Mapping Data

Experiment

• Experiment
  TEXT-Congenic
• Chromosome
  7
• Reference
  J:216971 Higuchi H, et al., Genetic basis of age-dependent synaptic abnormalities in the retina. Mamm Genome. 2015 Feb;26(1-2):21-32
• ID
  MGI:5828603

Genes

Gene
Rta1

Notes

• Experiment
  In this study an RI panel of AXB mice was used to study the differences in the rate of retinal aging to gain insight into the molecular mechanisms of the retinal aging process. Inbred A/J mice are susceptible to age dependent retinal abnormalities such as photoreceptor cell degradation, increased inflammation and more severe ectopic synapse formations, while inbred C57BL/6J (B6) mice are relatively less susceptible.
  
  QTL mapping was performed using 26 RI AXB lines, using 3 mice per line. Between 7-8 months of age the severity of the ectopic synapse phenotype was scored by 3 independent individuals (scored from mild to severe respectively). In order to observe age dependent synaptic changes as well as other age dependent abnormalities in the retina, the retina of A/J and B6 mice at 2, 8 and 17-20 months of age were also examined. Genotype data containing a total of 2445 DNA markers polymorphic between the parental strains were obtained from GeneNetwork.
  
  QTL analysis was performed to identify chromosomal loci affecting the severity of ectopic synapses was performed using the R/qtl package (NCBI Build 37). LOD scores were calculated with 1 cM steps, 1,000 genotype imputations and assuming an error of 0.01. A permutation test with 1,000 replications was used to determine the significance of the results. Two significant QTL affecting the severity of ectopic synapses were mapped on Chromosome 7 and Chromosome 19, respectively.
  
  QTL Rta1, retinal aging 1, mapped to Chr 7 between rs3675028 (74.6 Mbp) and rs3711806 (96.6 Mbp), LOD=4.86, p<0.05.
  
  QTL Rta2, retinal aging 2, mapped to Chr 19 between markers D19Mit127 (12.4 Mbp) and D19Mit40 (25.4 Mbp), LOD=6.53, p<0.01.
  
  Chromosome substitution strains C57BL/6J-Chr 7^A/J/NaJ and C57BL/6J-Chr 19^A/J/NaJ were used next to test the independent effect of each QTL on age-dependent synaptic phenotypes. Both strains exhibited a significant increase in ectopic localization of retinal photoreceptor cell synapses in the periphery of the retina at 8 months of age and in the central retina by 17 months of age, characteristic of the A/J phenotype.
  
  Other retinal phenotypes were also observed in the consomic lines. Neither strain exhibited a significant increase in ONLT (outer nuclear thickness) at 8 or 17 months and followed a pattern similar to B6. The level of retinal stress marker GFAP was elevated in both lines compared to the B6 retina at 8 months of age. The number of cone cells in both lines was significantly decreased compared to B6. A significant increase in total number of microglia in both A/J and C57BL/6J-Chr 19^A/J/NaJ mice was observed compared to B6 controls. C57BL/6J-Chr 7^A/J/NaJ mice exhibited a significantly lower frequency of total microglia and activated microglia compared to A/J mice, which was similar to B6 mice.
  
  Using the MGI (Mouse Genome Informatics) resource, sequences for A/J and B6 strains were compared to identify SNP differences between the two strains within the respective QTL chromosomal regions. The candidate gene list was also narrowed by choosing genes expressed in the eye based on the gene expression data in MGI. Genes within the QTL that were known to have slight expression differences in B6 and A/J eye tissue were also considered. Candidate genes were listed in Table 1 and Table 2.