Misexpression of inactive genes in whole blood is associated with nearby rare structural variants.

aberrant expression ectopic expression misexpression structural variants transcript fusion transcriptional readthrough transcriptomic outlier

Journal

American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475

Informations de publication

Date de publication:
17 Jul 2024
Historique:
received: 12 01 2024
revised: 27 06 2024
accepted: 27 06 2024
medline: 26 7 2024
pubmed: 26 7 2024
entrez: 25 7 2024
Statut: aheadofprint

Résumé

Gene misexpression is the aberrant transcription of a gene in a context where it is usually inactive. Despite its known pathological consequences in specific rare diseases, we have a limited understanding of its wider prevalence and mechanisms in humans. To address this, we analyzed gene misexpression in 4,568 whole-blood bulk RNA sequencing samples from INTERVAL study blood donors. We found that while individual misexpression events occur rarely, in aggregate they were found in almost all samples and a third of inactive protein-coding genes. Using 2,821 paired whole-genome and RNA sequencing samples, we identified that misexpression events are enriched in cis for rare structural variants. We established putative mechanisms through which a subset of SVs lead to gene misexpression, including transcriptional readthrough, transcript fusions, and gene inversion. Overall, we develop misexpression as a type of transcriptomic outlier analysis and extend our understanding of the variety of mechanisms by which genetic variants can influence gene expression.

Identifiants

DOI: 10.1016/j.ajhg.2024.06.017 PMID: 39053458
pubmed: 39053458
pii: S0002-9297(24)00223-4
doi: 10.1016/j.ajhg.2024.06.017
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests The authors declare the following interests: T.V. has received PhD studentship funding from AstraZeneca. J.M. completed this work while employed by the University of Cambridge but is now an employee of Genomics plc. S.P. is a current employee and stockholder of AstraZeneca. D.J.R. is an employee of NHS Blood and Transplant. A.B. is currently an employee of Bayer AG, Research and Early Development Precision Medicine, Research & Development, Pharmaceutical Division, Wuppertal, DE. A.P. is a current employee and stockholder of AstraZeneca. D.S.P. is a current employee and stockholder of AstraZeneca. K.K. is a current employee and stockholder of AstraZeneca. J.D. serves on scientific advisory boards for AstraZeneca, Novartis, and UK Biobank and has received multiple grants from academic, charitable, and industry sources outside of the submitted work. M.I. is a trustee of the Public Health Genomics (PHG) Foundation, is a member of the Scientific Advisory Board of Open Targets, and has a research collaboration with AstraZeneca, which is unrelated to this study.

Auteurs

Thomas Vanderstichele (T)

Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.

Katie L Burnham (KL)

Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.

Niek de Klein (N)

Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.

Manuel Tardaguila (M)

Human Technopole, Fondazione Human Technopole, Milan, Italy.

Brittany Howell (B)

Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.

Klaudia Walter (K)

Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.

Kousik Kundu (K)

Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Puddicombe Way, Cambridge, UK.

Jonas Koeppel (J)

Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.

Wanseon Lee (W)

Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.

Alex Tokolyi (A)

Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.

Elodie Persyn (E)

British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK; Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, UK; Cambridge Baker Systems Genomics Initiative, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

Artika P Nath (AP)

Cambridge Baker Systems Genomics Initiative, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK; Cambridge Baker Systems Genomics Initiative, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.

Jonathan Marten (J)

British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

Slavé Petrovski (S)

Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK; Department of Medicine, University of Melbourne, Austin Health, Melbourne, VIC, Australia.

David J Roberts (DJ)

Radcliffe Department of Medicine, John Radcliffe Hospital, Oxford, UK; Clinical Services, NHS Blood and Transplant, Oxford Centre, John Radcliffe Hospital, Oxford, UK.

Emanuele Di Angelantonio (E)

Human Technopole, Fondazione Human Technopole, Milan, Italy; British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK; Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, UK; British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK; National Institute for Health and Care Research Blood and Transplant Research Unit in Donor Health and Behaviour, University of Cambridge, Cambridge, UK; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK.

John Danesh (J)

Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK; British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK; Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, UK; British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK; National Institute for Health and Care Research Blood and Transplant Research Unit in Donor Health and Behaviour, University of Cambridge, Cambridge, UK; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK.

Alix Berton (A)

Translational Science and Experimental Medicine, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Molndal, Sweden.

Adam Platt (A)

Translational Science and Experimental Medicine, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.

Adam S Butterworth (AS)

British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK; Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, UK; British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK; National Institute for Health and Care Research Blood and Transplant Research Unit in Donor Health and Behaviour, University of Cambridge, Cambridge, UK; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK.

Nicole Soranzo (N)

Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK; Human Technopole, Fondazione Human Technopole, Milan, Italy; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Puddicombe Way, Cambridge, UK; British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK; National Institute for Health and Care Research Blood and Transplant Research Unit in Donor Health and Behaviour, University of Cambridge, Cambridge, UK.

Leopold Parts (L)

Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.

Michael Inouye (M)

British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK; Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, UK; Cambridge Baker Systems Genomics Initiative, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK; Cambridge Baker Systems Genomics Initiative, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia; British Heart Foundation Centre of Research Excellence, University of Cambridge, Cambridge, UK; Health Data Research UK Cambridge, Wellcome Genome Campus and University of Cambridge, Cambridge, UK.

Dirk S Paul (DS)

British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK; Victor Phillip Dahdaleh Heart and Lung Research Institute, University of Cambridge, Cambridge, UK; Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.

Emma E Davenport (EE)

Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK. Electronic address: ed5@sanger.ac.uk.

Classifications MeSH