Gene misexpression is common in healthy people

New ways in which genes can be misexpressed have been uncovered in healthy patients, offering opportunities to study and treat complex diseases.

Using blood samples from over 4000 healthy individuals, researchers from the Wellcome Sanger Institute, the University of Cambridge, and AstraZeneca demonstrated how some genes can remain active despite appearing to be switched off. While this is rare at the level of individual genes, misexpression was still observed in the vast majority of samples, as well as in over half of normally inactive genes. These results could shed light on mechanisms behind complex disorders.

'Until now, we have been looking at disease risk through the lens of highly active genes' said Thomas Vanderstichele, the PhD student who was first author of the study. '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.'

Proper regulation of gene expression is essential to enable our cells to carry out the processes they are supposed to. Given the range of functions required of various cells, genes must be turned off and on depending on the cells' roles, with misexpression of genes causing abnormal cell activity.

Gene misexpression has been previously implicated in cancer, as well as in rare diseases including congenital limb malformations and hyperinsulinism. However, the roles of gene misexpression in these diseases focussed on specific disease-related regions, and did not consider whether this was a feature in the broader population.

Using transcriptomic data from samples from the INTERVAL study, a cohort of 50,000 blood donors, the researchers mapped out the range and features of gene misexpression in healthy blood. Importantly, they also showed where gene misexpression could be tolerated.

'Interestingly, while over half of genes occasionally misexpress, we find certain critical genes, particularly those governing development, rarely make such mistakes', said Dr Katie Burnham, who also contributed to the study. 'This suggests that when these essential genes do misexpress, the consequences for health and disease are likely to be more severe.'

Additionally, the authors provided potential mechanisms which could explain the sources of gene misexpression. Using matched genomic data, they found that misexpression was often associated with rare alterations in the structure of DNA, which would lead to its irregular transcription.

Results were published in the American Journal of Human Genetics.