Abstract

The retina is the light-sensitive tissue of the eye that facilitates vision. Mutations within genes affecting eye development and retinal function cause a host of degenerative visual diseases, including retinitis pigmentosa and anophthalmia/microphthalmia. The characin fish Astyanax mexicanus includes both eyed (surface fish) and eyeless (cavefish) morphs that initially develop eyes with normal retina; however, early in development, the eyes of cavefish degenerate. Since both surface and cave morphs are members of the same species, they serve as excellent evolutionary mutant models with which to identify genes causing retinal degeneration. In this study, we crossed the eyed and eyeless forms of A. mexicanus and quantified the thickness of individual retinal layers among 115 F2 hybrid progeny. We used next generation sequencing (RAD-seq) and microsatellite mapping to construct a dense genetic map of the Astyanax genome, scan for quantitative trait loci (QTL) affecting retinal thickness, and identify candidate genes within these QTL regions. The map we constructed for Astyanax includes nearly 700 markers assembled into 25 linkage groups. Based on our scans with this map, we identified four QTL, one each associated with the thickness of the ganglion, inner nuclear, outer plexiform, and outer nuclear layers of the retina. For all but one QTL, cavefish alleles resulted in a clear reduction in the thickness of the affected layer. Comparative mapping of genetic markers within each QTL revealed that each QTL corresponds to an approximately 35 Mb region of the zebrafish genome. Within each region, we identified several candidate genes associated with the function of each affected retinal layer. Our study is the first to examine Astyanax retinal degeneration in the context of QTL mapping. The regions we identify serve as a starting point for future studies on the genetics of retinal degeneration and eye disease using the evolutionary mutant model Astyanax.

Highlights

  • The retina is a thin tissue lining the back of the eye that is responsible for light detection and vision [1]

  • Our results suggest that the photoreceptor cell layer (PCL), ONL, INL, and ganglion cell layer (GCL) are the layers most impacted by apoptosis in cavefish–the same retinal layers impacted in human cases of retinitis pigmentosa and albinism [3,25]

  • The genes we describe below do not represent an exhaustive list of possible loci, we believe they represent the best candidates for retinal degeneration in Astyanax given their association with these retinal layers and ocular diseases such as retinitis pigmentosa and anophthalmia/microphthalmia

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Summary

Introduction

The retina is a thin tissue lining the back of the eye that is responsible for light detection and vision [1]. A final layer, the retinal pigment epithelium (RPE), contains no neuronal cells but promotes the development and maintenance of the PCL and reduces glare by absorbing excess light [1]. The neurogenesis of these layers is controlled by a host of genetic and cellular factors (for a review, see [2]). Mutations affecting these and other genes are collectively responsible for many cases of retinal degeneration and blindness in humans (e.g., [3]). The most dramatic mutations affecting retinal degeneration have been identified within laboratory model species like mice and zebrafish, evolutionary mutant models–outbred species which exhibit phenotypes that mimic human diseases–can help dissect the genetic basis of human retinal disease and provide candidates for gene therapy [4]

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