Researchers have uncovered a vulnerability in our genome that leads to developmental abnormalities such as additional fingers. Moreover, more severe complications like heart diseases can also arise.
Our genome contains precise instructions on how our bodies should grow and develop. Millions of genomic switches, known as enhancers, regulate which genes should be active at what time and in which part of the body. This ensures that the right proteins are produced in the right cells at the right time during our lives.
When these switches are altered or defective, developmental disorders and diseases can occur. Indeed, most genetically inherited diseases result from mutations and changes in these enhancers, as previous studies have shown. However, not all enhancer variants are automatically harmful; some mutations have no effects. Distinguishing relevant changes from irrelevant ones has been akin to finding a needle in a haystack for researchers.
How Do Genomic Switches Work?
A research team led by Fabian Lim from the University of California, San Diego, delved into how enhancers function. They particularly examined the enhancer named ZRS, which is known to be associated with extra limbs in humans and mice.
Biomedical researchers initially investigated in mouse models and various in vitro experiments which gene the ZRS enhancer activates and the molecular mechanism through which this occurs. Subsequently, the researchers compared how this mechanism changed when different point mutations were present in the DNA segment of the enhancer.
Importance of Binding Intensity
The findings revealed that the genetic switch ZRS activates the expression of the Shh gene by binding to specific proteins called transcription factors—surprisingly, however, this binding was extremely weak. Lim and his colleagues found the same principle in subsequent experiments with other enhancers and their transcription factors. Due to weak binding, enhancers generally fine-tune which gene should be active where, when, and to what extent, the researchers concluded.
However, when a point mutation occurred within the genome segment of the ZRS enhancer, resulting in the exchange of a base pair, transcription factors could bind more strongly to the enhancer in some of the examined cases. This effect is also applicable 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, leading to more or less dramatic developmental disorders—for example, one or two extra fingers in the case of the ZRS enhancer.
Targeted Search for Mutated Enhancers Made Possible
“Our study highlights a central vulnerability in our genome: individual 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, San Diego. Mutations in enhancers that lead to weaker binding of transcription factors, on the other hand, did not result in developmental disorders.
“By specifically searching for such DNA base pair changes in enhancers that lead to stronger binding of transcription factors, we can now much more quickly identify health-relevant enhancer variants,” she adds. For this purpose, researchers have developed a specialized test to expedite the detection of such mutations.
Predictable Consequences of Harmful Mutations
Using this test, biomedical researchers have already compared various genomes and enhancer variants. Based on the findings, they can now accurately predict which enhancer mutations would lead to changes in gene expression and the consequences this would have on physical development. This applies not only to limb changes and not only to humans. For instance, in a second study, Lim and his colleagues found that sea squirts develop a second heart when certain enhancers for heart development are mutated.
Understanding how genomic switches function also opens new avenues for personalized medicine, according to the researchers. “The use of this knowledge will allow us to better predict which enhancer variants underlie a disease,” says Farley.
Therefore, individual mutations in certain DNA segments, the enhancers, can alter instructions for gene expression, as reported in “Nature.” Consequently, incorrect proteins are produced, disrupting physical development.
Original source: This information was Initially covered by focus and has been translated for our readers.