Unknown mechanism for malformations deciphered – healing practice

What does junk DNA do? Breakthrough in genetic research

A team of international scientists showed that a part of human DNA that was considered useless, which was previously referred to as junk DNA or junk DNA, could have a decisive influence on development and that the causes of many hereditary diseases may be in this largely unexplored part of the genome can be found.

An international research team with the participation of the Max Planck Institute for Molecular Genetics and the Charité – Universitätsmedizin Berlin discovered a previously unknown genetic mechanism that is responsible for severe malformations of the limbs. The study results were recently published in the renowned specialist journal “Nature” presented.

Breakthrough in research into hereditary diseases

The working group not only discovered a rare genetic disease that manifests itself in severe malformations of the limbs, they were also able to decipher a previously unknown genetic mechanism that could also play a role in other congenital diseases.

Big surprise in the human genome

Around 20 years ago, scientists were able to sequence the human genome for the first time. There was already the first big surprise: Only 20,000 genes seem to contain the blueprints for proteins that control almost all body functions. However, these 20,000 genes make up less than two percent of the entire genome. This raised the question: What is the function of the much larger part of the genome that does not encode proteins?

Stamped as scrap DNA

The researchers were unable to discover any function of the so-called “non-coding DNA”, which is why they classified it as “junk DNA”. Today there are better ways to read “between the lines of the genome”, as the working group of the current study calls it. According to this, the junk DNA contains important and previously overlooked information in order to switch genetic activity on or off at the right time in the right place.

Scrap DNA seems to activate important genes

The researchers were able to discover a new disease mechanism in this scrap DNA, which causes a genetic hereditary disease. DNA segments from the scrap DNA influence the long-known “engrailed-1” (En1) gene, which plays a central role in the development of the extremities, the brain, the sternum and the ribs. According to the study, the activation of En1 is activated by sections of the scrap DNA. If this process is disturbed, severe malformations of the limbs can occur.

New evidence of genetic diseases

“I expect that there will be more genetic diseases with comparable causes that have only so far eluded our attention,” comments Professor Dr. Stefan Mundlos the study results. He is research group leader at the Max Planck Institute for Molecular Genetics. The study provides new starting points for the development of genetic diseases. The causes of more than half of these diseases are still unknown.

Mechanism can cause extraordinary malformations

According to the researchers, the malformations that can be caused by errors in the newly discovered mechanism are of an extraordinary nature, as shown by the example of three people affected. For example, knee joints can be directed forward, fingers fused together or fingernails grow on the inside of the hand.

“Apparently, during the development of the limbs, the distinction between the ventral and dorsal side – that is, the palm or sole of the foot and the back – was lost in the extremities,” explains Professor Mundlos. The victims were first noticed by doctors in Brazil and India, who then sent DNA samples to human geneticist Professor Dr. Andrea Superti-Furga from the University of Lausanne sent. His team discovered that everyone was missing a similar piece of non-coding DNA. To get to the bottom of the matter, they teamed up with Professor Mundlos’ working group in Berlin.

New assessment of the scrap DNA

The scientist Dr. Lila Allou at the Max Planck Institute for Molecular Genetics investigated the molecular cause of the puzzling disease. “At first we only knew that the three patients were missing a similar small piece of genetic material,” she reports. But the sequence is located in a “great genetic desert”, ie in a section of non-coding DNA about which nothing is known.

Evidence of the cause

In a mouse model, it was possible to prove that the missing piece in the non-coding DNA, which was thought to be useless, was actually the cause of the disease. Using the so-called CRISPR-Cas technology, the researchers removed the corresponding DNA sequence from the genome of the mice, which then simulated the disease. “The results confirmed that the missing section of DNA was the cause of the disease,” emphasizes Dr. Allou.

Further studies showed that the genetically modified animals no longer had any activity of the En1 gene in their limbs. The particularly important gene was practically not switched on at all. Incorrect regulation of En1 has been associated with developmental disorders for decades. At that time, however, it was not yet known why the missing piece of genetic material led to the loss of En1 activity.

Read between the lines of the genes

But the researchers were also able to solve this riddle. It turned out that an RNA molecule was copied in the region that was missing. The team named this copy “Maenli” (for Master regulator of En1 in the Limb). The RNA usually acts as a messenger for information and contains the blueprint for a protein. In this case, however, the information on the molecule could not be translated.

Error in the genetic source code?

“This type of transcribed snippet is found in large numbers in the genome, which of them are important and which are not, is often difficult to say,” says Dr. Allou. Many scientists believe that these molecules have no function, but in this case the researchers were able to show that this is not always the case – or maybe even never.

In the further course of the study, the team investigated the function of Maenli RNA by creating a mutation that prematurely interrupted transcription. Mice with an inactivated Maenli showed the same malformations as the animals with the missing section. This confirms that it was really the missing RNA that caused the disease.

The reading itself seems to play an important role

In addition, it appeared that the structure and sequence of the RNA molecule were of secondary importance. The activity itself is more important, i.e. the reading at the respective location on the genome. Because after Dr. Allou had replaced the sequence with a completely different section, the animals still showed signs of the disease, but less strongly than when Maenli was completely inactivated. Reading a completely different sequence at this point is apparently sufficient to activate the En1 gene – albeit to a lesser extent than the original, natural sequence was able to do.

Research with far-reaching consequences

How reading it off leads to the activation of En1 is currently still unclear and is the subject of future research, sums up the working group. Nevertheless, it is foreseeable that the new findings will have far-reaching consequences. “Our results touch the fields of human genetics, RNA research, gene regulation and developmental biology,” summarizes Professor Mundlos. “From the point of view of developmental biology, we have identified a new genetic mechanism that determines cells during early embryonic development to become the ventral part of the limbs,” adds Dr. Allou.

90 percent of the gene variants so far ignored

The scientist believes that the results will also influence future diagnostics of genetic diseases and can help to elucidate the causes of other rare genetic diseases. “Over 90 percent of the gene variants are in the non-coding part of the genome, but it is very difficult to interpret them and use them for diagnostic purposes,” said Dr. Allou. Research clearly shows that genetic variants that have previously been ignored can be essential for understanding the molecular causes of diseases.

“What we assume is unimportant could actually hold the key to essential knowledge,” comments Dr. Allou in conclusion.

Author and source information

This text complies with the requirements of specialist medical literature, medical guidelines and current studies and has been checked by medical professionals.


Diploma-Editor (FH) Volker Blasek


  • Charité – Universitätsmedizin Berlin: Between the lines of the genome (published: 02/10/2021), charite.de
  • Lila Allou, Sara Balzano, Andrea Superti-Furga, et al.: Non-coding deletions identify Maenli lncRNA as a limb-specific En1 regulator; in: Naure, 2021, nature.com

Important NOTE:
This article is for general guidance only and should not be used for self-diagnosis or self-treatment. He can not substitute a visit at the doctor.


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