Professor Andrey, a brief summary of your work?

I've been interested in the genetic mechanisms of development since the beginning of my career. During a post-doctorate in Berlin, I started working on genetic switches which, although they are part of the non-coding part of the genome, are increasingly appearing to be the key to understanding many pathologies. Their role is to activate and deactivate the expression of a gene, in the right place and at the right time. Their discovery has made it possible to revisit what we call the "cold cases" of genetics: developmental syndromes that have been known for decades but for which we have been unable to identify the origin.

Such as the Liebenberg syndrome, a rare anomaly in which arms adopt morphological characteristics typical of legs?

Exactly. The Liebenberg syndrome was first described in the 1970s, but it wasn't until 50 years later that we understood its cause: it's not a mutation in a gene, but a mutation in the non-coding part of the genome that disrupts the regulation of a gene essential for leg development, PITX1. The gene remains unchanged, but communication with one of its enhancers is altered. In this case, the enhancer is brought closer to the gene, which it then activates incorrectly in the embryonic buds of the arms. The arm develops but is parasitised by the "leg" programme. However, not all patients present the same genetic variations, or the same malformations.

And why is that?

This is precisely what we have been able to decipher in our latest study, published in Nature Communications. In a mouse model of Liebenberg syndrome, Olimpia Bompadre, a PhD student in my laboratory, labelled the mouse Pitx1 gene with a green fluorescent protein that allows to monitor its activation during embryonic development. The closer the enhancer, the higher the percentage of cells expressing the gene, and the more severe the malformations. Without the syndrome, the enhancer is 330,000 nucleotides away from the gene, and no cells express Pitx1. At 216,000 nucleotides, 1/3 closer than normal, 6% of cells express it. At 100,000 nucleotides, this rises to 27% of cells and already severe malformations. When you get even closer, 62% of cells express the gene and you're looking at a hind leg instead of a front leg. Hence, what really matters is the proportion of cells expressing the gene, and not the overall level of expression as previously thought.

Could what you have shown in Liebenberg syndrome be similar elsewhere?

Indeed, our study is a good model for a whole class of diseases known as "enhanceropathies", where a defective enhancer activates or deactivates a gene either in the wrong place or at the wrong time. All organs can potentially be affected. This goes well beyond development, as metabolic disorders such as diabetes and certain cancers have already been linked to enhanceropathies.
Thanks to the development of genome investigation technologies, research into these switches has expanded considerably over the last ten years. This is mainly due to progress in whole genome sequencing, the computing power made possible by bioinformatics, and above all the very large genomic databases with hundreds of thousands of individuals, which are essential for identifying pathological variants. This is fascinating for scientists and opens a whole new field of research that could change the lives of people affected by genetic diseases that are still poorly understood. It will make it possible to make a diagnosis, predict the likely course of the disease and even, I hope, cure diseases that are still incurable today. The first treatment based on CRISPR-Cas9 technology, for sickle cell anaemia, has been approved. It modifies the enhancer of a gene that is important for the function of red blood cells, without affecting the gene itself.

And, now, on what line of research would you like to focus?

The core of my laboratory's research is to understand the physiological and pathological mechanisms that regulate genes in development. We now want to develop a very precise conceptual framework of how genes are regulated during development: the different phases, activation, maintenance and then deactivation of genes, in order to annotate the human non-coding genome at high resolution and, ultimately, to be able to predict the effect of genetic variations on embryonic development.

Guillaume ANDREY
Associate Professor
Department of Genetic Medicine and Development, Faculty of Medicine & IGE3

Developmental Genomics Lab
Guillaume.Andrey@unige.ch 

Reference
Bompadre, O., Rouco, R., Darbellay, F. et al. Liebenberg syndrome severity arises from variations in Pitx1 locus topology and proportion of ectopically transcribing cells. Nat Commun 16, 6321 (2025). https://doi.org/10.1038/s41467-025-61615-2