The central objective is a definition of the molecular genetics of human color vision at the photopigment level and to correlate heterogeneity of molecular genotypes of X-linked red-green color vision defects with advanced phenotype measurements. The red-green pigment genes are arranged as a gene complex consisting of a single red and one or more green pigment genes. Color vision defects are caused by illegitimate recombinations producing deletions or hybrid genes (green-red or red- green). The ratio of retinal cones expressing either the red or green pigment ha not been determined directly. Indirect estimates using psychophysical methods vary widely. We will attempt to delineate the exact ratio and spatial distribution of red and green cones by in situ molecular techniques on human retinas. These findings will be of fundamental importance for the visual sciences. Studies will be performed on human volunteers whose color vision genotypes will be determined in leukocyte DNA. The exact position of hybrid genes will be determined on our hypotheses that only the most proximal green or hybrid genes are expressed in the retina. Peak absorbance of the various normal and abnormal pigments will be correlate with molecular and psychophysical results. Human visual pigment genes will be expressed in mouse retinae by transgenic techniques to determine if dichromatic mice can develop trichromatic vision. If this approach works, it can be concluded that novel neuronal circuitry is not required to achieve more complex color discrimination. This result will help to elucidate whether tetrachromacy in heterozygous human females is possible. Differences in color perception as determined by the serine/alanine polymorphism at position 180 in the red pigment gene will be explored in females by combined molecular and psychophysical methods. Molecular genotype will be determined in several ethnic populations with different color vision frequencies. The remarkable phenomenon of skewed and opposite X chromosome inactivation in identical female twin pairs heterozygous for color visio defects which makes one twin color vision defective and the other twin normal will be studied in a large sample of identical twins to determine the frequency of this interesting biological phenomenon. On a practical plane, these studies may lead to blood tests for color vision defects. Elucidation of the molecular genetic structure of this locus affecting sensory perception together with psychophysical investigations is a model for the advanced study of genotype/phenotype correlation in human neurogenetics.
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