Changes in DNA interfere with team play in cells

Some pathological changes in DNA do not cause proteins themselves to change, but prompt a change in the way they interact with other proteins. This is the conclusion drawn by geneticists working in the Department of Genetics, University Medical Center Groningen. Their findings are published in the April 3rd edition of the renowned scientific journal Nature Genetics.

Every cell is a tiny factory in which various proteins work together as a close team. The information needed to produce these proteins is stored in the genes of our DNA. It has already been established that errors in the DNA can cause a change in gene activity, resulting in damaged proteins and ultimately causing disease. Geneticist Lude Franke: ‘Proteins work together in various teams, to control the energy metabolism, for example, or to ensure that cells can divide efficiently. Team play is essential: when a cell divides, specific proteins have to be present at exactly the right moment to act together. We know for certain diseases that a genetic defect disrupts the function of one of these proteins, causing the disease to develop, but surprisingly, we have now seen that some genetic defects alter the interaction between the proteins.’

Interactio​​​n between genes

Using single-cell RNA-sequencing, the researchers studied genetic changes in 45 healthy subjects from the Lifelines biobank to see how these changes affected the interaction between the genes. Using this new technology, the researchers were able to examine the gene activity of about 700 cells for each of the 45 test subjects, thereby allowing the identification of pairs of genes working together in each individual. They discovered that certain changes in the DNA actually reinforced the interaction between genes.

Disease caused by genetic risk factors

The researchers hope that in the coming years this technique will help us to understand why certain genetic risk factors lead to particular diseases. Geneticist Monique van der Wijst: ‘This approach will enable us to study the effect of DNA changes known to increase the risk of diabetes, for example, on the interaction between genes. For the majority of changes in the DNA, we have no idea why they contribute to disease development. By studying not only individual genes, but entire teams of genes, we hope to gain a better understanding of how changes in the DNA lead to diseases. Possibly, many of these genetic changes act by altering the interactions between and within these teams. This information could provide vital clues in discovering why drugs work well for some people, but not for others. It might be because the proteins in some people’s cells work together, whereas those in other people’s cells do not.’

Single-cell RNA sequencing identifies celltype-specific cis-eQTLs and co-expression QTLs
Monique G. P. van der Wijst, Harm Brugge, Dylan H. de Vries, Patrick Deelen, Morris A. Swertz, ifeLines Cohort Study, BIOS Consortium & Lude Franke
Nature Genetics 50:493–497 (2018) doi:10.1038/s41588-018-0089-9​