The central objective of this proposal is to define the molecular genetics of red/green color vision by relating the molecular genetics of the X- linked photopigment genes to their expression in the retina and to the color vision phenotype. The red and green pigment genes are arranged in an array on the X-chromosome consisting of a single red and one or more green pigment genes. Deletion of genes or formation of hybrid genes (red-green and green-red) due to illegitimate recombination at this locus causes color vision defects. However, not all other gens of the red/green array are expressed in the retina, creating uncertainties in predicting color vision phenotype from genotype. Understanding the mechanism by which selective expression of these genes is accomplished is fundamental to defining genotype-phenotype relationships. We have delineated critical regulatory regions of the red-green gene locus and detected proteins that bind to them. A major aim of this proposal is to clone and character the transcription factors that play major roles in regulating expression of the visual pigment genes. We will map the genes encoding these factors on human and mouse chromosomes. Map positions will be correlated with known loci associated with retinal diseases. We developed a rapid method for determining gene order in males who have up to three pigment genes in their arrays and found evidence for a role of gene order in gene expression and color vision. We propose to advance their method in order to determine gene order in the majority of individuals. Knowing the sequence and gene order will allow more precise prediction of the spectral sensitivities of clones and the color vision phenotype. The ratio of red to green cones was determined indirectly by measuring relative levels of mRNA in postmortem human retinae. We propose to determine the ratio and distribution of cones in the retina directly by in situ molecular techniques. The findings will be of fundamental importance for the visual sciences. We observed a very high frequency of green-red hybrid genes among Africans. We will investigate the sequence of these hybrids and determine their position in the array. Elucidation of the molecular mechanism of expression of this locus affecting sensory perception is a model for expression of genes in other complex loci. These studies may lead to rapid and accurate blood tests for color vision defects. The novel photoreceptor-specific genes we propose to clone may be good candidates for some of the inherited retinal diseases.
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