New Insights into the Mechanisms of Gene Misbehavior

Researchers have discovered that a startlingly widespread occurrence in the healthy human population is "gene misbehavior," or the state in which genes are active when they should be inactive.

The group also pinpoints a number of mechanisms underlying these errors in gene activity. This could facilitate the development of targeted therapies to correct expression and help inform precision medicine approaches.

For the first time, scientists from AstraZeneca, the University of Cambridge, and the Wellcome Sanger Institute examined the activity of dormant genes in a sizable, healthy population. Even though they are uncommon at the individual gene level, they showed that misexpression affects over half of the genes that should be dormant in samples.

The research provides fresh insight into the workings of the genetic code and was published, in the American Journal of Human Genetics. The methodology may be applied to the study of different complex diseases in the future.

There are roughly 19,900 genes in the human genome. These genes encode the proteins required for cells to function, acting as a portion of the human body's instruction manual. Turning these gene instructions on and off in accordance with the particular function of a cell or external circumstances is part of proper gene regulation. Normal cell function can be disrupted when this regulation breaks down and a normally inactive gene becomes activated, or “expressed.”

Although gene misexpression has been connected in the past to a number of uncommon illnesses, including congenital limb syndromes, it is unknown how frequently or why this might occur in the general population.

Researchers examined blood samples from 4,568 healthy participants in the INTERVAL study for this new investigation. The researchers employed whole genome sequencing to find the genetic alterations underlying erratic gene activity and sophisticated RNA sequencing techniques to quantify gene activity.

The scientists discovered that although misexpression events were uncommon at the individual gene level (occurring in only 0.07 % of genes), misexpression was present in nearly all samples (96%), with over half of the normally dormant genes exhibiting misexpression. Also, the scientists discovered that infrequent structural alterations in DNA can be the source of these occurrences.

Although these results demonstrate the prevalence of gene misbehavior, health problems may not always result from it. Further exploration into the intricacies of human genetics and disease is made possible by this enhanced comprehension of the frequency and mechanisms of gene misexpression. This could be useful in the diagnosis and treatment of disorders brought on by misinterpretation.

Until now, we have been looking at disease risk through the lens of highly active genes. Our study reveals ‘unusual’ gene activity is far more usual than previously thought and we need to consider the full picture, including genes that shouldn’t be active but sometimes are. This is a big step towards more personalized healthcare, enabling a more comprehensive understanding of all the ways our genes impact our health.”

Thomas Vanderstichele, Study First Author, Wellcome Sanger Institute

Dr. Katie Burnham, Study Author, Wellcome Sanger Institute said, “Interestingly, while over half of genes occasionally misexpress, we find certain critical genes, particularly those governing development, rarely make such mistakes. This suggests that when these essential genes do misexpress, the consequences for health and disease are likely to be more severe.”

The work of this pioneering large-scale study is testament to the incredible ‘genomics ecosystem’ in Cambridge that brought together experts from the Sanger Institute, the University of Cambridge, and AstraZeneca. The findings open avenues for research into gene misexpression across different tissues, to understand its role in various diseases and potential treatments.”

Dr. Emma Davenport, Study Senior Author, Wellcome Sanger Institute