The long-term objectives of this proposal are to fully define the molecular genetics of human color vision and its common defects, and to elucidate the mechanisms of regulation of expression of the X-linked red-green color vision locus. A remarkable heterogeneity of genotypes and phenotypes exist at this locus due to the existence of common spectral variants of the long wave sensitive (L) and middle wave sensitive (M) pigments causing various color vision defects. Preliminary studies have shown that some women who carry three forms of the L and M pigment genes have additional color discrimination capacity. We will investigate the genetic basis for this extended color discrimination capacity. The long wave sensitive (L) or red pigment gene and the middle wave sensitive (M) or green pigment gene are located next to each other on the X chromosome but a retinal cone only expresses either the L or the M pigment gene - a finding that is fundamental for red/green color vision. Our discovery that the human retinoblastoma cell line WERI expresses the red and green pigment genes in a mutually exclusive manner and that cell division resets the type of gene expressed in daughter cells provides a unique opportunity to elucidate regulatory mechanisms. This system furnishes an elegant model to study a basic regulatory process that controls the on and off switch of an array of closely related genes in a specialized cell. Recent technological advances have facilitated high resolution mapping of regulatory modules across genes, and allowed identification of regulatory proteins that bind to these modules. We will apply these efficient and rapid approaches to our studies on the red/green color locus. In addition, we will functionally dissect the role of some of these proteins in expression of the L and M pigment genes by the recently developed and powerful method of RNA inhibition (RNAi) in WERI cells. Elucidation of the molecular mechanisms of regulation of the genes of this locus affecting sensory perception is a model for expression of genes in analogous complex loci. The novel photoreceptor genes we propose to identify may be good candidates for some inherited retinal diseases.
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