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J. A. Guggenheim, T. Zayats, A. Prashar, J. T. Erichsen, P. M. Hocking; Mapping Quantitative Trait Loci (QTL) Controlling Natural Variation in Eye Size-Related Traits in a Chicken Advanced Intercross Line. Invest. Ophthalmol. Vis. Sci. 2009;50(13):3835.
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High myopia is typically characterised by excessive enlargement of the eye during post-natal development. Our investigation was designed to identify genes that act in the pathways controlling this period of eye growth, as these are attractive therapeutic targets for slowing disease progression.
The Roslin Institute chicken advanced intercross line (AIL) was derived from a broiler (large body and eye size) and a layer (small body and eye size) parental line. Normal chickens from the F10 generation of the AIL were phenotyped at 3 wks of age, using a range of tests including in vivo video-keratometry and high resolution A-scan ultrasonography. Measurements of ex vivo eye diameter and eye weight were also obtained. DNA extracted from blood samples was genotyped for a panel of SNP markers distributed across the genome. QTL were mapped using a variety of complementary methods: BimBam for single marker analysis, Unphased for haplotype analysis, and GenABEL for single marker analysis after correcting for relatedness. Genomewide significance was assessed using permutation tests and/or Bonferroni correction for the number of markers tested.
Data were available for 510 F10 chickens, including genotypes at 1667 informative SNP loci. For each trait investigated (corneal curvature, lens thickness, axial length, eye diameter, eye weight), BimBam and Unphased typically detected >50 genomewide significant QTL (-log10 P > 4.5). Haplotype analysis appeared more powerful than single marker analysis. Roughly half of the QTL retained significance after controlling for body size during the analysis, suggesting they are eye-size specific (whilst the others influence both eye and body size). However, because the BimBam and Unphased analyses did not take into account that the chickens were related, we predict that the majority of these supposed genomewide significant QTL are false positives. GenABEL analysis, which accounts for relatedness, typically identified only ~1 genomewide significant QTL for each trait. Haplotype analysis accounting for relatedness and fine-mapping are planned.
The Roslin AIL is a powerful resource for mapping QTL that influence eye size. Fine mapping of the QTL identified here may lead to new insights into the pathways regulating natural variations in eye size in chickens. If conserved across species, similar pathways may be important in human high myopia development.
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