Analysis of genetic networks regulating refractive eye development in collaborative cross progenitor strain mice reveals new genes and pathways underlying human myopia

Abstract

Background Population studies suggest that genetic factors play an important role in refractive error development; however, the precise role of genetic background and the composition of the signaling pathways underlying refractive eye development remain poorly understood. Methods Here, we analyzed normal refractive development and susceptibility to form-deprivation myopia in the eight progenitor mouse strains of the Collaborative Cross (CC). We used RNA-seq to analyze gene expression in the retinae of these mice and reconstruct genetic networks and signaling pathways underlying refractive eye development. We also utilized genome-wide gene-based association analysis to identify mouse genes and pathways associated with myopia in humans. Results Genetic background strongly influenced both baseline refractive development and susceptibility to environmentally-induced myopia. Baseline refractive errors ranged from − 21.2 diopters (D) in 129S1/svlmj mice to + 22.0 D in CAST/EiJ mice and represented a continuous distribution typical of a quantitative genetic trait. The extent of induced form-deprivation myopia ranged from − 5.6 D in NZO/HILtJ mice to − 20.0 D in CAST/EiJ mice and also followed a continuous distribution. Whole-genome (RNA-seq) gene expression profiling in retinae from CC progenitor strains identified genes whose expression level correlated with either baseline refractive error or susceptibility to myopia. Expression levels of 2,302 genes correlated with the baseline refractive state of the eye, whereas 1,917 genes correlated with susceptibility to induced myopia. Genome-wide gene-based association analysis in the CREAM and UK Biobank human cohorts revealed that 985 of the above genes were associated with myopia in humans, including 847 genes which were implicated in the development of human myopia for the first time. Although the gene sets controlling baseline refractive development and those regulating susceptibility to myopia overlapped, these two processes appeared to be controlled by largely distinct sets of genes. Conclusions Comparison with data for other animal models of myopia revealed that the genes identified in this study comprise a well-defined set of retinal signaling pathways, which are highly conserved across different vertebrate species. These results identify major signaling pathways involved in refractive eye development and provide attractive targets for the development of anti-myopia drugs. Electronic supplementary material The online version of this article (10.1186/s12920-019-0560-1) contains supplementary material, which is available to authorized users.

Genome-wide analysis of retinal transcriptome reveals common genetic network underlying perception of contrast and optical defocus detection

“…however, our findings and recent studies point to a potentially important role of TJP2 in refractive eye development (113,150,151). Another interesting gene, which we found to be linked to both contrast perception and susceptibility to form-deprivation myopia, is PER1.…”

“…Cronin-Golomb et al (101) found that genetic factors have a significant contribution to contrast sensitivity in humans. The retina converts information about optical defocus into molecular signals, which are transmitted across the back of the eye via a multilayered signaling cascade encoded by an elaborate genetic network (12, [102][103][104][105][106][107][108][109][110][111][112][113][114][115]. It is critical to characterize the genetic networks and signaling pathways underlying contrast perception and determine their role in refractive eye development.…”

“…In-utero epigenetic factors were found to be associated with refractive status in young children, and grandmothers' smoking causing epigenetic modifications of the genome was shown to be linked to less myopic refractive errors in children (118)(119)(120)(121)(122). Lightinduced signaling and the phototransduction pathway were also implicated in refractive eye development (12,113,114,123).…”

Three-dimensional data capture and analysis of intact eye lenses evidences emmetropia-associated changes in epithelial cell organization

“…We additionally evidence the importance of standardizing the measurement of lens metrics and expanding on their integration with geometric eye properties. Creating a fully integrated map of molecular, cellular, and geometric lens characteristics will enhance our understanding of refraction in the eye and will allow the exploration of the mechanistic detail that leads, for example, to myopia 30 . www.nature.com/scientificreports/ Previous reports have tracked the total LEC number across the lifespan of the C57/BL6J mouse 11,14 .…”

“…In many mammals, including the mouse, this is established in the postnatal period between weeks 4 and 6 in the C57/ BL6J strain 7,22 when the lens is in its most active growth phase 14 . The mouse has only recently been accepted as a model to study emmetropia due to differences observed between C57/BL6J and other inbred strains 7,21,30 . Practical issues for measuring refraction in such a small eye also had to be overcome in order to monitor emmetropia in the mouse eye 5,21,22,31 .…”