'Gene misbehaviour' surprisingly common in healthy people

Researchers from the Wellcome Sanger Institute, the University of Cambridge and AstraZeneca have discovered that ‘gene misbehaviour’ — where genes are active when they were expected to be switched off — is a surprisingly common phenomenon in the healthy human population.

The team also identified several mechanisms behind these gene activity errors, which may help inform precision medicine approaches and enable the development of targeted therapies to correct expression. Their work has been published in the American Journal of Human Genetics, and could be used in future research to investigate various complex diseases.

The human genome contains about 19,900 genes. These genes form part of the instruction manual for our bodies, encoding proteins needed to carry out cell functions. Proper gene regulation involves turning these gene instructions on and off as needed, depending on a cell’s specific role or environmental factors. When this regulation fails and a typically inactive gene is activated, or ‘expressed’, it can disrupt normal cell function.

While gene misexpression has previously been linked to several rare diseases, such as congenital limb syndromes, it is not known how often or why this may happen in the general population. In this new study, researchers analysed blood samples from 4568 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.

The team found that while misexpression events were rare at the individual gene level — occurring in only 0.07% of genes — a whopping 96% of samples had some misexpression, with over half of the normally inactive genes showing misexpression. They also found these events can be caused by rare structural changes in the DNA.

While these findings show that gene misbehaviour is common, it may not always lead to health issues. This new understanding of the prevalence and mechanisms of gene misexpression provides a valuable tool for further investigation into the complexities of human genetics and disease. This could help in diagnosing and developing treatments for conditions caused by misexpression.

“Until now, we have been looking at disease risk through the lens of highly active genes,” said first author Thomas Vanderstichele, from the Wellcome Sanger Institute. “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 health care, enabling a more comprehensive understanding of all the ways our genes impact our health.”

Study author Dr Katie Burnham, also from the Wellcome Sanger Institute, added, “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.”

Senior author Dr Emma Davenport, from the Wellcome Sanger Institute, concluded, “The findings open avenues for research into gene misexpression across different tissues, to understand its role in various diseases and potential treatments.”

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