Quantitative genetics of age-related retinal degeneration: asecond F1 intercross between the A/J and C57BL/6 strains

[摘要] Purpose: Previously, several quantitative trait loci (QTL) thatinfluence age-related retinal degeneration (ageRD) were demonstrated ina cross between the C57BL/6J-c2J and BALB/cByJ strains (B x C). Inthis study, as a complementary approach to ongoing recombinant progenytesting for the purpose of identifying candidate quantitative traitgenes (QTG), a second test cross using the A/J and the pigmentedC57BL/6J strains (A x B) was carried out. The albino A/J strain wasselected because it had the most amount of ageRD among several inbredstrains tested, and the pigmented C57BL/6J strain was selected becausealong with its coisogenic counterpart C57BL/6J-c2J it had theleast amount of ageRD. Thus, the effect of pigment on ageRD could betested at the same time that the C57BL/6 genetic background was kept incommon between the crosses from the two studies for the purpose ofcomparison.Methods: A non-reciprocal F1 intercross between the A/J and C57BL/6Jstrains produced 170 F2 progeny. At 8 months of age after beingmaintained in relatively dim light, F2 mice, control mice and mice ofother strains were evaluated for retinal degeneration by measurement ofthe thickness of the outer nuclear layer of the retina. The F2 mice weregenotyped with dinucleotide repeat markers spanning the genome.Correlation of genotype with phenotype was made with Map Manager QTXsoftware.Results: Comparison of several strains of mice including thepigmented strains 129S1/SvImJ and C57BL/6J and the albino strains A/J,NZW/LacJ, BALB/cByJ and C57BL/6J-c2J, showed significantdifferences in ageRD. The greatest difference was between the albino A/Jstrain and the pigmented C57BL/6J strain. However, there was nosignificant difference between the pigmented C57BL/6J and its albinocoisogenic counterpart C57BL/6J-c2J. Neither was there significantdifference between the pigmented and albino F2 mice from the A x Bcross. On the other hand, F2 males had a small but significantly loweramount of ageRD than females. Several QTL were identified in the A x Bcross but surprisingly none of the 3 major QTL present in the original Bx C cross (Chrs 6, 10, and 16) was present. There were minor QTL onproximal 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 studyinvolving the B and C strains. At least one sex-limited QTL was presenton the X chromosome with a peak in a different location from that of asex-limited QTL in the previous B x C study. In addition, the protectiveX allele was from the BALB/cByJ strain in the B x C cross and fromC57BL/6J in the A x B cross. In both crosses, the C57BL/6J X-chromosomeallele was recessive.Conclusions: Significant differences were observed in ageRD amongseveral inbred strains of mice maintained in relatively dim light. AgeRDwas not influenced by pigment but was influenced by gender, albeit to asmall degree. The presence of the same QTL in one light-induced and twoageRD studies suggests at least partial commonality in retinaldegeneration pathways of different primary cause. However, the threemain 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 greatersensitivity to ageRD of BALB/cByJ and A/J relative to C57BL/6J are notthe same. This is supported by the presence of sex-limited X-chromosomeQTL in the two crosses in which the C57BL/6J allele is protectiverelative to the A allele and sensitive relative to the C allele. Thefindings in the two studies of differing allelic relationships of QTG,and differing QTL aid the identification of candidate genes mapping tocritical QTL. Identifying natural modifying genes that influence retinaldegeneration resulting from any causal pathway, especially those QTGthat are protective, will open avenues of study that may lead to broadbased therapies for people suffering retinal degenerative diseases.

[学科分类] 生物化学/生物物理