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Roberto Yu Cordero, Robert W. Williams, Lu Lu, Claire L. Simpson; QTL remapping of murine eye weight reveals novel candidate genes for ocular growth. Invest. Ophthalmol. Vis. Sci. 2019;60(9):5888.
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© ARVO (1962-2015); The Authors (2016-present)
The global prevalence of myopia is growing and may affect almost half of the world's population by 2050. Myopia is caused by abnormal eye growth, causing light to be focused just short of the retina. A pioneering study of mouse eye weight used interval mapping to locate quantitative trait loci (QTLs) that control normal variation in the architecture of the eye, lens, and retina in laboratory mice. The novel QTLs successfully mapped near the centromere of chromosome (Chr) 5 and on proximal Chr 17. Advancements in genetics and bioinformatics have now made it possible to do expression analysis in the small mouse eye and to further investigate the molecular mechanisms of myopia. In this study, we increased the sample size, resulting in a 4-fold increase in strains and 16-fold increase in cases. We then utilized new genetic resources to remap the eye weight data to identify the loci modulating mice eye weight.
Eye weights obtained from a total of 11,206 cases representing 109 BXD strains and two parental strains, C57BL/6J and DBA/2J, had an average age of 200 days (Mean eye weight = 23.9±0.2 mg). Datasets are publicly published in GeneNetwork. All eye weight measurements were corrected by multiple linear regression analysis to statistically control for covariance between eye weight and other variables such as body weight, sex, and age. QTL mapping was conducted using 2017 genotypes of the GeneNetwork module employing a linear mixed model (LMM) with leave-one-chromosome-out (LOCO) approach.
We performed QTL remapping of adjusted eye weight and found a significant locus on Chr 19 from 53Mb to 58Mb with LOD peak of 7.33 at 55.3Mb. Of the 68 genes in this locus, we found 3 strong candidate genes Shoc2, Nhlrc2 and Dclre1a which are well expressed in the eye and associated with a very significant cis eQTL. We also mapped the data limited to the original 26 BXD strains using the new algorithm and new markers and again found a signal in Chr 5. Here, we have a strong candidate gene Steap2 which is well expressed in the eye and associated with a very significant cis eQTL (LOD of 10).
Our findings illustrate the power of using enhanced bioinformatics tools and new mouse genotypes in mapping to improve localization of murine eye weight QTLs and identify promising genes. This will be helpful in our understanding of the mechanisms behind eye growth and its effect on eye diseases like myopia.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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