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A Strong and Highly Significant QTL on Chromosome 6 That Protects The A Strong and Highly Significant QTL on Chromosome 6 that Protects the Mouse from Age-Related Retinal Degeneration Michael Danciger,1 Jessica Lyon,1 Danielle Worrill,1 Matthew M. LaVail,2 and Haidong Yang2 PURPOSE. BALB/cByJ (C) albino mice have significantly more etiology. Many studies have attempted to determine environ- retinal degeneration as they age than C57BL/6J-c2J (B6) albinos. mental risk factors that may be associated with AMD, but only To discover the genetic loci that influence age-related retinal smoking has been consistently demonstrated to be one of them degeneration (ARD), a quantitative genetics study was per- (for reviews, see 6–9). In contrast, twin studies and population- formed with 8-month-old progeny from an intercross between based familial aggregate studies have made it clear that genes these two strains. play a significant role in AMD. 10–13 It is also clear that AMD is 14,15 METHODS. The thickness of the outer nuclear layer of the retina a complex genetic disorder, one that first appears most was used as the quantitative trait. A genome-wide scan was commonly in elderly individuals, typically in those older than performed with 86 genetic markers at an average distance of 50 years. Because of the age of onset, informative family ped- 15.7 cM. Map Manager QTX was used to analyze the data. igrees of the size needed to identify genetic loci are difficult to find. Only one such locus (with a LOD score of 3.0) has been RESULTS. Three highly significant quantitative trait loci (QTLs) reported.16 Identifying AMD genetic loci with family-based were detected on mouse chromosomes (Chrs) 6, 10, and 16. aggregate studies is difficult for the same reason and because The B6 alleles were protective against ARD in the first two, and the phenotype of AMD is heterogeneous. Is it one disease or a the C allele was protective in the third. Several suggestive, group of diseases? Are different phenotypes caused by the weak QTLs were also found, along with a gender-related effect. same or various genetic factors? To our knowledge, only one The strongest and most highly significant QTL on Chr 6 ac- study of this type has been reported. In the latest refinement of counted for 30% of the total genetic effect with a LOD score of this study, several loci were found in a very large cohort with 13.5. The RPE65/MET450 variant of major influence on con- LOD scores ranging from 2.0 to 3.16.15 stant light-induced retinal degeneration (LRD) in a previous study of these same two mouse strains had no influence on Therefore, when we observed that two albino mouse strains undergo significantly different rates of retinal degeneration as ARD, and only some of the weak, suggestive QTLs influencing 17 ARD were also observed in LRD. they age, we decided to perform a quantitative genetic study to find the chromosomal loci of the mouse genes responsible CONCLUSIONS. Because none of the ARD QTLs was homologous to for the difference. This would be the first step toward finding human chromosomal loci so far implicated in age-related macular the genes themselves—particularly the protective alleles of degeneration, each represents a new candidate gene for potential those genes—that influence age-related retinal degeneration. study. The gene represented by the Chr 6 QTL is of particular Compared with studies in humans, experiments with mice are interest because it has broad influence, very high significance, and much simpler to perform and are statistically more powerful. a B6 allele that protects against ARD. (Invest Ophthalmol Vis Sci. There are only two alleles to consider, one from each of the 2003;44:2442–2449) DOI:10.1167/iovs.02-1252 inbred strains. There is no problem with variation in pheno- type, because measurement of the thickness of the outer nu- ge-related macular degeneration (AMD) is the most com- clear layer (ONL) of the retina serves as a quantitative trait. Amon cause of severe, irreversible vision loss in developed There is no problem with confounding environmental influ- 1–5 nations, but little conclusive information is known about its ences because all the mice are exposed to the same conditions in the vivarium, and there is no problem recruiting subjects. Genes found to influence age-related retinal degeneration in From the 1Department of Biology, Loyola Marymount University, the mouse would be excellent candidates for study in human Los Angeles, California; and 2Beckman Vision Center, University of AMD (even though the mouse does not have a macula or a California San Francisco School of Medicine, San Francisco, California. fovea), because mouse and human genes involved in vision are Supported in part by NIH Grants EY13280 (MD) and EY01919 and often similar in effect. This is exemplified by the fact that EY02162 (MML), the Foundation Fighting Blindness (MD, MML), Re- mutations in several mouse vision genes such as Pdeb, Prph2, search to Prevent Blindness, That Man May See, Inc., and the Macula and Nr2e3 cause the same type of disease in mice that muta- Vision Research Foundation (MML). The Center for Inherited Disease tions in human orthologous genes (PDE6B, RDS-peripherin, Research is fully funded through a federal contract from the National 18–28 Institutes of Health to The Johns Hopkins University (Contract Number and NR2E3) cause in humans. N01-HG-65403). MML is a Research to Prevent Blindness Senior Scien- In this study, with a large F1 intercross between the mouse tist Investigator. strains BALB/cByJ (C) and C57BL/6J-c2J (B6), we identified a Submitted for publication December 6, 2002; revised January 21, number of quantitative trait loci (QTLs) containing genes that 2003; accepted February 13, 2003. influence age-related retinal degeneration. Among them were Disclosure: M. Danciger, None; J. Lyon, None; D. Worrill, three strong and highly significant QTLs and several weaker None; M.M. LaVail, None; H. Yang, None QTLs. Although most of the QTLs reflected B6 alleles that were The publication costs of this article were defrayed in part by page protective, a few were the opposite; C alleles were protective. charge payment. This article must therefore be marked “advertise- ment” in accordance with 18 U.S.C. §1734 solely to indicate this fact. In addition, although the net relationship between B6, F1, and Corresponding author: Michael Danciger, Department of Biology, BALB/cByJ age-related, retinal degeneration control animals Loyola Marymount University, Los Angeles, CA 90045-2959; was dominant for B6, QTLs with additive and recessive rela- [email protected]. tionships also were found once the loci were teased apart. Investigative Ophthalmology & Visual Science, June 2003, Vol. 44, No. 6 2442 Copyright © Association for Research in Vision and Ophthalmology Downloaded from iovs.arvojournals.org on 09/27/2021 IOVS, June 2003, Vol. 44, No. 6 QTL Protective against Age-Related Retinal Degeneration 2443 Although the C57BL/6J-c2J albino isogenic to C57BL/6J was a the two most distal markers were 45 cM apart, Chr 8 where the two good choice to cross with the albino BALB/cByJ, it introduced most proximal markers were 39 cM apart, and Chrs 2, 5, 11, 12, and X potential epistatic confounds. The c allele (mutant tyrosinase where the most proximal markers were 48, 20, 17, 16, and 17 cM from gene) may have masked retinal degeneration gene alleles that the centromere, respectively. A list of markers used in crosses between would have been expressed on a pigmented C57BL back- C57BL and BALB/cByJ mice is available on the CIDR Web site (http:// ground or exposed alleles that would not have been expressed www.cidr.jhmi.edu/). A few additional dinucleotide repeat markers on that background. Last, because we used these same two within QTLs were analyzed in our laboratory. These were amplified by strains of mice in a previous quantitative genetic study of standard PCR methods and electrophoresed in 4% agarose gels for light-induced retinal damage,17 we were able to compare the allele determination by size. All map positions were based on the QTLs between the two studies to determine what influence the Encyclopedia of the Mouse Genome from Jackson Laboratories Mouse genes that modify light-induced retinal degeneration have on Genome Informatics (MGI; http://www.informatics.jax.org/; provided age-related retinal degeneration. in the public domain by Jackson Laboratories, Bar Harbor, ME). Mouse Genomic DNAs MATERIALS AND METHODS Genomic DNAs were isolated from liver tissue with a kit (Puregene; Mice Gentra Systems, Minneapolis, MN). BALB/cByJ and C57BL/6J-c2J albino mice were originally purchased Data Analysis from the Jackson Laboratories (Bar Harbor, ME) although some were maintained through many generations in our vivarium before study. Genotypes versus quantitative traits were analyzed with the Map Man- 30 C57BL/6J-c2J mice are derived from a C57BL/6J strain that underwent ager QTb17X program (http://mapmgr.roswellpark.org/mapmgr. a mutation that inactivated the tyrosinase gene (c) to make it albino. html/; provided in the public domain by Rosewell Park Cancer Insti- Therefore, the strain is isogenic with C57BL/6J. By convention, the tute, Buffalo, NY). With this program, a likelihood ratio statistic (LRS) abbreviation for C57BL/6J mice is “B6” or “B” and for BALB/cByJ mice was calculated for each of the 86 marker genotypes, with a probability is “C” or “CBy.” All mice were kept under a 12-hour light–dark cyclic inclusion level for further study of 0.05. Thus, any single-point LRS for light cycle with an in-cage illuminance of 2 to 7 ft-c. The temperature a marker that had only a 5% probability or less of occurring by chance of the vivarium was maintained between 18°C and 20°C.
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