Prevalence of Congenital Color Vision Deficiency in Southern Taiwan and Detection of Female Carriers by Visual Pigment Gene Analysis.

This study aimed to investigate the prevalence of color vision deficiencies (CVDs) and determine whether carriers could be detected by analyzing the visual pigment genes. Materials and Methods: The data of students who underwent routine CVD screening using the Ishihara color test in Kaohsiung, Southern Taiwan were analyzed. Furthermore, the DNA samples of 80 randomly selected females and four obligate carriers were analyzed. The most upstream genes, downstream genes, and the most downstream genes in the red/green pigment gene arrays were amplified separately using polymerase chain reaction (PCR), and exon 5 of each gene was analyzed. The prevalence of congenital red-green CVD in this study was 3.46% in males and 0.14% in females. The PCR analysis of the first gene, downstream gene, and last gene revealed normal patterns in 73 normal cases. Seven unusual patterns were detected in two proton carriers and five deutan carriers. Among the randomly selected females, 8.8% (7/80) were CVD carriers. The prevalence of CVD among male Taiwanese students in this study was 3.46%. Female carriers of congenital CVD can be identified by molecular analysis of the visual pigment genes. The proportion of CVD carriers among the randomly selected females was 8.8%, which was slightly higher than expected and further studies are warranted.

Rare variants in axonogenesis genes connect three families with sound-color synesthesia.

Synesthesia is a rare nonpathological phenomenon where stimulation of one sense automatically provokes a secondary perception in another. Hypothesized to result from differences in cortical wiring during development, synesthetes show atypical structural and functional neural connectivity, but the underlying molecular mechanisms are unknown. The trait also appears to be more common among people with autism spectrum disorder and savant abilities. Previous linkage studies searching for shared loci of large effect size across multiple families have had limited success. To address the critical lack of candidate genes, we applied whole-exome sequencing to three families with sound-color (auditory-visual) synesthesia affecting multiple relatives across three or more generations. We identified rare genetic variants that fully cosegregate with synesthesia in each family, uncovering 37 genes of interest. Consistent with reports indicating genetic heterogeneity, no variants were shared across families. Gene ontology analyses highlighted six genes-COL4A1, ITGA2, MYO10, ROBO3, SLC9A6, and SLIT2-associated with axonogenesis and expressed during early childhood when synesthetic associations are formed. These results are consistent with neuroimaging-based hypotheses about the role of hyperconnectivity in the etiology of synesthesia and offer a potential entry point into the neurobiology that organizes our sensory experiences.

Protanopia (red color-blindness) in medaka: a simple system for producing color-blind fish and testing their spectral sensitivity.

BACKGROUND: Color perception is important for fish to survive and reproduce in nature. Visual pigments in the retinal photoreceptor cells are responsible for receiving light stimuli, but the function of the pigments in vivo has not been directly investigated in many animals due to the lack of color-blind lines and appropriate color-perception tests. METHODS: In this study, we established a system for producing color-blind fish and testing their spectral sensitivity. First, we disrupted long-wavelength-sensitive (LWS) opsins of medaka (Oryzias latipes) using the CRISPR/Cas9 system to make red-color-blind lines. Single guide RNAs were designed using the consensus sequences between the paralogous LWSa and LWSb genes to simultaneously introduce double-frameshift mutations. Next, we developed a non-invasive and no-prior-learning test for spectral sensitivity by applying an optomotor response (OMR) test under an Okazaki Large Spectrograph (OLS), termed the O-O test. We constructed an electrical-rotary cylinder with black/white stripes, into which a glass aquarium containing one or more fish was placed under various monochromatic light conditions. The medaka were irradiated by the OLS every 10 nm, from wavelengths of 700 nm to 900 nm, and OMR was evaluated under each condition. RESULTS: We confirmed that the lws - medaka were indeed insensitive to red light (protanopia). While the control fish responded to wavelengths of up to 830 nm (λ = 830 nm), the lws - mutants responded up to λ = 740 nm; however, this difference was not observed after adaptation to dark: both the control and lws - fish could respond up to λ = 820 ~ 830 nm. CONCLUSIONS: These results suggest that the lws - mutants lost photopic red-cone vision, but retained scotopic rod vision. Considering that the peak absorption spectra (λmax) of medaka LWSs are about 560 nm, but the light-adapted control medaka could respond behaviorally to light at λ = 830 nm, red-cone vision could cover an unexpectedly wide range of wavelengths, and behavioral tests could be an effective way to measure spectral sensitivity. Using the CRISPR/Cas9 and O-O systems, the establishment of various other color-blind lines and assessment of their spectra sensitivity could be expected to proceed in the future.

