Seeing in tandem: Cis and trans-regulation of tandemly-duplicated cone opsin genes in zebrafish

The molecular basis for vertebrate color vision is expression of spectrally-selective opsin-based photopigments within distinct cone photoreceptor populations. In several primates including humans, and in numerous fish species, genes encoding duplicated, spectrally-divergent cone opsin proteins may be positioned in tandem arrays. This article reviews studies of the regulation of differential expression of these duplicated cone opsin genes in humans and fish, with an emphasis on knowledge derived from the zebrafish model. In humans, the long wavelength-sensitive/medium wavelength-sensitive (LWS/MWS; red/green) tandemly-duplicated array underlies trichromatic color vision; mutations in this array cause altered color vision and retinal degenerations. A foundational model posited that regulation of human LWS vs. MWS opsin expression is stochastic, whereby an upstream enhancer associates randomly with promoters of the proximal or distal gene, and one of these associations becomes permanent. Discoveries of tandemly-duplicated cone opsin genes in teleost fish, including the versatile zebrafish model, led to their use to further pursue mechanisms of differential expression. The tandemly-duplicated zebrafish lws1 and lws2 genes (encoding red-sensing cone opsins) share a common ancestral gene with human LWS and MWS. Subsequent studies revealed that differential expression of these genes is regulated by the paracrine signal retinoic acid (RA) and the endocrine signal thyroid hormone (TH). Further investigations identified additional cone transcripts distinguishing zebrafish LWS1 vs. LWS2 cones, plasticity of cone opsin expression across the lifespan in response to TH, and a candidate receptor and cis-regulatory element. The findings warrant updates to the foundational model and further consideration of hypotheses for regulation of the human LWS vs. MWS genes.