulting from any causal pathway, especially those QTG that are protective, will open avenues of study that may lead to broad based therapies for people suffering retinal degenerative diseases.
先前在C57BL/6J-c(2J)和BALB/cByJ品系（BxC）的杂交后代中发现了几个影响年龄相关性视网膜变性（ageRD）的数量性状基因座（QTL）。在本研究中，作为正在进行的用于鉴定候选数量性状基因（QTG）的重组后代测试的补充方法，使用A/J和有色C57BL/6J品系进行了第二次测交（AxB）。选择白化病A/J品系是因为在测试的几个近交系中它的ageRD程度最高，选择有色C57BL/6J品系是因为它与其同基因对应品系C57BL/6J-c(2J)一样ageRD程度最低。因此，在比较两项研究的杂交时，在保持C57BL/6遗传背景相同的同时，可以测试色素对ageRD的影响。
A/J和C57BL/6J品系之间的非互惠F1杂交产生了170只F2后代。在相对昏暗的光线下饲养8个月后，通过测量视网膜外核层的厚度，对F2小鼠、对照小鼠和其他品系的小鼠进行视网膜变性评估。使用跨越基因组的二核苷酸重复标记对F2小鼠进行基因分型。使用Map Manager QTX软件进行基因型与表型的相关性分析。
对包括有色品系129S1/SvImJ和C57BL/6J以及白化病品系A/J、NZW/LacJ、BALB/cByJ和C57BL/6J-c(2J)在内的几个品系小鼠的比较显示，ageRD存在显著差异。最大的差异存在于白化病A/J品系和有色C57BL/6J品系之间。然而，有色C57BL/6J与其白化病同基因对应品系C57BL/6J-c(2J)之间没有显著差异。来自AxB杂交的有色和白化病F2小鼠之间也没有显著差异。另一方面，F2雄性小鼠的ageRD程度虽小但显著低于雌性。在AxB杂交中鉴定出了几个QTL，但令人惊讶的是，原始BxC杂交中存在的3个主要QTL（第6、10和16号染色体）均不存在。两个杂交在近端第12号染色体和近端第14号染色体上有较小的QTL，并且近端第12号染色体QTL存在于先前一项涉及B和C品系的光损伤研究中。X染色体上至少存在一个性别限制QTL，其峰值位置与先前BxC研究中的性别限制QTL不同。此外，在BxC杂交中，保护性X等位基因来自BALB/cByJ品系，在AxB杂交中来自C57BL/6J品系。在两个杂交中，C57BL/6J X染色体等位基因均为隐性。
在相对昏暗的光线下饲养的几个近交系小鼠中，ageRD存在显著差异。AgeRD不受色素影响，但受性别影响，尽管程度较小。在一项光诱导研究和两项ageRD研究中存在相同的QTL，这表明不同主要原因的视网膜变性途径至少部分具有共性。然而，AxB杂交中不存在BxC杂交中存在的三个主要QTL。这表明，相对于C57BL/6J，BALB/cByJ和A/J对ageRD更敏感的遗传决定因素并不相同。这得到了两个杂交中性别限制X染色体QTL的支持，其中C57BL/6J等位基因相对于A等位基因具有保护作用，相对于C等位基因敏感。两项研究中QTG等位基因关系不同以及QTL不同的结果有助于鉴定映射到关键QTL的候选基因。鉴定影响任何因果途径导致的视网膜变性的天然修饰基因，尤其是那些具有保护作用的QTG，将开辟研究途径，可能为患有视网膜退行性疾病的人带来广泛的治疗方法。
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