Genetics of variation in human color vision and the retinal cone mosaic

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Variation in human color vision is mainly caused by one common polymorphism (Ser180Ala) in the L pigment, and to the frequent presence of hybrid genes that encode pigments with various spectral properties. Both recombination and gene conversion between the highly homologous L and M pigment genes have generated wide variation in genotype and color vision phenotype. The S, M and L cones are distributed randomly in the central retina. Unlike S cones, M and L cones vary widely in number within the central retina. Determining the number of the three classes of cone and their special distribution in the living retina has significantly advanced the ability to correlate the cone mosaic in normal and color-defective subjects with the color vision phenotype. The transcription factors NR2E3, TRβ2 and RXRγ play crucial roles in establishment of the retinal cone mosaic during eye development.

Introduction

Normal color vision in humans is trichromatic (see Glossary), being based on three classes of cone in the retina that are maximally sensitive to light at ∼420 nm (in the case of short-wave-sensitive, S cones), ∼530 nm (middle-wave-sensitive, M cones) and ∼560 nm (long-wave-sensitive, L cones). It is the ability of neural circuitry to compare light absorbed by these three classes of cone photoreceptor that enables the perception of red, yellow, green and blue colors individually or in various combinations. The synthesis of a single class of photopigment with a distinct absorption spectrum in each photoreceptor cell is fundamental to color vision. Photopigments are G-protein-coupled receptors composed of a protein moiety, opsin, which forms a transmembrane heptahelical bundle within which the chromophore 11-cis retinaldehyde is embedded. Differences in spectral characteristics of the photopigments are dictated by the interaction of amino acid side-chains at key positions in the opsin with the chromophore. Differences at positions 180 (encoded by exon 3), 277 and 285 (encoded by exon 5) account for the majority of the differences between the wavelength of maximal absorption (λmax) of the L and M pigments (Figure 1; for review, see [1••]). In addition, differences at positions 116, 230, 233 and 309 play minor roles [2, 3].

Ser180Ala, a common polymorphism of the L pigment, was shown to play a subtle role in variation in both normal [4] and defective red–green color vision (see below) [5, 6]. The λmax of an L pigment with Ser at position 180 was subsequently shown to be ∼4–7 nm longer than that with Ala when expressed in vitro [2, 3].

Males who have either no functional L-cones (protanopes, ∼1% of all males) or no functional M-cones (deuteranopes, ∼1% of all males) have severe color vision defects. They are referred to as having dichromatic color vision (see Glossary) that is based on functional S cones plus either M or L cones. Males with milder color vision defects have, in addition to S cones, either normal green plus anomalous M-like cones (protanomalous, ∼1%) or normal L plus anomalous M-like cones (deuteranomalous, ∼5% in Northern Europeans and 1–2% in other ethnic groups). These individuals have anomalous trichromatic color vision (see Glossary). The anomalous pigments are L–M chimeras encoded by hybrid genes (see below) [1••]. Loss of S-cone function is very rare and results in tritanopic color vision. The cone spectra of individuals with normal and defective color vision, and a simulation of how the visible spectrum looks to each class are shown in Figure 1. The absorption spectra of cones of anomalous trichromats (protanomalous and deuteranomalous) are shown in Figure 2. A much more severe type of color vision deficiency is blue cone monocromacy, in which individuals have no functional L and M cones.

Section snippets

Genetics of color vision

The cloning by Nathans and colleagues [7] of the genes that encode the S, M and L photoreceptor pigments paved the way for the discovery of the molecular basis of the common red–green color vision deficiencies. The genes encoding the L (OPN1LW [OPSIN 1 LONG-WAVE]) and M (OPNL1MW [OPNLW MIDDLE-WAVE]) photopigments are arranged in a head-to-tail tandem array on the X chromosome at Xq28 (Figure 3a, top array) [7]. The array is composed of a single OPN1LW followed by one or more OPN1MW genes. The

The human retinal cone mosaic

The topography of the S-, M- and L-cone mosaic, and the ratio of L to M cones in the primate retina have recently attracted considerable attention. The relative numbers and arrangement of the three cones are crucial for spatial vision and color perception. S cones are sparse (∼10% of all cones) and arranged randomly in the human retina, and they are absent in the central fovea, the central part of the retina [16]. Previously, the S and (L + M) cone mosaic was determined using psychophysical,

Genetics of cone photoreceptor patterning in the developing retina

Retinal progenitor cells differentiate into either rods or cones (Figure 6). The orphan nuclear receptor NR2E3 plays a crucial role in this decision by inducing rod formation and suppressing the cone pathway. It has been shown that NR2E3 interacts with the cone–rod homeobox transcription factor CRX to directly induce expression of the rhodopsin promoter and repress the S-opsin promoter [27]. Mutations in NR2E3 were shown to cause the human enhanced S-cone syndrome and increased S-cones in rd7

Conclusions

There is common variation in both normal and defective color vision. Recombination and gene conversion between the juxtaposed, highly homologous OPN1MW an OPN1LW genes underlie this variation.

The ability to define the cone mosaic in the living retina using adaptive optics gives the opportunity in the future to correlate visual performance with the ratio of the three classes of cone and their spatial distribution in the retina. For example, does variance in the L:M ratio have an impact on visual

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

Preparation of this review was supported by a National Institutes of Health (National Eye Institute) grant EY08295.

Glossary

Anomalous trichromacy
Trichromatic color vision based on either S, M and an anomalous M-like photoreceptor (protanomaly) or S, L and an anomalous L-like photoreceptor (deuteranomaly). The color vision defect is generally mild but might be severe in certain cases.
Deutan color vision
Otherwise known as deuteranopia or deuteranomaly.
Dichromatic color vision
Severely defective color vision deficiency based on the presence of only two types of cone photoreceptors, S plus either M (protanopia) or L

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