Do twins share the same dress code? Quantifying relative genetic and environmental contributions to subjective perceptions of "the dress" in a classical twin study.

The phenomenon of contrasting color perceptions of "the dress" photograph has gained scientific interest. The mechanism underlying why individuals differ is yet to be fully explained. We use the powerful twin model design to ascertain the relative contribution of genetic and environmental factors on perception variation. A sample of 466 twins from the British TwinsUK registry were invited to report what color they saw in a standard image of the dress in standard illumination. The mean age of the participants was 49.5 (SD = 17.8) years, and 85% were female. When asked to choose between white and gold (WG) or blue and black (BB), 328 reported WG (70.4%) and 135 (29.0%) reported BB. Subjects choosing WG were significantly older (p < 0.01), but there was no significant difference in gender. Monozygotic (MZ) twins were more concordant in their responses than dizygotic (DZ) twins (0.46 vs. 0.36). Twin modeling revealed that genetic factors accounted for 34% (95% confidence interval, 5%-59%) of variation in the reported color of the dress when adjusted for age, whereas environmental factors contributed 66% (95% CI, 41%-95%). This study suggests environmental factors play a significant role in how an individual perceives the color of "the dress."

Gene therapy for red-green colour blindness in adult primates.

Red-green colour blindness, which results from the absence of either the long- (L) or the middle- (M) wavelength-sensitive visual photopigments, is the most common single locus genetic disorder. Here we explore the possibility of curing colour blindness using gene therapy in experiments on adult monkeys that had been colour blind since birth. A third type of cone pigment was added to dichromatic retinas, providing the receptoral basis for trichromatic colour vision. This opened a new avenue to explore the requirements for establishing the neural circuits for a new dimension of colour sensation. Classic visual deprivation experiments have led to the expectation that neural connections established during development would not appropriately process an input that was not present from birth. Therefore, it was believed that the treatment of congenital vision disorders would be ineffective unless administered to the very young. However, here we show that the addition of a third opsin in adult red-green colour-deficient primates was sufficient to produce trichromatic colour vision behaviour. Thus, trichromacy can arise from a single addition of a third cone class and it does not require an early developmental process. This provides a positive outlook for the potential of gene therapy to cure adult vision disorders.

Individual differences provide psychophysical evidence for separate on- and off-pathways deriving from short-wave cones.

Distinct neural populations carry signals from short-wave (S) cones. We used individual differences to test whether two types of pathways, those that receive excitatory input (S+) and those that receive inhibitory input (S-), contribute independently to psychophysical performance. We also conducted a genome-wide association study (GWAS) to look for genetic correlates of the individual differences. Our psychophysical test was based on the Cambridge Color Test, but detection thresholds were measured separately for S-cone spatial increments and decrements. Our participants were 1060 healthy adults aged 16-40. Test-retest reliabilities for thresholds were good (ρ=0.64 for S-cone increments, 0.67 for decrements and 0.73 for the average of the two). "Regression scores," isolating variability unique to incremental or decremental sensitivity, were also reliable (ρ=0.53 for increments and ρ=0.51 for decrements). The correlation between incremental and decremental thresholds was ρ=0.65. No genetic markers reached genome-wide significance (p<5×10(-7)). We identified 18 "suggestive" loci (p<10(-5)). The significant test-retest reliabilities show stable individual differences in S-cone sensitivity in a normal adult population. Though a portion of the variance in sensitivity is shared between incremental and decremental sensitivity, over 26% of the variance is stable across individuals, but unique to increments or decrements, suggesting distinct neural substrates. Some of the variability in sensitivity is likely to be genetic. We note that four of the suggestive associations found in the GWAS are with genes that are involved in glucose metabolism or have been associated with diabetes.

Vertebrate pigmentation: from underlying genes to adaptive function.

Animal coloration is a powerful model for studying the genetic mechanisms that determine phenotype. Genetic crosses of laboratory mice have provided extensive information about the patterns of inheritance and pleiotropic effects of loci involved in pigmentation. Recently, the study of pigmentation genes and their functions has extended into wild populations, providing additional evidence that pigment gene function is largely conserved across disparate vertebrate taxa and can influence adaptive coloration, often in predictable ways. These new and integrative studies, along with those using a genetic approach to understand color perception, raise some important questions. Most notably, how does selection shape both phenotypic and genetic variation, and how can we use this information to further understand the phenotypic diversity generated by evolutionary processes?

