Their study published in Nature (click here to access the paper) shows that disease can not only be caused by changes in one of the 20,000 known genes resulting in a protein product, but also by changes in elements that are distant from a gene, which are not at all an “empty” stretch of DNA, but important for gene activation and regulation. The findings published in the science journal Nature have far reaching implications for the whole field of human and medical genetics.

“We researched into the cause of severe limb malformations in newborns, taking advantage from the technical expertise we developed over the years which we now apply on genetic conditions 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", Carlo Rivolta explains.

Every single piece of DNA becomes candidate for new functions and for genetic disorder

The interdisciplinary research team from the University Lausanne / Centre Hospitalier Universitaire Vaudois, the University of Basel / IOB and the Max Planck Institute / University of Berlin revealed a new mechanism for genetic disease.

“When we realized the importance of our findings, we were really stunned “says Professor Andrea Superti-Furga from the University Lausanne and Centre Hospitalier Universitaire Vaudois. Currently even the most sophisticated diagnostic tests, such as whole genome sequencing (WGS), allow a precise diagnosis in only half (50%) of cases of suspected genetic disease. The new results suggest that part of the undiagnosed cases may be associated with changes in “empty” regions of the genome. Although we knew that some of these regions (originally believed to contain inessential and referred to as “junk” DNA) could have a function, we never imagined that they could be responsible for important genetic diseases.

Remote activation of genes by long non-coding RNA

The Nature publication describes the research into the cause of limb malformations observed in four unrelated individuals. Surprisingly, none of the known human genes already identified in the human genome was found to have any variant that could have explained the malformations. Further studies revealed that the limb defects were caused by a small loss of DNA material in the middle of a so-called “gene desert”, some 300,000 nucleotides away from the nearest known gene. Bioinformatic analysis of this desert zone suggested that the missing segment of DNA contained a “long non-coding RNA (lncRNA)”, a piece of the genome that does not contain any information for producing a protein. In further experiments, it could be shown that this previously unknown lncRNA was indeed necessary to activate the closest nearby gene, EN1. Although the gene EN1 itself was intact, failure to activate this gene was responsible for the malformations.

Majority of non-protein-coding DNA is not “empty”

Approximately 8,000 different genetic conditions and diseases are known today, and the discovery of a novel one, while important for the affected individuals and their families, is no longer exceptional. However, what this study shows for the first time is that such disease can be produced not only by changes in one of the 20,000 known genes resulting in a protein product, but by changes in elements that are distant from a gene and yet are important for their activation and regulation. The majority of such elements remain unknown, just as the lncRNA identified in this paper that resided in what was considered an “empty” stretch of DNA. Thus, while the known protein-coding genes account for only 2% of the human genome, the remaining 98% of the genome can also have consequence for human health.

The research work has been performed in close collaboration by three groups led by Professor Andrea Superti-Furga (Uni Lausanne and Centre Hospitalier Universitaire Vaudois), Professor Carlo Rivolta (University of Basel and IOB), and Professor Stefan Mundlos (Max Planck Institute and Charité University and Hospital, Berlin).

Original publication

Noncoding deletions identify Maenli IncRNA as a limb-specific En1regulator

Nature (2021). https://doi.org/10.1038/s41586-021-03208-9