New study challenges traditional view of gene switches

Certain sequences in the genome cause genes to turn on or off. Until now, each of these gene switches, or so-called enhancers, was thought to have its own place in the DNA. Therefore, different enhancers separate from each other, even if they control the same gene, and activate it in different parts of the body. A recent study from the University of Bonn and LMU Munich challenges this idea. The findings are also important because gene switches are thought to play a central role in evolution. The study has been published in the journal Advances in Science.

The blueprint of plant and animal forms is encoded in their DNA. But only a small part of the genome – about two percent in mammals – contains genes, the instructions for making proteins. The rest largely controls when and where these genes are active: how many of their transcripts are produced, and thus how many proteins are produced from those transcripts.

Some of these control sequences, called “amplifiers”, act like the dimmer switches used to adjust the light in our living room. Indeed, they specifically increase the expression of a particular gene, where and when that gene is needed. Genes that control morphology often respond to several independent enhancers, each of which determines the expression of the gene in a different part of the body.

Control of amplifiers Drosophila coloration

Until now, amplifiers were thought to be modular. The term implies that each enhancer occupies an isolated segment of DNA. “We have shown, however, that this is not entirely true,” explains Mariam Museridze. She is a PhD student at the Institute of Organizational Biology in Bonn in the group of Prof. Dr. Nicolas Gompel and the first author of the study. Gompel is also a member of the Interdisciplinary Research Area (TRA) ‘Life & Health’ at the University of Bonn.

The researchers studied what a gene is called yellow adjustable on the fly Drosophila. This gene causes the insect to produce the brown pigment melanin. There are a number of enhancers that control its activity yellow. One of them, for example, is responsible for the pigmentation of the teeth of worms, while another is responsible for the formation of the striped pattern on the abdomen of the fly.

“We’ve taken a closer look at two of these amplifiers,” Museridze says. The first controls the formation of the color pattern on the wings, while the second controls the coloring of the head, thorax and abdomen. Both are active simultaneously during fly metamorphosis. The team discovered that the body enhancer is not, as expected, in a different region of DNA than the wing enhancer. In contrast, there are extensive regions of DNA that belong to both gene switches, i.e. they affect both wing and body pigmentation.

The results suggest that the architecture of regulatory sequences in the genome is much more complex than previously thought. This has far-reaching consequences for how traits change during evolution. According to current knowledge, enhancers play a key role in this process.

Amplifiers as an evolutionary playground

This is because many proteins are so important to an organism that a mutation in their gene (that is, the DNA sequence that contains the instructions for making the protein) would cause serious problems or even certain death. As a result, genes that control body shape, such as the number of wings or legs, rarely change during evolution. Enhancers offer a way out of this dilemma: when mutated, the activity of the corresponding gene changes, but only in a specific tissue and at a specific time.

“The cost of mutating an enhancer is often lower than the cost of directly mutating the gene,” says Mariam Museridze. This makes it easier to introduce new features during development. It’s like baking a cake: If you mix eggs, flour, milk and sugar, you can get completely different types of dough, depending on the mixing ratio. In this transfer, boosters will be responsible for the quantity of ingredients and not the type of ingredients.

A genetic mutation is like accidentally replacing an ingredient with something completely different – for example, using sawdust instead of flour. The result will definitely not be very good. A mutation in an enhancer, on the other hand, would change the amount of flour. “If the enhancers are not as modular as we thought, this means that mutations in them can have much broader effects,” says Museridze. This means that such a mutation could affect the amount of several components simultaneously. However, it is also possible that enhancers retain their independence and continue to control the amount of a single component, even though their sequences are intertwined and shared. “We now want to investigate these possibilities in more detail,” explains Professor Gompel. “We also want to know how general our findings are and how this affects our understanding of evolutionary mechanisms.”