Losses of functional opsin genes, short-wavelength cone photopigments, and color vision--a significant trend in the evolution of mammalian vision.

All mammalian cone photopigments are derived from the operation of representatives from two opsin gene families (SWS1 and LWS in marsupial and eutherian mammals; SWS2 and LWS in monotremes), a process that produces cone pigments with respective peak sensitivities in the short and middle-to-long wavelengths. With the exception of a number of primate taxa, the modal pattern for mammals is to have two types of cone photopigment, one drawn from each of the gene families. In recent years, it has been discovered that the SWS1 opsin genes of a widely divergent collection of eutherian mammals have accumulated mutational changes that render them nonfunctional. This alteration reduces the retinal complements of these species to a single cone type, thus rendering ordinary color vision impossible. At present, several dozen species from five mammalian orders have been identified as falling into this category, but the total number of mammalian species that have lost short-wavelength cones in this way is certain to be much larger, perhaps reaching as high as 10% of all species. A number of circumstances that might be used to explain this widespread cone loss can be identified. Among these, the single consistent fact is that the species so affected are nocturnal or, if they are not technically nocturnal, they at least feature retinal organizations that are typically associated with that lifestyle. At the same time, however, there are many nocturnal mammals that retain functional short-wavelength cones. Nocturnality thus appears to set the stage for loss of functional SWS1 opsin genes in mammals, but it cannot be the sole circumstance.

Position of a 'green-red' hybrid gene in the visual pigment array determines colour-vision phenotype.

The X-linked red- and green-pigment genes are arranged in a head-to-tail tandem array. The colour-vision defect of deuteranomaly (in 5% of males of European descent) is associated with a 5'-green-red-3' visual-pigment hybrid gene, which may also exist in males with normal colour vision. To explain why males with a normal red, a normal green and a green-red hybrid gene may have either normal or deutan colour vision, we hypothesized that only the first two genes are expressed and deuteranomaly results only if the green-red hybrid gene occupies the second position and is expressed preferentially over normal green-pigment genes occupying more distal positions. We used long-range PCR amplification and studied 10 deutan males (8 deuteranomalous and 2 deuteranopic) with 3 visual pigment genes (red, green and green-red hybrid) to investigate whether position of the hybrid gene in the array determined gene expression. The green-red hybrid gene was always at the second position (and the first position was always occupied by the red gene). Conversely, in two men with red, green and green-red hybrid genes and normal colour vision, the hybrid gene occupied the third position. When pigment gene mRNA expression was assessed in post-mortem retinae of three men with the red, green and green-red genotype, the green-red hybrid gene was expressed only when located in the second position. We conclude that the green-red hybrid gene will only cause deutan defects when it occupies the second position of the pigment gene array.

Defective colour vision associated with a missense mutation in the human green visual pigment gene.

All red/green colour vision defects described so far have been associated with gross rearrangements within the red/green opsin gene array (Xq28). We now describe a male with severe deuteranomaly without such a rearrangement. A substitution of a highly conserved cysteine by arginine at position 203 in the green opsins presumably accounted for his colour vision defect. Surprisingly, this mutation was fairly common (2%) in the population but apparently was not always expressed. In analogy with nonexpression of some 5'green-red hybrid genes in persons with normal colour vision, we suggest that failure of manifestation occurs when the mutant gene is located at a distal (3') position among several green opsin genes. This mutation might also predispose to certain X-linked retinal dystrophies.

Polymorphisms in the 5-HTTLPR gene mediate storage capacity of visual working memory.

Working memory (WM) is a limited capacity system that permeates nearly all levels of cognition, ranging from perceptual awareness to intelligence. Through behavioral, electrophysiological, and neuroimaging work, substantial gains have been made in understanding this capacity-limited system. In the current work, we examined genetic contributions to the storage capacity of WM. Multiple studies have demonstrated a link between the serotonin transporter-linked polymorphic region (5-HTTLPR) and cognition, where better performance is observed in individuals possessing a copy of the short (s) variant of the polymorphism compared with individuals homozygous for the long (l) variant. We predicted the same profile in WM performance, such that estimated capacities of l/l carriers should be smaller than s/s and s/l carriers. To measure WM capacity, we implemented a change detection task, which requires observers to actively maintain the color and spatial location of briefly presented squares over a short retention interval. In line with our prediction, we observed similar WM performance between s/s and s/l groups, and these individuals performed better than the l/l group. We then discuss the distribution of the serotonin transporter system and parallels between WM and attention to provide insight into how variation in the 5-HTT polymorphism could lead to individual differences in the storage capacity of WM.

