Creatures that spend their lives in dark caves tend to be changed by the experience. Gollum lost the hair on the tops of his feet and his taste for cooked food. Mexican cave fish lost their eyes.

Mexican tetra swam from surface waters into their caves around 1.5 million years ago. Like naked mole rats—another species that lives underground, in perennial darkness—they have no eyes. But whereas key genes controlling eye development in naked mole rats have mutations that inactivate them, there are no such inactivating mutations in the genes of the Mexican cave fish.

But mutations aren't the only way to change gene activity, and new research suggests a different explanation for the fish's lack of eyes. Epigenetic regulation is a means of controlling gene activity that does not alter the DNA sequence of the genes themselves. Genes undergoing epigenetic regulation can still make normal proteins, but the amount of the protein they make is modulated.

One method of epigenetic regulation is the addition of methyl groups to the DNA that controls the activity of specific genes. It is efficient, since it can be used to alter a whole bunch of genes at once. And it seems to explain the Mexican cave fish eye degeneration that has occurred over the past million years—a proverbial blink of an eye in evolutionary terms.

These cave fish have elevated levels of an enzyme that adds methyl groups to DNA compared to surface fish. This enzyme is expressed in the developing eye, where it decorates genes important in eye development with methyl groups. This reduces their expression to about half of the levels seen in surface fish.

A number of the methylated genes are known to be lost or defective in human eye disorders like colorblindness, night blindness, and even complete blindness. One of these genes controls the expression of a whole host of other eye genes, amplifying the effect.

There's evidence that altered methylation is central to the changes in these fish. A drug called 5-Azacytidine is an inhibitor of methylation (it's used by people with myelodysplastic syndrome, a rare disorder in which blood cells do not mature properly). Injections of the drug into cave fish embryo eyes could partially rescue their development, confirming that their loss is due to changes in methylation.

While this sounds like an evolutionary change that isn't reliant on mutations, that may not be the case. The genetic mechanism responsible for the upregulation of the methylating enzyme in cave fish is not yet known. It's likely that some changes in DNA sequences were involved there.

Nature Ecology and Evolution, 2018. DOI: 10.1038/s41559-018-0569-4 (About DOIs).