* Scientific study references are indicated in (). These can be found at the bottom of the article, and can be clicked on to access the original reports. In these paintings, Australian artist Concetta Antico aims to capture her extraordinary visual experiences, which she describes as consisting of a mosaic of vibrant colours. In an interview with the BBC, Concetta reflected on the sight of a pebble pathway, which most people perceive as grey: ‘The little stones jump out at me with oranges, yellows, greens, blues and pinks’ (1).

In 2012, a genetic analysis confirmed that Concetta’s enhanced colour vision can be explained by a genetic quirk that causes her eyes to produce four types of cone cells, instead of the regular three which underpin colour vision in most humans. Four cones give Concetta the potential for what researchers call tetrachromacy (from Greek ‘tetra’ – four, and ‘khrōma’ – colour), instead of normal trichromatic colour vision (from Greek ‘tria‘– three). This means that her eyes can enjoy a diversity of colours that is about 100 times greater than what is accessible to the rest of us.

While tetrachromacy is so rare that it makes headlines every time a new case emerges, it might come as a surprise that women with four cone types in their retinas are actually more common than we think. Researchers estimate that they represent as much as 12% of the female population (4). So why aren’t we surrounded by women with extraordinary colour vision? Researchers have found that only a small fraction of women who possess an extra cone type actually get to enjoy more colours. So what does it take to be a true tetrachromat? How does the human retina come to produce four cone types, and why does it only concern women? More importantly, why don’t all women fulfil their genetic potential? And how do we find the special women who do?

The fourth cone – science fiction?

The three cone types that most of us have in our retinas allow us to see millions of colours. Each cone’s membrane is packed with molecules, called opsins, which absorb lights of some wavelengths and cause the cone to send electrical signals to the brain. The opsin molecules vary between the three cone types, so that each type is sensitive to different wavelengths from the visible spectrum (3). Together, these cone cells allow the brain to identify the wavelengths of light that our eyes encounter – colour is experienced as a way of registering this information in our consciousness.

Individuals who happen to be born with a fourth cone type containing a new light-absorbing opsin molecule technically have the potential to distinguish a greater number of wavelengths, and thus perceive more colours. So are these extra colours like something taken from a sci-fi movie?

So far, there are no documented cases of humans with a fourth cone that captures light beyond the wavelength range of 400-700 nanometres, which is the normal visible spectrum. Thus, the existence of four cones isn’t quite the epic sci-fi scenario in which the eye becomes a hybrid between a human and some other species, like a bee or snake that can see ultraviolet light (7,8). Instead, the most common cause of a fourth cone is if an individual inherits a subtle change in DNA sequence (mutation) in one of the already existing genes for the light-absorbing opsin molecules that fill either the M- or L- cones. The human eye gains slightly superhuman abilities within the visible spectrum.

The genetic origins of four-cone retinas

An extra cone might come about if a mutation in one of the opsin genes affects the physical structure of the resulting opsin molecule in a way which influences its sensitivity to light. This change can essentially create a new cone type, because cone cells which contain the altered molecule react differently to various wavelengths compared to cones which contain the original opsin made from the non-mutated gene.

Since the M- and L- cone opsin genes are located on the X-chromosome, only women could possibly enjoy the benefits of such a mutation. A male inherits only one X-chromosome. Thus, if the single X-chromosome he receives from his mother carries a change in the M-cone opsin gene, his retina will ultimately produce three cone types: normal S-cones with opsins from a gene chromosome 7, and regular L-cones as well as abnormal M-cones containing mutated opsins from the same X-chromosome. This man would be classified as an anomalous trichromat since, like in most humans, his three cone types allow him to experience roughly the same number of colours, albeit slightly differently.