Quantal noise from human red cone pigment.

The rod pigment, rhodopsin, shows spontaneous isomerization activity. This quantal noise produces a dark light of approximately 0.01 photons s(-1) rod(-1) in human, setting the threshold for rod vision. The spontaneous isomerization activity of human cone pigments has long remained a mystery because the effect of a single isomerized pigment molecule in cones, unlike that in rods, is small and beyond measurement. We have now overcome this problem by expressing human red cone pigment transgenically in mouse rods in order to exploit their large single-photon response, especially after genetic removal of a key negative-feedback regulation. Extrapolating the measured quantal noise of transgenic cone pigment to native human red cones, we obtained a dark rate of approximately 10 false events s(-1) cone(-1), almost 10(3)-fold lower than the overall dark transduction noise previously reported in primate cones. Our measurements provide a rationale for why mammalian red, green and blue cones have comparable sensitivities, unlike their amphibian counterparts.

High diversity of arthropod colour vision: from genes to ecology.

Colour vision allows animals to use the information contained in the spectrum of light to control important behavioural decisions such as selection of habitats, food or mates. Among arthropods, the largest animal phylum, we find completely colour-blind species as well as species with up to 40 different opsin genes or more than 10 spectral types of photoreceptors, we find a large diversity of optical methods shaping spectral sensitivity, we find eyes with different colour vision systems looking into the dorsal and ventral hemisphere, and species in which males and females see the world in different colours. The behavioural use of colour vision shows an equally astonishing diversity. Only the neural mechanisms underlying this sensory ability seems surprisingly conserved-not only within the phylum, but even between arthropods and the other well-studied phylum, chordates. The papers in this special issue allow a glimpse into the colourful world of arthropod colour vision, and besides giving an overview this introduction highlights how much more research is needed to fill in the many missing pieces of this large puzzle. This article is part of the theme issue 'Understanding colour vision: molecular, physiological, neuronal and behavioural studies in arthropods'.

Environment and culture shape both the colour lexicon and the genetics of colour perception.

Many languages express 'blue' and 'green' under an umbrella term 'grue'. To explain this variation, it has been suggested that changes in eye physiology, due to UV-light incidence, can lead to abnormalities in blue-green color perception which causes the color lexicon to adapt. Here, we apply advanced statistics on a set of 142 populations to model how different factors shape the presence of a specific term for blue. In addition, we examined if the ontogenetic effect of UV-light on color perception generates a negative selection pressure against inherited abnormal red-green perception. We found the presence of a specific term for blue was influenced by UV incidence as well as several additional factors, including cultural complexity. Moreover, there was evidence that UV incidence was negatively related to abnormal red-green color perception. These results demonstrate that variation in languages can only be understood in the context of their cultural, biological, and physical environments.

Light environment drives evolution of color vision genes in butterflies and moths.

Opsins, combined with a chromophore, are the primary light-sensing molecules in animals and are crucial for color vision. Throughout animal evolution, duplications and losses of opsin proteins are common, but it is unclear what is driving these gains and losses. Light availability is implicated, and dim environments are often associated with low opsin diversity and loss. Correlations between high opsin diversity and bright environments, however, are tenuous. To test if increased light availability is associated with opsin diversification, we examined diel niche and identified opsins using transcriptomes and genomes of 175 butterflies and moths (Lepidoptera). We found 14 independent opsin duplications associated with bright environments. Estimating their rates of evolution revealed that opsins from diurnal taxa evolve faster-at least 13 amino acids were identified with higher dN/dS rates, with a subset close enough to the chromophore to tune the opsin. These results demonstrate that high light availability increases opsin diversity and evolution rate in Lepidoptera.

Genomic organization of duplicated short wave-sensitive and long wave-sensitive opsin genes in the green swordtail, Xiphophorus helleri.

