Research Article: Quantitative trait loci on chromosome 1 for cataract and AMD-like retinopathy in senescence-accelerated OXYS rats

Date Published: January 31, 2012

Publisher: Impact Journals LLC

Author(s): Elena E. Korbolina, Ouyna S. Kozhevnikova, Nataliya A. Stefanova, Natalia G. Kolosova.



Age-related macular degeneration (AMD) and cataract are common age-related diseases in humans. Previously we showed that senescence-accelerated OXYS rats develop retinopathy and cataract, which are comparable to human AMD and senile cataract. Here we focused on the identification of quantitative trait loci (QTLs), which affect early-onset cataract and retinopathy in OXYS rats, using F2 hybrids bred by a reciprocal cross (OXYS×WAG and WAG×OXYS). Chromosome 1 showed significant associations between retinopathy and loci in the regions of markers D1Rat30 and D1Rat219 (QTL1) as well as D1Rat219 and D1Rat81 (QTL2); and between early cataract development with the locus in the region of the markers D1Rat219 and D1Rat81 (QTL2). To determine the effects of these QTLs, we generated two congenic strains by transferring chromosome 1 regions from OXYS into WAG background. Both congenic strains (named WAG/OXYS-1.1 and WAG/OXYS-1.2, respectively) display early cataract and retinopathy development. Thus, we confirmed that genes located in the analyzed regions of chromosome 1 are associated with the development of these diseases in OXYS rats.

Partial Text

Age-related macular degeneration (AMD) and cataract are the most frequent eye disorders in elderly people worldwide [8, 31]. Development of cataract and AMD is influenced by a large number of genetic and environmental factors [29, 32], which remain poorly understood. Whereas early stages of these diseases cannot be studied in humans, existing animal models of complex multifactorial diseases (such as cataract and AMD) are not sufficient because of the complexity of their genetic background and/or deleterious effects of environmental factors [7, 24, 36].

QTL mapping approach is only the first step toward identifying the specific genes whose mutations or differential expression modulates ocular pathologies. As shown in Figure 1, the available information gives only a rough approximation of the position of the gene, or genes, in the broad chromosomal regions identified by a chromosomal or whole-genome scan. A limitation of our study is that only five markers were used to map chromosome 1 in the F2 hybrid population. Accordingly, we were able to statistically link the inheritance of disease-related phenotypes to chromosome loci of approximately 80 Mb each. The small number of appropriate markers is due to the fact that WAG and OXYS inbred strains are barely polymorphic at the majority of known microsatellite marker sites in their genomes. Thus, it is conceivable that there are other, possibly stronger genetic determinants for retinopathy that are not detectable in a cross between WAG and OXYS progenitors because these strains carry the same alleles. There are reports in literature of abnormalities in the WAG/Rij rat strain that were first thought to be an inherited retinal degeneration but later dismissed as a light-induced retinal change [17]. In this regard, the WAG strain proved useful in identifying different phenotypic variants in F2 populations because we found no signs of cataract and retinopathy in paternal rats of the WAG strain.