Subtle Differences
New bioinformatics tools help identify pathogenic variants in the genome.
Structural variants and so-called tandem repeats are individual differences in the human genome. They are increasingly linked to diseases, but analyzing and interpreting them poses challenges for researchers. In two new studies published in the journals NAR Genomics and Bioinformatics and Genome Biology, Martin Vingron’s laboratory at the Max Planck Institute for Molecular Genetics is now presenting new bioinformatics tools. These tools are designed to help identify pathogenic structural variants and tandem repeats in the genome more easily, thereby facilitating the genetic diagnosis of many diseases.
With the help of modern sequencing methods, the causes of many diseases can be precisely located in the genome. Nevertheless, only about 30 to 40 percent of patients receive a clear molecular diagnosis. One reason for this is that, for a long time, the focus was primarily on point mutations – that is, the substitution of individual letters in the genetic sequence. Only recently have so-called structural variants and tandem repeats come to the forefront. Structural variants affect entire sections of the genome: they may be missing, duplicated, or displaced. Tandem repeats, on the other hand, are short sequences repeated many times. Both make every genome unique and are increasingly linked to diseases. “The most common approach in genetic diagnostics is short-read sequencing, which reads short stretches of DNA,” explains Nico Alavi, the first author of the study in Genome Biology. “Because structural variants are often larger than the read segments themselves, they are difficult to detect in this data.”
Computer algorithms learn variant patterns
The research group has now turned to machine learning. “The core idea is that this method allows us to learn the patterns behind real structural variants and thus correctly classify new variants,” explains Nico Alavi. This makes structural variants useful for diagnostics, as it remedies a major problem with previous methods, in which false positives often arise and must be checked manually. The researchers then tested their approach using patient data. Their tool, called “Dicast,” was able to detect all pathogenic structural variants while also filtering out a large number of false-positive artifacts.
Counting repetitive elements
A special case of the individual genome, often overlapping with structural variants, is so-called “tandem repeats.” These are genetic sequences repeated multiple times directly one after another. The number of these repeats differs greatly both among healthy individuals and in disease states. Tandem repeats therefore play an important role in paternity testing and forensics. Because of replication errors, they are also responsible for various diseases, especially neurological ones. “In the second paper, we have developed an algorithm that can quickly and precisely count, based on sequencing data, how often a basic motif is repeated. We also provide a tool that visualizes this data,” says Martin Vingron. This makes it possible to quickly identify pathological repeats in patient data, as the researchers led by first authors Lion Ward Al Raei and Maryam Ghareghani were able to demonstrate using concrete examples.
Potential for diagnostics
Both tools can already be used in basic research and in diagnostic pipelines. They can thus help researchers answer fundamental questions about the individual genome. In clinical applications they could help establish accurate diagnoses for rare diseases. Some of the researchers aim to further develop the potential of structural variants for research and medicine into concrete applications through the startup Lucid Genomics. “Current sequencing technologies, combined with our specialized analysis algorithms, promise to further improve genetic diagnostics,” says Martin Vingron, the lead author of both studies.