BACKGROUND: Long wave-sensitive (LWS) opsin genes have undergone multiple lineage-specific duplication events throughout the evolution of teleost fishes. LWS repertoire expansions in live-bearing fishes (family Poeciliidae) have equipped multiple species in this family with up to four LWS genes. Given that color vision, especially attraction to orange male coloration, is important to mate choice within poeciliids, LWS opsins have been proposed as candidate genes driving sexual selection in this family. To date the genomic organization of these genes has not been described in the family Poeciliidae, and little is known about the mechanisms regulating the expression of LWS opsins in any teleost. RESULTS: Two BAC clones containing the complete genomic repertoire of LWS opsin genes in the green swordtail fish, Xiphophorus helleri, were identified and sequenced. Three of the four LWS loci identified here were linked in a tandem array downstream of two tightly linked short wave-sensitive 2 (SWS2) opsin genes. The fourth LWS opsin gene, containing only a single intron, was not linked to the other three and is the product of a retrotransposition event. Genomic and phylogenetic results demonstrate that the LWS genes described here share a common evolutionary origin with those previously characterized in other poeciliids. Using qualitative RT-PCR and MSP we showed that each of the LWS and SWS2 opsins, as well as three other cone opsin genes and a single rod opsin gene, were expressed in the eyes of adult female and male X. helleri, contributing to six separate classes of adult retinal cone and rod cells with average lambdamax values of 365 nm, 405 nm, 459 nm, 499 nm, 534 nm and 568 nm. Comparative genomic analysis identified two candidate teleost opsin regulatory regions containing putative CRX binding sites and hormone response elements in upstream sequences of LWS gene regions of seven teleost species, including X. helleri. CONCLUSIONS: We report the first complete genomic description of LWS and SWS2 genes in poeciliids. These data will serve as a reference for future work seeking to understand the relationship between LWS opsin genomic organization, gene expression, gene family evolution, sexual selection and speciation in this fish family.

Color vision: mice see hue too.

A transgenic mouse has been generated with three cone types, instead of the normal murine two. Remarkably, some of these mice use the extra cone to make trichromatic color discriminations similar to those that are the basis of human color vision.

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

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, TRbeta2 and RXRgamma play crucial roles in establishment of the retinal cone mosaic during eye development.

Impaired sense of smell and color discrimination in monogenic and idiopathic Parkinson's disease.

Olfaction is typically impaired in idiopathic Parkinson's disease (IPD), but its role is uncertain in monogenic PD. Diminished color discrimination has been suggested as another early sign of dopaminergic dysfunction but not been systematically studied. Furthermore, it is unknown whether both deficits are linked. We examined 100 patients with IPD, 27 manifesting mutation carriers (MC), 20 nonmanifesting mutation carriers (NMC), and 110 controls. Participants underwent a standardized neurological examination, the University of Pennsylvania Smell Identification Test (UPSIT), the Farnsworth-Munsell (FM) color discrimination test, and mutation testing in known PD genes. The monogenic group consisted of 15 Parkin (6MC/9NMC), 17 PINK1 (10MC/7NMC), 8 LRRK2 (4MC/4NMC), 3 SNCA (MC), and 4 ATP13A2 (MC) carriers. Olfaction was most impaired in IPD (UPSIT percentiles 10.1 ± 13.5) compared with all other groups (MC 13.8 ± 11.9, NMC 19.6 ± 13.0, controls 33.8 ± 22.4). Within MC, carriers of two mutations in Parkin and PINK1 showed higher UPSIT percentiles than LRRK2 and SNCA carriers. Color discrimination was reduced in IPD (FM total error score 134.8 ± 92.7). In MC (122.4 ± 142.4), the reduction was most pronounced in LRRK2, NMC (80.0 ± 38.8) were comparable with controls (97.2 ± 61.1). UPSIT and FM scores were correlated in the control (r = -0.305; P = 0.002) and the IPD group (r = -0.303; P = 0.006) but not among mutation carriers. First, we confirmed olfaction and color discrimination to be impaired in IPD and suggest olfaction to be a premotor sign. Second, olfaction differed between carriers with one and two mutations in Parkin/PINK1-associated PD. Third, olfaction and color discrimination impairment do not necessarily evolve in parallel.

Pollinating birds differ in spectral sensitivity.

Pollinating animals and their angiosperm hosts often show strong co-adaptation in traits that increase the likelihood of a successful transfer of pollen and nutrient rewards. One such adaptation is the reported colour difference caused by unequal distribution of anthocyanidin pigments amongst plant species visited by hummingbirds and passerines. This phenomenon has been suggested to reflect possible differences in the colour vision of these pollinating birds. The presence of any such difference in colour vision would arguably affect the ecological and evolutionary interactions between flowers and their visitors, accentuating differences in floral displays and attractiveness of plants to the favoured avian pollinators. We have tested for differences in colour vision, as indicated by the amino acid present at certain key positions in the short-wavelength-sensitive type 1 (SWS1) visual pigment opsin, between the major groups of pollinating birds: the non-passerine Trochilidae (hummingbirds), the passerine Meliphagidae (honeyeaters) and Nectariniidae (sunbirds) plus five other Passerida passerine families. The results reveal gross spectral sensitivity differences between hummingbirds and honeyeaters, on the one hand, and the Passerida species, on the other.