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R.W. Williams, J. Xu, H. Zhai, L. Lu; Complex Trait Analysis of Mouse Retinal Horizontal Cell Number . Invest. Ophthalmol. Vis. Sci. 2003;44(13):4560.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Horizontal cells play a key role in shaping the surround responses of photoreceptors and bipolar cells. We have previously shown that there are very large differences in densities of these cells among the inbred strains of mice (Williams et al., 1998; see www.nervenet.org). Here we have mapped a major quantitative trait locus (QTL) controlling variation in horizontal cell number.Methods: Our samples consists of C57BL/6J (B6), A/J, and 21 AXB /BXA recombinant inbred (RI) strains. We used an antibody directed against the 28-kDa calcium-binding molecule (calbindin 28K) to label essentially the entire population of horizontal cells in flat mounted retinas of mouse. Horizontal cells of ~110 mice (average of 5 mice per strain) were counted. Genomic DNA was extracted from all RI strains and typed at 670 microsatellite markers spanning the whole genome. Map Manager QTX was used for analysis. Results:Total horizontal cell populations of the parental strains, B6 and A/J, are 11,000 ± 570 and 6,500 ± 200, respectively. This 42% difference is highly significant. The group average for all 21 AXB/BXA strains is 8,100 ± 360, and ranged from a low of 5,700 ± 500 in BXA8 to a high of 11,200 ± 440 in BXA13. Broad-sense heritability for variation is ~60%. The major QTL responsible for variation in this retinal cell population is located on chromosome 18 with a peak likelihood ratio statistic of 18 near the marker D18Mit94 at ~38 +/- 10 megabases. Strains with two B alleles have about 2,000 more cells than strains with two A alleles. This interval corresponds to human chromosomes 18q12, 2q14-21, and 5q31–5q22. Candidate genes in the QTL support interval include Cdc25c, Apc, Camk4, Hegfl, the cadherin complex, Diap1, and Fgf1. Conclusions: Heritability of variation of horizontal cell number is as high as that of retinal ganglion cells and maps to a novel locus on Chr 18. We are currently fine-mapping the locus in anticipation of candidate gene analysis using microarray and sequencing methods.
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