Said the Mouse to the Other Mouse, “Dude, You Would Not Believe The Colors I’m Seeing….”

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Scientists often stick genes into organism in order to create something new. Remote-controlled flies, for example, or photographic E. coli. But by creating new kinds of life, scientists can also learn about the history of life. Give a mouse human vision, for example, and you may learn something important about how our own eyes evolved.

As mammals go, we have unusual eyes. Most mammals produce two kinds of pigments for catching light. One is sensitive to short wavelength light (at the blue end of the spectrum). The other is sensitive to a longer wavelength, in the green or red part of the spectrum. Each pigment is encoded in a single gene, and any given photoreceptor in the retina uses only one. Each photoreceptor is most likely to fire a signal to the brain in response to a single wavelength of light. But it also has a smaller probability of firing off in response to photons of close wavelengths. By comparing all the signals coming from all the photoreceptors, a mammal can perceive a wide range of colors, rather than just seeing a world made up of green and blue pixels.

We humans–along with our closest primate relatives, the apes and the monkeys of Africa and Asia–can make three pigments, not two. We carry a gene for a blue pigment (S for short, at 420 nanometer wavelength), a green pigment (M for medium, 530 nm), and a red pigment (L for long, 560 nm). This so-called trichromatic vision makes us a particularly good at making out different colors down at the yellow-to-red end of the spectrum. On the other hand, we don’t see up in the ultraviolet range, unlike many vertebrates.

The most plausible explanation for this difference is that at some point in our history, our ancestors parted ways with other mammals, and acquired a third pigment gene. And many pieces of evidence suggest that what happened was this: the red and green genes are the product of an accidental duplication of an ancestral gene. For one thing, they are very similar to one another, differing by just three amino acids. For another, they sit close to one another on the X chromosome. They even appear to be controlled by the same “on-off switch,” which turns on red pigments in some photoreceptors and green in others.

(Incidentally, this is why color blindness tends to appear in men. Men have only one X chromosome, while women have two. A mutation to a pigment gene on the X chromosome can knock out a pigment entirely from a man’s eyes, while a woman may still be able to make good pigments off of the genes on her other X.)

The third piece of evidence for a red-green duplication is particularly intriguing. The closet living relatives to the lineage of humans, apes, and Old World Monkeys are the New World Monkeys. And they have a very odd sort of vision. They carry a blue (S) pigment like us, but they only have a single pigment gene on the X chromosome. Males can only have two pigments in their eyes. But in many species, there are different versions of the pigment gene on the X chromosome, and each gene encodes a pigment sensitive to a different wavelength. Female monkeys, with their two X chromosomes, may inherit two copies of the same X gene, and thus have two pigments as well. Or they may carry a different version on each X chromosome. In each photoreceptor, one of the X chromosomes is shut down, so that only one kind of pigment gets made. They thus end up trichromatic. Making the whole situation even stranger, many variants of the X chromosome pigment may float around a population of New World Monkeys, which means that from female to female, their vision may differ drastically. (See this pdf for a review.)

Evolutionary biologists have proposed a hypothesis for this difference by looking at the ecology of primates and their pigments. In a 2003 paper, one team of researchers proposed that ancestral monkeys ate figs and other fruit. Monkeys with three pigments might sometimes be able to pick out ripe fruit, while monkeys with two pigments might do a better job of picking out hidden fruits because they wouldn’t be distracted by extra colors. The variation from monkey to monkey might benefit an entire monkey troupe. But about 30 million years ago, Old World Monkeys shifted to eating leaves, the scientists argue. They needed to be very sensitive to reddish hues in order to tell tender young leaves from inedible older ones.

The evidence from the genes of primates suggests one way in which Old World monkeys and apes got their third pigment gene. Like New World monkeys, a population of ancestral primates had a few different versions of pigment genes on the X chromosome. A mutation in a female caused the gene on one X chromosome to be pasted alongside the gene on the other X chromosome. Her descendants now inherited two genes on the same chromosome. Subsequent mutations changed the sensitivity of each pigment, to create the blue-green-red vision we now have.

While this hypothesis is consistent with the evidence, it raises many questions (like any other scientific hypothesis). Color vision, after all, is more than a matter of pigments. Once a photoreceptor snags a photon of a certain wavelength, an animal needs the right sort of circuitry in its nervous system to make sense of the sensation–to turn the signal into the perception of a color. Now imagine the first time an ancient female primate inherited two distinct X-chromosome pigments from her parents. How could her brain suddenly make sense of three separate channels of information, when her ancestors were accustomed to just two?

Over the past few years, Jeremy Nathans, a neuroscientist at Johns Hopkins, and his colleagues have working towards some answers to that question. They have figured out how to insert human pigment genes into mice. Mice, like most mammals, have two pigments. Mice have a medium-wavelength pigment sensitive to green (510 nm) and a very short wavelength pigment that’s sensitive in the ultraviolet. Red is pretty much meaningless to them, in other words. Nathans’s team replaced the green pigment gene in mice with the human red gene (560 nm). They then bred the mice with ordinary ones. Their offspring inherited these genes according to Mendel’s rules. Males inherited either the mouse-green or human-red gene on their one X chromosome. Females could either have two copies of either gene, or they could have one of each. In other words, they resembled New World Monkeys, in which some females carry three different pigment genes.

In 2003, Nathans’s group reported that mice could not only inherit all three genes, but they could also produce all three pigment in their retinas. They even found that the retinas became sensitive to UV, green, and red light. The next challenge was to move into the brain–to see if the mice could actually make sense of all three colors.

Today in the journal Science the researchers report that the answer is yes. They carried out behavioral tests on the mice, showing them three colored panels. In some cases one of the panels was a different color, and in others they were the same. They gave the mice a reward of soy milk if they could correctly recognize when the colors were different. Not surprisingly, ordinary mice only got the right answer a third of the time, even after thousands of trials. In other words, they could only guess. But female mice with all three pigments got the right answer four times out of five.

What’s particularly intriguing about these results is that we–and other primates–have a special system of neurons called midget cells dedicated to distinguishing between red and green on the way to the brain. Mice and other mammals lack midget cells. And yet it’s obvious that they didn’t need a special set of neurons to take in this extra dimension of color. Their brains simply organized themselves in such a way that they could perceive it.

If you didn’t know this, you might wonder if trichromatic vision is too complex to have evolved–that adding an extra color was impossible because you need a complicated system made of many parts in order to see if at all. But that’s not true. When a single mutation occurs, altering a single gene, its effects can ripple out across an animal’s body. Simply moving a pigment gene from one chromosome to another appears to have triggered a drastic rewiring of the brain, taking advantage of the brain’s ability to adjust itself. Natural selection could have fine-tuned the connections from the eye to brain in later generations, producing midget cells and other adaptations, in order to improve color perception. What seems complex now may not be so complex in the first place.