The Mexican blind cavefish raises the challenging evolutionary question: Does disuse lead to degeneration or disappearance of a feature? Here, an answer Darwin would have loved.

Illustration by Adam Billyeald

The manner in which the evolution of flightless birds or eyeless, cave-dwelling animals might have come about was a problem that Charles Darwin considered; his answer was that disuse would lead to the progressive reduction, or degeneration, of organs over time. We do not believe this is correct anymore, but many share Darwin’s confusion, even today. Stephen Jay Gould, in his 2002 magnum opus, The Structure of Evolutionary Theory, listed the three things that his readers found most confusing, as measured by the correspondence he received:

“I can testify that three items top the list of puzzlement: (1) evolution seen as anagenesis rather than branching (‘if humans evolved from apes, why are apes still around’); (2) panselectionism (‘what is the adaptive significance of male nipples’); and (3) Lamarckism and the failure of natural selection (‘doesn’t the blindness of cavefishes imply a necessary space for Lamarckian evolution by disuse’).”

While all three are interesting questions, let’s consider just the third, which Darwin failed to answer. Why should animals living in total darkness lose their eyes? It’s a question that highlights the importance of developmental biology in explaining some evolutionary phenomena…and it’s also an excellent way to introduce this new column, in which I’ll regularly be discussing the evo-devo way of thinking.

One possible answer is that it is an economical adaptation. This scenario allows that it requires energy and effort to build something as intricate and fragile as an eye, so shutting off that pathway would be a sensible strategy in the embryo. The energy that would be used in constructing and maintaining the eye could instead be diverted to other growing organs. For the cavefish, those embryos that did not bother to build an eye that would never be used acquired some slight advantage over their fellows that did bear the burden of an eye, and so gradually came to dominate the cave population.

In the case of the Mexican blind cavefish, though, there is a striking observation against this explanation: The embryos make eyes! They initially develop, they form an eye cup, they develop the beginnings of neural circuitry, neurons proliferate…and then they stop. The rest of the skull continues to grow, overwhelming the budding eye with new tissue. It’s as if one paid to have a picture window built into a house and then, halfway through construction, had it ripped out and a wall put in. This would hardly be economical.

Another possible answer could be that loss of an eye in a cavefish does not impose any cost. The eyes disappear in the population by random chance, and without selection for sightedness, there is nothing to prevent the blind variants from competing equally with their sighted counterparts. This is a neutral theory of the loss of unused characters, which suggests that mutations that knocked out genes needed for development of the eye wouldn’t necessarily have any advantage, but they’d also have no cost. The eye is lost by harmless attrition and would be represented by broken genes in the animal’s genome.

This explanation doesn’t seem to fit the facts, either. The genes involved in generating the eye all seem to be present and functional in the blind cavefish. Transplanting a lens from a cavefish species with eyes to the blind cavefish embryo is enough to rescue the eye, which then develops into a perfect and functional visual organ. It becomes apparent, then, that the problem isn’t caused by outright broken genes, but by genes that are being regulated in a different way. Something is actively switching off lens formation and thereby removing a signal for eye development, and in fact, analysis of gene expression in the developing blind cavefish eye reveals that many genes are more active than they are in the sighted fish.

If neither the economical nor the neutral hypothesis adequately explains how cavefish lose their eyes, what is the answer? Recent work by W.R. Jeffrey and his colleagues on the Mexican blind cavefish suggests a third alternative, an explanation based on pleiotropy and developmental interactions.

Pleiotropy is a common phenomenon in genetics: All it means is that a single gene may have many different effects on the organism. Two genes that interact with one another in this system are a ‘master gene,’ called pax6, controlling the development of the eye, and hedgehog, a signaling molecule that plays an important role in setting up the midline of the animal. Pax6 is a transcription factor (a gene that regulates the expression of other genes), is active in the region of the embryonic head where eyes will form, is expressed in the eye cup and lens, and regulates the development of the eye. Hedgehog is a protein that is secreted at the midline and diffuses laterally to regulate many other processes. Its function is complex, but one role is to inhibit and separate structures. One effect of mutations in hedgehog is midline defects, such as cyclopia, where the eyes fuse together in the absence of a hedgehog boundary. Among those effects is an inhibition of pax6.

Hedgehog is also expressed in teeth, tastebuds, and the jaw. This is what we mean by pleiotropy—the gene is a midline gene that suppresses the eye gene pax6, but it’s also a jaw gene and a tooth gene and a tastebud gene. Now imagine a population of fish feeding and swimming in total darkness; which individuals will be most adept at finding food, and therefore most likely to pass on their genes to the next generation? Those that are best at using senses other than vision, that can use the tactile senses of their lower jaw to probe the environment for a meal, and that can use taste instead of sight to discriminate among food choices. What this suggests is that animals with expanded hedgehog function would thrive best, and selection would work to increase the frequency of greater hedgehog expression in the population.

There is a side effect—pleiotropy at work—in that hedgehog also inhibits pax6 expression, which means that expanding jaws and tastebuds will lead to a concomitant reduction of the eyes. What we have is a perfect example of an evolutionary tradeoff. Because hedgehog and pax6 are negatively coupled to one another, one can be expanded only at the expense of the other, and what is going on in the blind cavefish is not selection for an economical reduction of the eyes, nor the accidental loss of an organ that has no effect: It is positive selection for a feature that is only indirectly related to the eyes.

Gould would have appreciated this discovery. The cause of the blindness is the interrelationship between two genes that have complementary roles in development in establishing the architecture of the face. This is not a necessary relationship—not all genes have to be coupled to one another in this way—but a result of the evolutionary history of the organism, and a different kind of economy. The lower part of the face can be expanded, but only at the expense of the upper half.

The general lesson from this analysis is that understanding selection is not enough. We also need to understand the developmental interactions present in an organism to understand how selection for one feature might lead to a surprising pleiotropic change in a completely different one.

Originally published January 10, 2007

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