NIHR Cambridge BRC researchers have been involved in a major study published this week in the American Journal of Human Genetics that shows that gene misbehaviour – where genes are active when they should be switched off – is a common phenomenon in the healthy human population. Data Science and Population Health Theme Lead Professor Michael Inouye, fellow researchers Adam Butterworth, Emanuele Di Angelantonio, John Danesh and former colleague Dirk Paul at AstraZeneca took part in the research led by the Wellcome Sanger Institute that studied the activity of inactive genes in a large, healthy population for the first time.
While gene misexpression has previously been linked to several rare diseases, it is not known how often or why this may happen in the general population – but this study showed that misexpression is widespread across samples and involved more than half of the genes that should be inactive.
The surprising finding sheds new light on how our genetic code operates – and the approach could be used in future research to investigate, diagnose and develop treatments for various complex diseases caused by misexpression.
Study author Dr Katie Burnham at the Wellcome Sanger Institute said:
“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.”
In this study, researchers analysed blood samples from 4,568 healthy individuals from the INTERVAL study 3. They used advanced RNA sequencing techniques to measure gene activity and whole genome sequencing to identify genetic changes behind irregular gene activity.
Transcript fusion and gene inversions lead to gene misexpression
(A) Schematic diagram of a deletion resulting in transcript fusion and chimeric gene misexpression. The deletion of the 3′ end of an active gene (green) and 5′ end of an inactive gene (blue) results in a fusion transcript containing portions of the active and inactive gene’s transcripts. (B) Schematic diagram of a tandem duplication resulting in transcript fusion and gene misexpression. The duplication of the 3′ end of an inactive gene (blue) and 5′ end of an active gene (green) in tandem results in a fusion transcript containing portions of the active and inactive gene’s transcripts. (C) Expression of MYH1 comparing a sample with duplication chr17:10,078,018–10,512,685 (GRCh38) to samples without this duplication. Red color indicates samples passing the misexpression threshold TPM >0.5 and Z score >2; gray samples are below this threshold. (D) FusionInspector visualization of the GAS7–MYH1 fusion transcript. Duplication chr17:10,078,018–10,512,685 (GRCh38) breakpoints are labeled in green. Introns have been shortened for visualization, and breakpoint positions have been approximated accordingly. In the sashimi plot, the line width corresponds to the number of reads spanning a given junction. The misexpressed gene and the fusion reads are highlighted in orange. (E) Expression of ROPN1B comparing samples with inversion chr3:125,966,617–125,980,782 (GRCh38) and samples without this inversion. Red color indicates samples passing the misexpression threshold TPM >0.5 and Z score >2; gray samples are below this threshold. (F) Location of inversion chr3:125,966,617–125,980,782 (GRCh38) showing all ROPN1B transcripts. The Ensembl canonical transcript is labeled with an asterisk and the major misexpressed transcript with a double asterisk. (G) Percentage expression of ROPN1B transcripts for all samples with inversion chr3:125,966,617–125,980,782 (GRCh38) compared to the average transcript percentage across 170 samples without the inversion and with non-zero transcript expression. (H) Distribution of misexpression Z scores across different types of misexpression mechanisms. Text labels indicate the number of misexpression events for each putative mechanism.
Dr. Anne Forde, Patient and Public Involvement and Engagement Manager at the Cardiovascular Epidemiology Unit, University of Cambridge, said:
“This research was based on the 50,000 population cohort recruited for INTERVAL on blood donation frequency, and we are grateful to the NIHR and the Cambridge BRC for your ongoing support and collaboration.”
Source – NIHR Cambridge Biomedical Research Centre
Vanderstichele T, Burnham KL, de Klein N, Tardaguila M, Howell B, Walter K, Kundu K, Koeppel J, Lee W, Tokolyi A, Persyn E, Nath AP, Marten J, Petrovski S, Roberts DJ, Di Angelantonio E, Danesh J, Berton A, Platt A, Butterworth AS, Soranzo N, Parts L, Inouye M, Paul DS, Davenport EE. (2024) Misexpression of inactive genes in whole blood is associated with nearby rare structural variants. Am J Hum Genet [Epub ahead of print]. [article]