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

Thomas Vanderstichele; Katie L Burnham; Niek de Klein; Manuel Tardaguila; Brittany Howell; Klaudia Walter; Kousik Kundu; Jonas Koeppel; Wanseon Lee; Alex Tokolyi; Elodie Persyn; Artika P Nath; Jonathan Marten; Slavé Petrovski; David J Roberts; Emanuele Di Angelantonio; John Danesh; Alix Berton; Adam Platt; Adam S Butterworth; Nicole Soranzo; Leopold Parts; Michael Inouye; Dirk S Paul; Emma E Davenport
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.
Journal AMERICAN JOURNAL OF HUMAN GENETICS
ISSN 1537-6605
Published 17 Jul 2024
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DOI 10.1016/j.ajhg.2024.06.017
Type Journal Article
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