Researchers have discovered a vulnerability in our genome. This leads to developmental problems such as extra fingers. But more serious complications such as heart disease can also occur.
Our genome contains precise instructions on how our bodies should grow and develop. Millions of genomic switches, so-called enhancers, control which genes should be active at what time and in which part of the body. This in turn ensures that the right proteins are produced in the right cells at the right time throughout our lives.
If these switches are altered or defective, developmental problems and illnesses can occur. In fact, most genetic diseases are caused by mutations and changes in these enhancers, as previous studies show. But not all enhancer variants are automatically harmful; some mutations also have no effect. However, distinguishing the relevant from the irrelevant changes has so far been like looking for a needle in a haystack for researchers.
How do the genomic switches work?
A research group led by Fabian Lim from the University of California in San Diego has now examined in more detail how the enhancers work. To do this, the researchers particularly analyzed the enhancer called ZRS, which is known to be associated with additional limbs in humans and mice.
In mouse models and various in-vitro experiments, the biomedical scientists first investigated which gene the ZRS enhancer activates and the molecular mechanism through which this occurs. The biomedical scientists then compared how this mechanism changes when there are different point mutations in the DNA section of the enhancer.
Intensity of bond is crucial
It was shown that the genetic switch ZRS activates the expression of the Shh gene by binding certain proteins, so-called transcription factors – but surprisingly only extremely weakly. In subsequent experiments, Lim and his colleagues also found the same principle with other enhancers and their transcription factors. Thanks to the weak binding, the enhancers can usually fine-tune which gene should be active at which location, at what time and to what extent, the researchers conclude.
However, if a point mutation occurred within the genome section of the ZRS enhancer, causing a base pair to be exchanged, the transcription factors were able to bind more strongly to the enhancer in some of the cases examined. This effect can also be transferred to other enhancers, as subsequent experiments showed. In all cases, the fine-tuning of gene regulation was lost due to the stronger binding to the transcription factor, as Lim and his colleagues report. This resulted in more or less dramatic developmental problems – with the ZRS-Enhancer, for example, one or two additional fingers.
Targeted search for mutated enhancers possible
“Our study highlights a central weakness in our genome: Single base pair changes that cause transcription factors to bind slightly more strongly to an enhancer can lead to developmental disorders,” says senior author Emma Farley from the University of California in San Diego. However, mutations in enhancers that led to weaker binding of transcription factors did not result in developmental disorders.
“By specifically looking for DNA base pair changes in enhancers that lead to stronger binding of transcription factors, we can now find health-relevant enhancer variants much more quickly,” she adds. The researchers have developed a special test that can be used to find such mutations more quickly.
Consequences of harmful mutations can be predicted
Using this test, biomedical scientists have already compared different genomes and enhancer variants. Based on the findings, they can now predict in detail which enhancer mutations would lead to changes in gene expression and what consequences this would have for physical development. This doesn’t just apply to changes in limbs and not just in humans. For example, in a second study, Lim and his colleagues found that sea squirts develop a second heart when certain enhancers for heart development are mutated.
Knowledge of how genomic switches work now also opens up new opportunities for personalized medicine, according to the researchers. “Using this knowledge will allow us to better predict which enhancer variants underlie a disease,” says Farley.
Accordingly, individual mutations in certain sections of DNA, the enhancers, can change the instructions for gene expression, as the researchers report in “Nature”. As a result, the wrong proteins are produced, thereby disrupting physical development.
By Claudia Krapp