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Jennifer Buenaventura Cordero, Robert W. Williams, Lu Lu, Claire L. Simpson; A novel locus identified in chromosome 14 modulates lens weight on mouse using Genome-wide Efficient Mixed Model Association. Invest. Ophthalmol. Vis. Sci. 2019;60(9):5876.
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Abnormalities of the size and shape of the lens will affect ocular refractive power and impair vision. In previous work, we mapped eye size of a large family of 700 mice to define major-effect quantitative trait loci (QTLs) that modulate eye size and retinal area, but we failed to detect any loci specifically controlling lens mass. In contrast, two loci were mapped to the proximal ends of chromosomes 5 and 17 that control overall eye size. Here, we exploited the power of new advanced mapping methods that account for kinship and much improved genotypes to remap our original lens data and to define a novel lens-specific locus.
Lens weight was measured in a subset of 122 young adult cases from a family of 26 BXD recombinant inbred strains and both parents-C57BL/6J and DBA/2J. Data were normalized by linear regression to minimize variance associated with sex and age. In the original study, we used Haley-Knott mapping methods and about 300 markers. In the reanalysis, we exploit Genome-wide Efficient Mixed Model Association (GEMMA) software with leave-one-chromosome-out (LOCO) scheme as well as 7000 markers that are now integrated into the GeneNetwork2 mapping platform (gn2.genenetwork.org).
Using the new code and marker maps, we uncovered a locus that specifically affects lens weight in the mouse, but has no detectable effect on overall eye weight. It maps to chromosome (Chr) 14 between 60 and 70 Mb with a peak LOD score near Wdfy2 (62.5 Mb) of 4.8. We detected a well-known secondary locus that maps to Chr 5 near Hgf (LOD 3.7). This second locus aligns perfectly with a locus that controls overall eye weight in mouse and myopia in humans. The Chr 5 locus therefore has a global influence on both eye and lens whereas the newly discovered locus on Chr 14 is lens-specific.
The discovery of a specific locus modulating lens weight may contribute to the understanding of genetic and molecular mechanisms of lens development, coordination of ocular growth to achieve emmetropia, and perhaps disorders caused by structure abnormalities. Given the specificity of lens gene expression patterns and the precision of the mapping, identifying the causal gene will be practical. Our findings also highlight the power of new algorithms and better genetic maps to reevaluate older but high quality ocular data sets and revealing replication with significant improvement.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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