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Patrick William Keeley, Benjamin E Reese; Genomic Control of Horizontal Cell Regularity. Invest. Ophthalmol. Vis. Sci. 2014;55(13):718.
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© ARVO (1962-2015); The Authors (2016-present)
Retinal neurons are often arranged in nonrandom mosaics, as their somata are distributed to minimize proximity to neighboring cells of the same type. The mosaic of horizontal cells (HC) is an exemplar of such a distribution, but little is known of molecular determinants controlling its patterning. We have previously shown that different strains of mice vary in the regularity of their HC mosaics, indicating a genetic component to this trait.
The present study adopted a forward genetic approach to seek candidate genes controlling nerve cell patterning, quantifying the regularity of the HC mosaic in 25 genetically diverse recombinant inbred strains of mice, each of known genotype, being derived from the C57BL/6J and A/J inbred laboratory strains. For each strain (n ~ 3 mice), we sampled the population of horizontal cells at eight retinal locations in every mouse and calculated four spatial statistics: nearest neighbor regularity index (NNRI), Voronoi domain regularity index (VDRI), effective radius (ER), and packing factor (PF).
The regularity indexes varied across the 25 RI strains, increasing by 24% from the lowest to the highest strain, while the coefficient of variation (CoV) within each strain showed relatively little variation (average CoV=0.04). The estimated heritability of these indexes was ~0.5, indicating a sizeable proportion of the variation in trait values across all 95 mice could be ascribed to an effect of genotype. The two regularity indexes correlated highly with one another across the recombinant inbred strains (r=0.80), and each was significantly correlated with PF (r=0.78 and 0.81 for NNRI and VDRI, respectively). These indexes were moderately correlated with ER (r=0.59 and 0.46), while showing no significant correlation with cell density (r=-0.27 and -0.15). Using quantitative trait loci mapping, we identified two genomic loci, on Chromosomes 1 and 14, that modulate the regularity of the HC mosaic. Together, these two quantitative trait loci account for ~44% and ~31% of the interstrain variation in NNRI and VDRI, respectively.
Using the population of horizontal cells, we show that mosaic regularity and packing are heritable traits, and that these traits can be mapped to discrete genomic loci. Further interrogation of these loci should identify candidate gene variants responsible for this variation in mosaic patterning, ultimately revealing the molecular mechanisms of mosaic assembly.
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