One mutation can counterbalance another

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A deleterious mutation, represented here by a break in a biological process (ora
A deleterious mutation, represented here by a break in a biological process (orange), can be compensated for and thus rescued by a mutation called a "suppressor" (pink). ©

In most diseases caused by a single gene, the deleterious mutation could be corrected by another mutation, called a "genetic suppressor". This is what researchers at the University of Lausanne, led by Jolanda van Leeuwen, have discovered, opening up potential new therapeutic avenues.

Genetic mutations are constantly appearing in the DNA of our cells. In humans, the mutation rate is less than 1%, but never reaches zero. These mutations do not necessarily have pathological consequences, but they can have deleterious effects on the functioning of our genes, leading in some cases to the development of disease.

However, Nature has a way of doing things: mutations, known as ’genetic suppressors’, can compensate for the damaging effect of the former. This is well known for certain genetic diseases, such as sickle-cell anemia (a blood disorder) and cystic fibrosis (a disorder of the respiratory and digestive tracts). But what about other pathologies? The team led by Jolanda van Leeuwen, Assistant Professor at the Centre intégratif de génomique in the Faculty of Biology and Medicine at the University of Lausanne, has answered this question in collaboration with a research group from Barcelona, Spain. Their results were published on October 12, 2023 in Genome Medicine.

The researchers systematically investigated genetic suppressors. Specific keywords were submitted to various databases, where 2,400 scientific articles were found and examined. Nearly 500 of these referenced cases of human genetic diseases for which suppressors were identified. Half of the 1,000 interactions identified were unique, with the vast majority involving a single suppressor gene linked to a single deleterious mutation. This selection of biomedical literature dealt exclusively with the human species, with more than 60% of the articles based on human cell cultures, and almost 40% on in vivo patient studies.

Furthermore, at the level of cross-species comparison, the scientists detected high conservation of suppressor genes, testifying to their importance for cell survival and good health.

From yeast to human beings

In a previous publication by Jolanda van Leeuwen’s research group in May 2021 (see news ), the mechanisms behind the protective role of suppressors were described in yeast. Their new data set enabled them to confirm that the same processes were at work in humans. Two categories were highlighted. On the one hand, the action can be direct, in which case the defect introduced by the mutation is directly corrected", explains Betül Ünlü , co-first author and former post-doctoral fellow in Jolanda van Leeuwen’s laboratory. Sickle cell anemia, for example, affects red blood cells and is characterized by a mutation in hemoglobin, which can no longer transport oxygen normally in the blood. A suppressor is capable of countering this dysfunction by replacing the abnormal part of the hemoglobin with a functional one. On the other hand, the mechanism can be indirect, i.e. by targeting biological pathways other than the one directly affected by the mutation", adds Betül Ünlü. Cystic fibrosis, characterized by defective respiratory and digestive mucus, is a good example of this second class. At the origin of this defect, mutations in a receptor responsible for transporting chlorine across cell membranes cause its degradation. In this example of an indirect process, the suppressor gene prevents the receptor from being degraded.

Compared with yeast, the study in Genome Medicine shows that the frequency and diversity of indirect mechanisms were higher in humans. This is undoubtedly due to the greater complexity of our organism, and in particular to the existence of our immune system, which yeasts do not possess", adds Jolanda van Leeuwen, last author of the article.

Fromin silico to in vitro, from the computer to the laboratory bench

Using mathematical models applied to the entire human genome, biologists from Lausanne and Barcelona have succeeded in predicting suppressors for other monogenic pathologies (due to a single gene), such as Fanconi anemia, a rare genetic disorder that affects DNA repair and is characterized by an increased risk of developing cancer.

Next, the putative suppressors were investigated through laboratory experiments. I mutated a gene associated with Fanconi anemia in a cell line. Then I analyzed its effect in pairs with over 18,000 other mutated genes. I found three that succeeded in rescuing the cells and that had been predicted by bioinformatics", explains Amandine Batté , postdoctoral fellow in Jolanda van Leeuwen’s research group.

To improve mathematical models, more examples of genetic suppressors are needed. Several of the University of Lausanne team’s projects are already focusing on this line of research. Finally, the results of the recently published article suggest that there may be saviour mutations for almost all known genetic diseases. This exhaustive knowledge could help us to better understand the processes responsible for each of these pathologies. The identification of these suppressors opens the way to potential new therapeutic avenues", hopes Jolanda van Leeuwen.