Abstract
Genetic variants modulate the numbers of various retinal cell types in mice. For instance, there is minimal variation in the number of rod bipolar cells (RBCs) in two inbred strains of mice (A/J and C57BL/6J), yet their F1 offspring contain significantly more RBCs than either parental strain. To investigate the genetic source of this variation, we mapped the variation in the number of RBCs across 24 genetically distinct recombinant inbred (RI) strains (the AXB/BXA strain-set), seeking to identify quantitative trait loci (QTL). We then sought to identify candidate genes and potential casual variants at those genomic loci. Variation in RBC number mapped to three genomic loci, each modulating cell number in excess of one-third of the range observed across the RI strains. At each of these loci, we identified candidate genes containing variants that might alter gene function or expression. The latter genes were also analyzed using a transcriptome database, revealing a subset for which expression correlated with variation in RBC number. Using an electroporation strategy, we demonstrate that early postnatal expression of one of them, Ggct (gamma-glutamyl cyclotransferase), modulates bipolar cell number. We identify candidate regulatory variants for this gene, finding a large structural variant (SV) in the putative promoter that reduces expression using a luciferase assay. This SV reducing Ggct expression in vitro is likely the causal variant within the gene associated with the variation in Ggct expression in vivo, implicating it as a quantitative trait variant (QTV) participating in the control of RBC number.
Highlights
The nervous systems of different laboratory mouse strains show conspicuous phenotypic variation, and often that variation can be traced to causal genetic variants
We were interested in a number of genes for which their own expression correlated with the variation in rod bipolar cells (RBCs) number across the recombinant inbred (RI) strains, and for which that variation in expression mapped to the genomic location of the genes themselves, suggesting that transcript abundance participates in the modulation of cell number
This increase in the total number of RBCs observed in the F1 strains, relative to the parental strains, suggests the presence of countervailing variant genes that result in comparable RBC numbers between the parental strains
Summary
The nervous systems of different laboratory mouse strains show conspicuous phenotypic variation, and often that variation can be traced to causal genetic variants. Different mouse strains have been shown to contain large differences in the number of particular types of neurons within the retina (Williams et al, 1998), in some cases exhibiting a two-fold or greater variation (Keeley et al, 2014), and much of that variation has been mapped to genomic loci where such causal variants must be present. In some of those cases, candidate genes containing putative causal variants have been identified, and gene-knockout mice have confirmed an effect upon cell number directly (Whitney et al, 2009, 2011a). We identified a structural variant (SV) upstream of the transcriptional start site (TSS) in the A/J genome and confirmed its suppressive effect on gene expression via luciferase assay
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