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Patrick William Keeley, Benjamin E Reese; QTLs on Chromosomes 3 and 13 interact to modulate horizontal cell number in the mouse retina. Invest. Ophthalmol. Vis. Sci. 2018;59(9):595.
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© ARVO (1962-2015); The Authors (2016-present)
Complex processes shape the neuronal composition of the retina including proliferation, differentiation, and apoptosis, requiring the coordination and interaction of many genes during development. Using a set of recombinant inbred (RI) strains of mice, we previously identified a quantitative trait locus (QTL) on Chr 13 that modulates horizontal cell number in the retina, narrowed this locus to the gene Isl1, and found a potential causal variant (an SNP creating an E-box for bHLH transcription factors) that may regulate its expression (Whitney et al., 2011). This locus does not account for all of the variation seen across the RI strains, however, indicating that other variant genes must exist that also alter this complex trait. The current study sought to identify other QTL controlling horizontal cell number and assess the genes present at such loci for potential roles in this process.
GeneNetwork (genenetwork.org) was used to perform composite interval mapping and pair-scan analyses to identify novel QTL controlling horizontal cell number, using previously collected data from the AXB/BXA strain-set of RI mice (record ID: 10132). Bioinformatic databases were used to rank potential candidate genes based on genetic variants, gene expression patterns, and functional annotations.
Composite interval mapping controlling for the effects of the Chr 13 QTL revealed a novel suggestive QTL on the distal end of Chr 3 (119.7-129.6Mb, mm10), where the presence of two B6/J alleles was predicted to increase horizontal cell number by ~1,500 cells, or 24% of the variation seen across the RI strains. Pair-scan analysis suggested that an epistatic interaction between the loci on Chr 3 and Chr 13 existed, and that the effect of having B6/J alleles at both QTL was to synergistically increase horizontal cell number. Bioinformatic analysis narrowed the list of candidate genes at the Chr 3 QTL from 61 to 8, which included Neurog2, a proneural bHLH transcription factor expressed in the developing retina that is known to interact with Isl1 in other systems.
Neurog2 is a top candidate gene to modulate horizontal cell number in the mouse retina, potentially through an interaction with Isl1, and variants present in the B6/J alleles of both genes may alter this interaction in a synergistic manner.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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