The cause of genetic diseases can also be found in "gene deserts”
Large parts of the human genome do not contain protein-coding genes. Now, however, a research team with participation from the University of Basel has discovered the cause of a severe hereditary defect in such a "gene desert". The study in the scientific journal Nature shows that a single genetic change in the "junk DNA" long thought to be useless can have serious consequences.
11 February 2021
An interdisciplinary research team from Lausanne, Berlin and Basel has uncovered a new mechanism for inherited diseases. The findings, published in the journal Nature, have far-reaching implications for the entire field of medical genetics. The study involved researchers from the Institute of Molecular and Clinical Ophthalmology (IOB) at the University of Basel, the University and University Hospital of Lausanne (CHUV), the Max Planck Institute and the University of Berlin.
“When we realized the importance of our findings, we were really stunned,“ says Professor Andrea Superti-Furga from the University Lausanne and CHUV. Even the most sophisticated diagnostic tests, such as whole genome sequencing, provide an accurate diagnosis of the genetic defect in only half of the cases in which a genetic cause for a disease is suspected. The new results suggest that some of the undiagnosed cases may be due to changes in "empty" regions of the genome.
“Although we knew that some of these regions – originally believed to contain inessential sequences and referred to as “junk” DNA – could have a function, we never imagined that they could be responsible for important genetic diseases," Superti-Furga states.
Puzzling hereditary defect
The study focused on severe limb malformations in four unrelated newborns, behind which a genetic defect was suspected. Surprisingly, no variant was found in any of the genes already identified in the human genome that could have explained the malformations.
In their search for the genetic cause, the team benefited from the technical expertise that Professor Carlo Rivolta and his team at the IOB of the University of Basel have accumulated on genetic diseases of the eye. "We identified the genomic event that was responsible for this invalidating condition according to the same bioinformatic and molecular protocols we would have used for a rare and recessive form of retinal degeneration, and we were successful", Rivolta explains.
According to the study, the cause for the malformations lies in the loss of a small section in the genetic material that is located in the middle of a so-called "gene desert", far away from the next known gene. A bioinformatic analysis of this apparently informationless section of the genome indicated that the missing DNA segment contained a so-called "long non-coding RNA" (lncRNA). This is a section of the genome that is transcribed to RNA, but the transcript is not used as a template for making a protein. Instead, the RNA molecule itself serves as an element involved in the regulation of cellular processes.
Further experiments revealed that this previously unknown lncRNA was indeed necessary to activate the nearest gene called EN1. Although the EN1 gene itself was intact, the lack of activation of this gene was responsible for the malformations.
Important information hidden in the “junk DNA”
Today, about 8000 different genetic disorders and diseases are known, and the discovery of a new one, while important for affected individuals and their families, is no longer exceptional. However, the current study shows that such a disease, triggered by a single genetic alteration, can be caused not only by defects in one of the approximately 20,000 known genes that lead to a protein product. The cause may also lie in alterations in elements that are far removed from a gene and yet important for its activation and regulation.
The majority of such elements are still unknown, as was the lncRNA now identified in a section of the genome considered "empty." Thus, while the known protein-coding genes, which make up only 2 % of the human genome, are the basic functional elements for the life of a cell and an organism, single changes in the remaining 98 % of the genome may also have consequences for human health.
Original publication
Lila Allou et al.
Noncoding deletions identify Maenli IncRNA as a limb-specific En1regulator
Nature (2021), doi: 10.1038/s41586-021-03208-9
Further information
Prof. Dr. Carlo Rivolta, University of Basel, Institute of Molecular and Clinical Ophthalmology, email: carlo.rivolta@unibas.ch
