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

Affiliations
  • 1Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
  • 2Human Technopole, Fondazione Human Technopole, Milan, Italy.
  • 3Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK; Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Puddicombe Way, Cambridge, UK.
  • 4British 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.
  • 5Cambridge 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.
  • 6British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  • 7Radcliffe Department of Medicine, John Radcliffe Hospital, Oxford, UK; Clinical Services, NHS Blood and Transplant, Oxford Centre, John Radcliffe Hospital, Oxford, UK.
  • 8Human 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.
  • 9Wellcome 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.
  • 10Translational Science and Experimental Medicine, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Molndal, Sweden.
  • 11Translational Science and Experimental Medicine, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
  • 12Wellcome 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.
  • 13Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK. Electronic address: ed5@sanger.ac.uk.

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July 25, 2024

Abstract

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.

Keywords:

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