The Chameleolyser method that Steyaert developed together with Gilissen not only detects gene and pseudogene combinations in the existing exome sequencing data. The method can also visualize the genetic variations between the two. “We are now picking up a lot of genetic variation that was previously invisible. We find approximately sixty extra genetic variants per exome with the Chameleolyser method. For a number of people, we were able to definitively determine the cause of their illness with this data. With a new sequencing technique from PacBio, which analyzes longer stretches of DNA, we have established the reliability of the Chameleolyser method,” explains Wouter Steyaert.
Exome sequencing has been used by scientists for ten to fifteen years to map the genes of individual patients with rare diseases. This technique cuts the approximately 20,000 human genes into small pieces, so that the letters of the DNA can be read. This creates a huge mountain of small DNA fragments. These can then be put together like a jigsaw puzzle to form entire genes. The result is an overview of the 20,000 genes of that one person.
However, because our genome, hereditary material, evolves, that overview is never completely complete. Copying DNA does not always go well. Sometimes pieces of DNA disappear and in other cases pieces are added again. Some parts are also copied more often and it sometimes happens that a copied gene is placed somewhere else in the genome. This creates a so-called pseudogene in addition to the original gene. “These genetic ‘sloppiness’ are of great importance, because they are the driving force behind evolution. This is how genetic changes arise. Changes that can be without effect or beneficial, but sometimes also cause new diseases,” says Christian Gilissen, professor of Genome Bioinformatics.
These pseudogenes, unlike the good genes, usually have no function. Ultimately, mutations can arise in both the gene and the pseudogene. Because the gene and pseudogene are largely identical, it cannot be determined during sequencing what belongs to the gene and what belongs to the pseudogene. “For that reason, those DNA areas are not included in the analysis. A mutation found may come from the pseudogene and have no significance. If you add that mutation to the normal gene, you would make an incorrect diagnosis. We don’t want that,” Gilissen said.
The Chameleolyser method that Steyaert and Gilissen developed can be applied to existing exome sequencing data. This means that patients need to be re-examined. The method can therefore be used by any sequencing center in the world. “Such a large-scale analysis can also provide new biological insights. For many conditions, the genetic cause can only be determined in half of the patients. We think that we will also find new disease genes in those gene-pseudogene combinations. For some of these patients, this may be the genetic cause of their condition,” Gilissen concludes. The full publication of the Chameleolyser method can be found in Nature Communications.
A lot of research is being done worldwide into DNA and (abnormalities in) genes that may contribute to the development of known or unknown diseases. For example, researchers from UNC Utrecht within the International League Against Epilepsy (ILAE) partnership recently announced that they have discovered specific changes in our DNA that can increase the risk of developing epilepsy.
In addition, research has already been conducted into the added value of tailoring medication based on DNA for the treatment of various diseases. One of these studies, conducted under the leadership of the Leiden University Medical Center (LUMC), showed that medication whose dosage is tailored to the patient’s DNA leads to 30% fewer serious side effects.