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A recent study by researchers from the Wellcome Sanger Institute, the University of Cambridge, and AstraZeneca has discovered that 'gene misbehavior'—where genes are active when they are expected to be switched off—is a surprisingly common phenomenon in the healthy human population. This finding has significant implications for understanding gene regulation and developing targeted therapies in precision medicine.
The research, published in the American Journal of Human Genetics, focused on analyzing the activity of normally inactive genes in a large cohort of healthy individuals. Using advanced RNA sequencing techniques to measure gene activity and whole genome sequencing to identify genetic changes, the team studied blood samples from 4,568 participants in the INTERVAL study.
They found that while misexpression events were rare at the individual gene level—occurring in only 0.07% of genes—almost all samples (96%) exhibited some level of misexpression. Notably, over half of the genes that should have been inactive showed some degree of misexpression.
Mechanisms Behind Gene Misexpression
The study identified several mechanisms that might contribute to these gene activity errors, including rare structural changes in DNA. Thomas Vanderstichele, the first author of the study at the Wellcome Sanger Institute, remarked, "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."
Gene regulation is a critical process where genes are turned on and off based on a cell’s role or environmental factors. When this regulation fails and typically inactive genes are expressed, it can disrupt normal cell functions. While gene misexpression has been linked to rare diseases like congenital limb syndromes, this study provides new insights into its prevalence in the general population.
Implications for Precision Medicine
The discovery that gene misbehavior is widespread yet may not always lead to health issues provides a valuable tool for further investigation into human genetics and disease. Dr. Katie Burnham from the Wellcome Sanger Institute commented, "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 team's findings suggest that gene misexpression could inform precision medicine approaches and enable the development of therapies to correct gene expression errors. Dr. Emma
Davenport, senior author of the study, highlighted the collaborative effort: "The work of this 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.
The research, published in the American Journal of Human Genetics, focused on analyzing the activity of normally inactive genes in a large cohort of healthy individuals. Using advanced RNA sequencing techniques to measure gene activity and whole genome sequencing to identify genetic changes, the team studied blood samples from 4,568 participants in the INTERVAL study.
They found that while misexpression events were rare at the individual gene level—occurring in only 0.07% of genes—almost all samples (96%) exhibited some level of misexpression. Notably, over half of the genes that should have been inactive showed some degree of misexpression.
Mechanisms Behind Gene Misexpression
The study identified several mechanisms that might contribute to these gene activity errors, including rare structural changes in DNA. Thomas Vanderstichele, the first author of the study at the Wellcome Sanger Institute, remarked, "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."
Gene regulation is a critical process where genes are turned on and off based on a cell’s role or environmental factors. When this regulation fails and typically inactive genes are expressed, it can disrupt normal cell functions. While gene misexpression has been linked to rare diseases like congenital limb syndromes, this study provides new insights into its prevalence in the general population.
Implications for Precision Medicine
The discovery that gene misbehavior is widespread yet may not always lead to health issues provides a valuable tool for further investigation into human genetics and disease. Dr. Katie Burnham from the Wellcome Sanger Institute commented, "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 team's findings suggest that gene misexpression could inform precision medicine approaches and enable the development of therapies to correct gene expression errors. Dr. Emma
Davenport, senior author of the study, highlighted the collaborative effort: "The work of this 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.