In mammals, only 3% of the genome is made up of coding genes that, when transcribed into proteins, ensure the biological functions of the organism and the in utero development of future individuals. But genes do not function alone. They are regulated by other sequences in the genome that, like switches, activate or deactivate them as needed.
Skeleton of a mouse embryo visible by fluorescence.
© Darbellay et al.
A team from the University of Geneva (UNIGE) has identified and located 2,700 genetic switches—among millions of non-coding genetic sequences—that precisely regulate the genes responsible for bone growth. This discovery highlights one of the key factors that influence an individual's height in adulthood, and why their failure could be the cause of certain bone malformations. These results are detailed in
Nature Communications.
Tall or short, our height is largely inherited from our parents. Additionally, there are numerous genetic diseases affecting bone growth, the exact cause of which often remains unknown. Could the explanation lie not within the genes themselves, but in other parts of the genome responsible for their activation?
"Short sequences of DNA—true switches—indeed give the signal for the transcription of DNA into RNA, which will then be translated into proteins," explains Guillaume Andrey, Assistant Professor in the Department of Genetic Medicine and Development at the UNIGE Faculty of Medicine and at the Geneva Institute of Genetics and Genomics (IGE3), who led this work. "While we know the genes regulating bone formation and their location in the genome, this is not the case for the switches that control them."
Fluorescent bones
Guillaume Andrey and his team developed an innovative experimental technique, awarded in 2023 by the
Swiss 3R Competence Center, which allows for the creation of mouse embryos with a precise genetic configuration from murine stem cells. "In this case, our mouse embryos have fluorescent bones, visible through imaging, which allow us to isolate the cells we are interested in and analyze the switches at work during bone development," says Fabrice Darbellay, a post-doctoral researcher in Professor Andrey's lab and the first author of this work.
The team thus monitored the activity of chromatin, the structure in which DNA is packaged, specifically in fluorescent bone cells. Using markers of genetic activation, the scientists were able to pinpoint which regulatory sequences came into play to control the genes responsible for bone construction. They then confirmed their discovery by selectively deactivating the switches without affecting the coding gene. "We observed a loss of activation of the genes in question, indicating that we had identified the correct switches and that their role is indeed crucial for the proper functioning of the gene," details Fabrice Darbellay.
A three-dimensional mapping
Out of the 2,700 switches identified in mice, 2,400 are found in humans. "Each chromosome is a long strand of DNA. Like beads on a necklace, the switches and the genes they control form small clumps of DNA on the same chromosomal strand. This physical proximity allows them to interact in such a controlled manner," explains Guillaume Andrey. Variations in the activity of these regions could also explain differences in height between humans: the activity of bone cells is linked to the size of the bones and therefore the individuals.
Moreover, many bone pathologies cannot be explained by a mutation affecting the sequence of a known gene. We must search elsewhere, specifically in the non-coding but regulatory regions of the genome. "There are already a few documented cases where a mutation in the switches, rather than in the genes themselves, is the cause of bone diseases. It is very likely that the number of cases is underestimated, especially when the genes of the patients appear normal," explain the authors. And beyond bones, failures of these various still little-known genetic switches could be the cause of many other developmental pathologies.