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Review
. 2011 Apr 13;51(7):633-51.
doi: 10.1016/j.visres.2010.12.002. Epub 2010 Dec 15.

The genetics of normal and defective color vision

Jay Neitz  1 , Maureen Neitz
Affiliations
Review

The genetics of normal and defective color vision

Jay Neitz et al. Vision Res. .

Abstract

The contributions of genetics research to the science of normal and defective color vision over the previous few decades are reviewed emphasizing the developments in the 25years since the last anniversary issue of Vision Research. Understanding of the biology underlying color vision has been vaulted forward through the application of the tools of molecular genetics. For all their complexity, the biological processes responsible for color vision are more accessible than for many other neural systems. This is partly because of the wealth of genetic variations that affect color perception, both within and across species, and because components of the color vision system lend themselves to genetic manipulation. Mutations and rearrangements in the genes encoding the long, middle, and short wavelength sensitive cone pigments are responsible for color vision deficiencies and mutations have been identified that affect the number of cone types, the absorption spectra of the pigments, the functionality and viability of the cones, and the topography of the cone mosaic. The addition of an opsin gene, as occurred in the evolution of primate color vision, and has been done in experimental animals can produce expanded color vision capacities and this has provided insight into the underlying neural circuitry.

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Figures

Fig.1
Fig.1
A) Spectral tuning of human L and M cone photopigments. A)L-class pigments absorb maximally near 560 nm. B) M-class pigments absorb maximally near 530 nm. C) Genes encoding the L and M opsins each have 6 exons represented by narrow white bars and numbered 1 through 6. The colored regions indicate the exons in the L and M opsin genes. The genes are drawn to scale. Codons that specify amino acids involved in spectral tuning are indicated using the single letter amino acid code and the codon number/amino acid position is indicated by the numbers in the middle of the panel. The single letter amino acid code is as follows: Y = tyrosine, T=threonine, A=alanine, I=isoleucine, S=serine, F=phenylalanine. The magnitude of the spectral shift in nanometers (nm) produced by the indicated amino acid differences specified by each exon are indicated on the far right and far left.
Fig.2
Fig.2
Recombination produces an opsin array that causes color vision deficiencies. A) Misalignment of the opsin gene arrays on the two X-chromosomes in a female allows a crossover in the region between the L and M genes in one array and the homologous region downstream of the M gene in the other array. This produces two new X-chromosome opsin gene arrays. One array has an L gene and two M genes and will confer normal color vision. The second array has a single opsin gene, an L gene, and produces the color vision defect, deuteranopia, when inherited by a male. B) Misalignment of the opsin gene arrays on the two X-chromosomes in a female allows a crossover between the L gene on one X chromosome and the M gene on the other X-chromosome. This produces two new arrays that differ in gene number from the parental arrays. A gene that derives part of its sequence from a parental L gene and part from a parental M gene encodes a pigment whose spectral sensitivity is primarily determined by the parental origin of exon 5. The array with one gene confers protanopia because the single gene derives exon 5 from the parental M gene. The array with three genes will cause a deutan color vision defect. The second gene in this array encodes an L-class pigment because it derives exon 5 from the parental L opsin gene. The severity of the deutan defect depends on the amino acid differences at the spectral tuning sites in the two L-class pigments. If there are no differences at the spectral tuning sites, deuteranopia will result; if there are differences, a male that inherits this array will be deuteranomalous. C) Recombination between an array with 3 opsin genes and another with 2 opsin genes is expected to produce arrays that cause color vision defects at a high frequency because the mismatch in gene number on the two arrays means there is no perfect alignment. Misalignment that results in a crossover between an L gene on one X-chromosome and the M gene on the other will produce two new arrays that cause color vision defects if inherited by a male. One array will have two genes, both of which encode opsins that form M-class pigments because the first gene in the array derives exon 5 from the parental M gene. Males inheriting such an array will have a protan defect, the severity of which is determined by amino acid differences specified at the spectral tuning sites. The second array produced has two L genes followed by an M gene. It will cause a male to have a deutan defect, the severity of which is determined by the spectral differences encoded by the genes encoding opsins that will form L-class pigments.
Fig. 3
Fig. 3
Spectral sensitivities of human L, M and S cones plotted on a scale that is uniform in units of log of wave number. On this scale, all photopigments assume a common shape, described by a template curve (solid lines). The curve together with information about the spectral positions of the cone photopigments can be used to completely describe the photopigment basis for color vision in any individual. The template was derived by fitting an equation given at www.neitzvision.com to an amalgam of photopigment spectral sensitivity curves (Carroll, McMahon, Neitz & Neitz, 2000). A) The spectral peak of the template has been adjusted to fit cone fundamentals derived from color matching (Stockman & Brainard, 2010). B) All the curves from (A) have been shifted to a best fit, illustrating the close similarity between the shapes of the L, M and S spectral sensitivities and the template. The slight differences in psychophysically derived fundamentals may derive, in part, from variation in the normal cone pigments.
Fig. 4
Fig. 4
Hubel and Wiesel's conception of cone photoreceptor contributions to circuitry responsible for red-green spectrally opponent cells recorded in the LGN. Excitatory connections were assumed to selectively connect to L cones, avoiding S and M cones. The inhibitory connections were assumed to selectively connect to M cones, avoiding S and M cones. Redrawn from Wiesel and Hubel (1966).
Fig. 5
Fig. 5
