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

Autor:	Vanderstichele T; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK., Burnham KL; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK., de Klein N; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK., Tardaguila M; Human Technopole, Fondazione Human Technopole, Milan, Italy., Howell B; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK., Walter K; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK., Kundu K; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Puddicombe Way, Cambridge, UK., Koeppel J; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK., Lee W; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK., Tokolyi A; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK., 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., 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., Marten J; British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK., 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., Roberts DJ; Radcliffe Department of Medicine, John Radcliffe Hospital, Oxford, UK; Clinical Services, NHS Blood and Transplant, Oxford Centre, John Radcliffe Hospital, Oxford, UK., 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., 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., Berton A; Translational Science and Experimental Medicine, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Molndal, Sweden., Platt A; Translational Science and Experimental Medicine, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., 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., 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., Parts L; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK., 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., 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., Davenport EE; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK. Electronic address: ed5@sanger.ac.uk.
Jazyk:	angličtina
Zdroj:	American journal of human genetics [Am J Hum Genet] 2024 Aug 08; Vol. 111 (8), pp. 1524-1543. Date of Electronic Publication: 2024 Jul 24.
DOI:	10.1016/j.ajhg.2024.06.017
Abstrakt:	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. Competing Interests: 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. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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