Disease-causing mutations cluster in specific genes
Some variants in human genes have no consequences – they are benign, while others cause disease – they are pathogenic and are called mutations. A team led by Carlo Rivolta, Head of our Ophthalmic Genetics Group, in collaboration with the teams of Andrea Superti-Furga (Lausanne University Hospital) and David Cooper (Cardiff University, UK), studied the distribution of all known pathogenic and benign variants in human genes. They found that mutations tend to cluster in specific areas, while benign variants are clustered in different regions or not at all. In other words: certain regions within a gene are more susceptible to be associated with disease, while others are not.
Important practical application – free download available
The finding allows scientists to describe the pathologic anatomy of the human genome far more precisely: from chromosomes to individual genes to specific regions within a gene. Adding the new «positional» information to already existing diagnostic algorithms makes them far more precise, the researchers in Basel have proven.
Their novel prediction software, based on artificial intelligence and called «MutScore», is freely available for non-commercial use on a website https://iob-genetic.shinyapps.io/mutscore/. The work of this team of scientists was published in February 2022 in the American Journal of Human Genetics and marks both a significant advance in human genetics and a contribution to better and more precise diagnostics of genetic diseases.
Some historical background
The discovery of the correct number of chromosomes in humans (23 pairs) in 1957 was the first step to the understanding of the human genome. Since then, the 25'000 genes in every human being have been «mapped» to their precise position on these chromosomes. In 1980, Victor McKusick, considered the founder of modern medical genetics, first defined the human genome as an «organ» with its specific pathology, says Prof. Superti-Furga.
Today’s most used diagnostic sequencing method, the so-called Next Generation Sequencing, often uncovers genetic variants that are neither clearly pathogenic nor clearly benign. They are then called «variants of uncertain significance» (VUS) and represent one of the major hurdles for precise genetic diagnosis. MutScore is particularly efficient in reclassifying VUS either as mutations or innocuous DNA variants, says Dr. Quinodoz, leading scientist of this study, and we hope it will concretely help physicians and scientists around the world.
Original publication
Analysis of missense variants in the human genome reveals widespread gene-specific clustering and improves prediction of pathogenicity
Mathieu Quinodoz, Virginie Peter, […], Andrea Superti-Furga, Carlo Rivolta
American Journal of Human Genetics AJHG, February 2022