A woman, on the other hand, has the potential to produce four cone types because she inherits two X-chromosomes. So if one of them contains a mutated opsin gene, she will have one X-chromosome to provide the normal M- and L-cone opsins, and an additional chromosome to produce the mutated ‘new’ opsin. The illustration below provides some more detail. As mentioned, researchers estimate that women born with four cones are quite common, while the actual capacity to see more colours is exceptionally rare. So how do we objectively test whether women with four cones experience a greater range of colours? And once we identify those who indeed see more hues, how do we explain why some, but not others, can enjoy the genetic potential of tetrachromacy?

Testing for tetrachromacy with different colours designed to seem identical to the rest of us

Researchers aiming to investigate how many women actually have superior colour vision first need to fish for potential tetrachromats in the massive human population. Since women with four cones have one mutated X-chromosome, they have a 50% chance of passing that X-chromosome to their sons. This makes them much more likely than other women to have sons who are anomalous trichromats, which I described earlier. Researchers use this when seeking candidates for tetrachromacy, as they advertise for female participants whose sons have colour vision anomalies (4). The next important dilemma is to figure out how to objectively measure these women’s visual abilities. Where do we even begin searching for hues that seem identical to us but might seem distinct to tetrachromats? This challenge is by no means trivial – if we were to test for tetrachromacy by asking women if they see differences between randomly selected colour mixtures, we’d have a ridiculously long experiment.

Conveniently enough, the anomalous trichromats born to these women provide a useful starting point. While they are poorer than most people at discriminating some colours that seem obviously different to us (which is why they are often considered ‘colour-deficient’), they can in fact distinguish some colours that we perceive as identical (2). Researchers assume that if a woman with four cones sees extra colours, they must be the same ones that her sons see, given that her retina possesses the same mutated cone type (although the mother also has a fourth cone type and thus avoids the impairment her sons have with some other colours).

The surprising existence of extra colours that are visible to anomalous trichromats means that we can test for tetrachromacy by asking women if they see differences between colours that appear identical to normal trichromats, but seem different to their sons. How do we design these colours? For starters, we can use valuable findings from scientific experiments.

In 1992, researchers used bits of human DNA to produce the S-, M- and L-cone opsins inside cells and study their reactions to lights of different wavelengths (5). This experiment showed that we can easily calculate the signal that each cone type will produce when stimulated with various wavelengths. As an example, let’s take the M-cone, shown below.

Knowing what we do about how different cones respond to various lights, we can design mixtures of wavelengths that would produce the exact same signals across the three cone types in the normal human eye, but not in the eye of an anomalous trichromat. These mixtures would seem identical to an individual with three regular cone types, but not to one with a mutated cone. Here’s a scenario where a normal trichromat can’t see the difference between two physically distinct colours, while an anomalous trichromat can.

Let’s start with the normal trichromat:

The signals that the regular cones ultimately produce when stimulated with 590 nm light are exactly the same for a mixture of 540 nm + 670 nm light! When the brain receives these identical signals, it has no way of distinguishing between the two types of light, and the trichromat perceives them as identical.

Now let’s look at an anomalous trichromat who has a mutated M-cone with a light sensitivity profile that, compared to the original M-cone, falls slightly closer to the regular L-cone.

Notice that the signals produced by these three cone types are quite different for 590 nm light and the mixture of 540 nm + 670 nm lights. This means that the anomalous trichromat’s brain can sense a distinction between these two types of light, and so the man himself can experience the difference in colour. As mentioned, this man’s mother has the same mutated M-cone in addition to three regular cones, making these types of colour mixtures ideal for testing if she can experience more colours.

This is exactly what researchers did in 2010 (4). They presented women with pairs of colour mixtures designed to appear identical to regular trichromats, but which their anomalous trichromat sons could distinguish. They were then asked to rate how similar these mixtures appeared on a scale of 1 to 10, and their answers were compared to those of normal trichromats’ mothers, who were unlikely to have four cones.

