In the eye of the beholder: Visual pigments and inherited variation in human vision

Abstract

Jeremy Nathans Howard Hughes Medical Institute Departments of Molecular Biology and Genetics, Neuroscience, and Ophthalmology Johns Hopkins University School of Medicine Baltimore, Maryland 21205 Each of us inhabits an internally consistent visual world. In everyday life we take the constancy of this world for granted and assume that others share it. Although this assumption is roughly valid when averaged over the popu- lation, psychophysical experiments over the past two cen- turies have revealed significant differences among individ- ual humans in many aspects of visual function. One source of these differences has recently been identified at a mo- lecular level: sequence variation in the genes encoding the visual pigments, the light-absorbing proteins in the rods and cones that initiate phototransduction. In humans there are four visual pigments. Each visual pigment consists of an integral membrane apoprotein bound to a chromophore, 1 l-cis retinal. Rhodopsin, the rod pigment, mediates vision in dim light. The three cone pigments, referred to as blue, green, and red, mediate color vision and function only in bright light. The absorption spectra of the four human visual pigments are shown in Figure 1. Inherited Variation in Co/or Vision The most common variation in human color vision arises from a serinelalanine polymorphism at position 180 in the red pigment gene. The absorption spectrum of the red(Ser- 180) allele is red-shifted 4-5 nm relative to the red(Ala-180) allele (Merbs and Nathans, 1992a; Asenjo et al., 1994). Males who carry the red(Ser-180) allele have a corre- spondingly greater sensitivity to long wavelength lights than do those who carry the red(Ala-180) allele (Wind- erickx et al., 1992b). In the Caucasian gene pool, the red(Ser-180) and red(Ala-180) alleles are found at frequen- cies of 82% and 38%, respectively. The common variations in red-green color vision that are colloquially referred to as color blindness arise from loss of either the red or the green cone pigment (dichro- macy) or from the production of a visual pigment with a shifted absorption spectrum (anomalous trichromacy). The high frequencies of these variations in males-approxi- mately 2% for dichromacy and, depending on the popula- tion, between 2% and 8% for anomalous trichromacy- reflect the X chromosome location of the red and green pigment genes, a relaxation of selective pressure for nor- mal trichromacy, and an unusually facile mutational mech- anism. The red and green pigment genes are organized in a head-to-tail tandem array in which the transcription units and intergenic spacer DNA are 98% identical at the nucleotide level, an arrangement that predisposes them to homologous but unequal recombination (reviewed by Nathans et al., 1992). Unequal intergenic recombination generates variant arrays in which entire repeat units are