‘Gene misbehaviour’ is surprisingly common in healthy people, Cambridge scientists find

‘Gene misbehaviour’, where genes are active when they were expected to be switched off, is surprisingly common in the healthy human population, scientists have found.

Several mechanisms behind these gene activity errors have also been identified, which may help to guide new precision medicine approaches, or enable the development of targeted therapies to correct gene expression.

The human genome contain about 19,900 genes, which form a key part of the instruction manual for our bodies by encoding the proteins that carry out cell functions.

Gene regulation turns these gene instructions on and off as needed, depending on the specific role of a cell, or environmental factors.

But when the regulation fails and a typically inactive gene is activated, or ‘expressed’, it can disrupt normal cell function.

For the first time, researchers from the Wellcome Sanger Institute, the University of Cambridge and AstraZeneca have now studied the activity of inactive genes in a large, healthy population. They analysed blood samples from 4,568 healthy individuals from the INTERVAL study, using advanced RNA sequencing techniques to measure gene activity and whole genome sequencing to identify genetic changes behind irregular gene activity.

They found that misexpression is rare at the individual gene level, occurring in only 0.07 per cent of genes, but it occurred in 96 per cent of samples - and involves more than half of the genes that should be inactive. They found these events can be caused by rare structural changes in the DNA

While misexpressions has previously been linked to several rare diseases, such as congenital limb syndromes, it is not known how often or why it happens in the general population.

However, while gene misbehaviour is common, it does not always lead to health issues.

Thomas Vanderstichele, first author of the study at the Wellcome Sanger Institute, said: “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 personalised healthcare, enabling a more comprehensive understanding of all the ways our genes impact our health.”

The findings were published last week in the American Journal of Human Genetics and could be used to investigate complex diseases.

Dr Katie Burnham, author of the study at the 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.”

Dr Emma Davenport, senior author of the study at the Wellcome Sanger Institute, added: “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.”