Here, the first signs appeared that four cones don’t automatically grant you superior colour vision. The mothers of regular trichromats and most mothers of anomalous trichromats behaved similarly in this experiment. The similarity ratings they gave to various pairs of colour mixtures on one occasion were not the same ones they gave when asked about the same pairs some other time. These women seemed to be giving pretty random responses, making it doubtful that any of them really saw differences between the colour mixtures. Genetic analyses confirmed that at least seven of the nine anomalous trichromats’ mothers did in fact have four distinct cone types in their retinas. And yet, their colour vision wasn’t any better than that of women with three cones. Quite the enigma.

Only one of the seven women with four cones behaved as if she actually perceived differences between the colour mixtures that were invisible to everyone apart from her sons. For any given pair of colour mixtures that she was asked to rate in terms of similarity, she gave the same number when asked on separate occasions. She clearly wasn’t just picking a random number every time, but seemed to actually see the colour differences. What makes her different from the other women with four cone types?

If having four cone types isn’t enough, what does it take to see more colours?

When it comes to genetic mutations, some are insignificant, as they produce molecules that differ only slightly, or not at all, from those made by non-mutated genes. Other mutations can have a dramatic effect on the structure of the protein that a gene goes on to produce. With opsin genes, some mutations cause massive shifts in the light sensitivity of the resulting opsin molecule, while other mutations make a smaller difference.

The challenge for most women with four cones is that their extra cone is simply not different enough from an already existing cone type to be useful to the brain. Let’s look at two women with four cone types.

The light sensitivity profile of the first woman’s extra cone overlaps heavily with the profile of the normal L-cone. So, when her retina is stimulated by lights of different wavelengths, the signals that the fourth cone sends to the brain don’t really differ from what the L-cone already provides. Remember – the only way cones allow us to see colours is by sending the brain different signals for different wavelengths. If cone signals remain the same for various wavelengths, how could the brain, and so the brain’s owner, possibly see a difference? Unfortunately, this woman’s fourth cone is so similar to the L-cone that the visual system doesn’t even notice its existence.

On the other hand, the light sensitivity profile of the second woman’s extra cone is comfortably couched between the normal M- and L-cone profiles. This cone is different enough from the rest that when the retina is stimulated by lights of various wavelengths, all four cone types produce different signals. This fourth cone becomes useful for discriminating more wavelengths, and its owner might see 100 times more colours than the rest of us. This is exactly what researchers found with the only true tetrachromat they discovered in their experiment. Analyses of the opsin genes on her X-chromosomes revealed that the light sensitivity of her fourth cone type was ideally separated from the neighbouring M- and L-cones by a comfortable 12 nanometers (4)! In most other candidates, the fourth cone was too similar to the closest existing cone, making it incapable of enhancing colour vision.

Ultimately, experiments teach us that cones are necessary tools for seeing colour. But if one tool is no different from the next, the brain simply discards it and settles for what it has. Of the millions of women in the world whose eyes have four cone types, only a few will have won the ‘ideal’ mutation lottery that allows them to experience a seashore of colours like the tetrachromat artist Concetta Antico.

PS. If you are interested in learning more about how regular trichromatic vision works, have a look my previous article.

References

Bosten, J. M. et al. (2005). Multidimensional scaling reveals a color dimension unique to ‘color-deficient’ observers. Current Biology 15, R950.

Hofer, H. et al. (2005). Organization of the human trichromatic cone mosaic. Journal of Neuroscience 25, 9669-9679.

Jordan, G. et al. (2010). The dimensionality of color vision in carriers of anomalous trichromacy. Journal of Vision, 10.

Merbs, S. L. and Nathans, J. (1992). Absorption spectra of human cone pigments. Nature 356, 433-435.

Ray, P. F. et al. (1997). XIST expression from the maternal X chromosome in human male preimplantation at the blastocyst stage. Human Molecular Genetics 6, 1323-1327.

Sillman, A. J. et al. (1999) The photoreceptors and visual pigments in the retina of a boid snake, the ball python (Python Regius). Journal of Experimental Biology 202, 1931-1938.

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