Primate retinal ganglion cells that receive cone selective connections and have the potential for playing a role in color vision. Upper and lower panels show how the addition of a third cone type changes the chromatic inputs to different ganglion cells in the primate. The cell bodies of ganglion cells are drawn as diamonds. Bipolar cells have circular cell bodies. Horizontal cells bodies are hexagonal. For the trichromat (lower panel), four ON/OFF pairs of midget ganglion cells are drawn. Different combinations of cone connectivity distinguish the four ganglion cell pairs. Two ON/OFF pairs of ganglion cells, one pair with an L cone center and one with an M cone center, receive input from cones that make contacts with H2 horizontal cells, which contact nearby S cones. Two other ganglion cell pairs (an L center and an M center) receive input from cones that do not have the potential for significant S cone input from the surround. Assuming that a small subset of ganglion cells receive S cone input from the surround, the M cones with S in the surround give rise to an OFF center ganglion cell with (S+L)-M opponency and an ON center ganglion cell with M-(S+L) providing the potential retinal basis for a red and green, respectively, hue pathway. L cones with S in the surround give rise to an OFF center ganglion cell with (S+M)-L opponency and an ON center ganglion cell with L-(S+M) providing the potential retinal basis for a blue and yellow, respectively, hue pathway. ON midget ganglion cells with no S cone input to the surround have L-M opponency when the center cone is L and M-L opponency when the center cone is M. M cones provide the center of one spectrally opponent ganglion cell but the surround of neighboring ganglion cells. If neighboring L-M and M-L are indiscriminately combined in the cortex, chromatic opponency for diffuse spots of light will cancel. This would make L-M and M-L ganglion cells the substrate for edge detectors that would also signal chromatic borders. Thus, the four pairs of midget ganglion cells could provide the retinal basis to serve red, green, blue and yellow hue perception and luminance/chromatic edge detection. One S cone bipolar cell is illustrated. It connects specifically to an S cone. It provides the S-ON input to the small bistratified ganglion cell, which is drawn showing dendritic arbors in both the ON and OFF sublamina (labeled OFF-CENTER and ON-CENTER). The single S cone bipolar cell also provides an S-OFF input via an inhibitory interneuron to the melanopsin ganglion cell (drawn in yellow with an “X” shaped dendritic arbor). Both the melanopsin ganglion cell and the small bistratified cells have large receptive fields so the ON component of the melanopsin and the OFF component of the small bistratified cell have M+L cone inputs, giving them (L+M)-S and S-(L+M) spectral opponency, respectively. A comparison of the “DICHROMAT” top panel with the “TRICHROMAT” bottom panel shows how the spectral opponent properties of each of the 10 ganglion cells illustrated change when the retina is transformed from having two cone types to having three. Those midget cells that are capable of only transmitting luminance information in the dichromat become L vs. M opponent in the trichromat. Putative midget ganglion cells with S vs. L inputs that could serve blue color vision are transformed into two pairs to serve blue-yellow and red-green color vision in the trichromat. An attempt was made to preserve some of the anatomical details of the retina in the cartoon. Cones and bipolar cells are shown with ribbon synapses. ON bipolars make connections to the ribbon and terminate in the ON lamina. OFF bipolar cells are shown making more lateral connections representing flat contacts and they terminate in the OFF sublamina. The inset illustrates that horizontal cells make reciprocal synapses.
Fig. 6
Fig. 6
Cone weights of LGN cells recorded by (Tailby et al., 2008). Each dot represents the response properties of one LGN neuron. Normalized weights assigned to each cone type by the cells are plotted. The weight attached to M-cone input is plotted against that for the L-cone. The distance from the diagonals reflects the magnitude of S cone input. Thus, a cell plotted at the origin would have only S cone input and one on a diagonal line would have no S cone input. Only those neurons that were determined to have significant S cone input are represented. LGN neurons were found that represent all the spectrally opponent ganglion cells shown in Figure 5. The cells have been color coded to represent their putative role in hue perception. The cells that plot in the upper left and lower right triangles have L vs. M opponency and either excitatory or inhibitory S cone inputs as required to match the cone input to human hue perception. LGN cells with all the correct cone inputs to account for human hue perception were identified: M-(S+L) for green, (S+M)-L for blue, L-(S+M) for yellow and (S+L)-M for red; however, only one cell with the correct cone inputs to account for red percepts, (S+L)-M, was recorded from. A threshold was used to decide which LGN cells to include as receiving S cone input, it may be that other (S+L)-M cells were present but fell below the threshold. This seems reasonable because only 5% S cone contribution is required to account for normal hue perception. Redrawn from (Tailby et al., 2008).
Fig. 7
Fig. 7
A) In a dichromat, midget ganglion cells with an S cone in the surround could provide the basis for blue-yellow color vision with yellow percepts being mediated by ON ganglion cells and blue percepts mediated by OFF ganglion cells. Spectral response properties of each of the two spectrally opponent cells types are plotted. B) The addition of a third cone type to the retina transforms the former blue and yellow pathways. What was a single S vs. L receptive field type is transformed into two different receptive fields, one with an L cone center and one with an M cone center. ON and OFF pathways split the L center receptive fields into L-(S+M) and (S+M)-L and the M center pathways into M-(S+L) and (S+L)-M. The spectrally opponent response properties of each of the four trichromatic ganglion cell types is shown. The cells responsible for red, green, blue and yellow are all derived from a blue-yellow ancestor, but they all differ significantly from the preexisting blue yellow system.
Fig. 8
Fig. 8
A possible scheme for explaining the chromatic properties of cortical cell receptive fields adapted from Hubel and Wiesel (Hubel & Wiesel, 1962). A number of LGN cells, of which four are illustrated, project upon a single cortical cell. The synapses are presumed to be excitatory in this “feed forward” model. In this model, a number of the inputs must be active at the same time in order to exceed the threshold of the cortical cell. Indiscriminate connectivity to L vs. M opponent cells in which L-M cells are always nearby M-L cells cancels opponent responses to diffuse colored lights, but responses to luminance edges are enhanced.
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