When DNA Changes, but Genetic Regulation Remains

Researchers from the Berlin Institute of Health at Charité (BIH) and the Max Planck Institute for Molecular Genetics, in collaboration with international colleagues, published a paper in Nature Genetics on a method to detect evolutionary conserved enhancers that diverged so much that their DNA sequences do not match anymore. In an interview, Dr. Daniel Ibrahim, study leader and last author of the publication, talks about the research results.

What question did you want to answer, what interested you in particular?

The development of organs such as the heart involves highly conserved genetic programs that are remarkably similar in humans and animals. This means that the sequences of the genes responsible for organ development have remained virtually unchanged for hundreds of millions of years – for example, between humans, mice, and chickens. Not only that, but the same genes are responsible for the development of the heart in humans and animals.

What has changed significantly, however, are the “regulatory” areas of the genome that determine in which cells or organs the genes are active. And here, it is well known among geneticists that these are even less conserved than one would expect. This did not make sense to me. Why should the genes and their activity be highly conserved, but the areas of the genome that control their activity be particularly low?

Our hypothesis was that current bioinformatic methods for identifying conserved enhancers focus too much on preserving the exact DNA sequence and overlook the fact that regulatory activity could also be preserved even if the sequence changes.

Heart-specific gene activity (blue staining) driven by evolutionary conserved DNA-sequences from mouse (top) and chicken (bottom) that share no sequence identity anymore© D. Ibrahim

What specific challenges did you face?

There was one central challenge: How do we know that two enhancers - for example in mice and humans - originate from the same precursor sequence if they no longer have the same sequence of As, Cs, Ts, and Gs?

Classically, one would assume that only if the DNA sequence is preseved, can the function be preserved. But for enhancers in particular, there are good reasons to assume that this is not the case and that two completely different sequences can cause a gene to be active primarily in the heart and not in other organs, for example.

To address this problem, we developed a new algorithm together with colleagues from Martin Vingron's group at the MPI for Molecular Genetics and Boris Lenhard from Imperial College London. This algorithm can be used to predict the equivalent position of e.g. an enhancer in another genome based on the exact position in the source genome (i.e. on which chromosome and where exactly).

Another challenge was to choose a suitable and clinically relevant model. We decided to look at the development of the heart, not least because many congenital heart defects have an unclear genetic cause and may be due to changes in important enhancers.

What surprised you and, if so, why? What was new?

I was surprised by how many functionally conserved enhancers could be identified using our new method—significantly more than previous methods had detected. Specifically, we were able to predict about five times as many conserved regulatory elements between mice and chickens as previously known!

What was remarkable was that when we compared these elements that do not have any sequence similarity, they were as similar in their genetic activity, i.e. in driving specific gene expression, as enhancers whose sequence has hardly changed since the last common ancestor (such enhancers also exist, of course). This was a clear indication that widespread functional conservation exists even without sequence conservation – an assumption that has often been neglected in the past.

What significance could this success have for future patients?

A key result of our work is a bioinformatic tool called IPP (Interspecies Point Projection), which we are making available to the scientific community. Anyone interested in knowing where, for example, human enhancers are located in the genome of mice, rats, chicken, or fish can use it immediately.

Such a Tool is of great importance for the interpretation of genetic variants in the non-coding genome, for example in in patients with unclear genetic diagnoses.
In addition, our tool opens up an important bridge for transferring findings from animal models to humans or for investigating clues from the clinic more precisely in animal models – an important step towards functionally informed diagnostics.

Where do you see the translational bridge between research and application?

In research, it is primarily important to find questions that you consider important to answer. However, a particular challenge in translation is then to make your own findings applicable.

With a genomic/bioninformatic tool like ours, this lies in the immediate applicability of the developed method. Our aim was not just to establish a new theoretical concept, write a paper, and be happy that we had solved a problem. It was important to us to present our work and findings in such a way that others could build on them as easily as possible.

We have attempted to do this by providing a well-documented and publicly accessible tool that can be quickly put into practice. If interested scientists have identified a number of interesting enhancers in specific immune cells or neurons, they can now use IPP to see directly whether these elements actually exist in other species and whether these regions are perhaps better researched in these model organisms than in humans.

Link to the publication

Phan*, Zehnder* et al (2025): Conservation of regulatory elements with highly diverged sequences across large evolutionary distances. Nature Genetics, 2025 May 27.