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

doi:10.1016/j.ajhg.2024.06.017

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. ButterworthNicole Soranzo, Leopold Parts, Michael Inouye, Dirk S. Paul, Emma E. Davenport^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	1524-1543
Number of pages	20
Journal	American Journal of Human Genetics
Volume	111
Issue number	8
DOIs	https://doi.org/10.1016/j.ajhg.2024.06.017
Publication status	Published - 8 Aug 2024
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2024 The Authors

Keywords

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

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10.1016/j.ajhg.2024.06.017

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Vanderstichele, T., Burnham, K. L., de Klein, N., Tardaguila, M., Howell, B., Walter, K., Kundu, K., Koeppel, J., Lee, W., Tokolyi, A., Persyn, E., Nath, A. P., Marten, J., Petrovski, S., Roberts, D. J., Di Angelantonio, E., Danesh, J., Berton, A., Platt, A., ... Davenport, E. E. (2024). Misexpression of inactive genes in whole blood is associated with nearby rare structural variants. American Journal of Human Genetics, 111(8), 1524-1543. https://doi.org/10.1016/j.ajhg.2024.06.017

@article{565445566dce440b87483a7c97ba0565,

title = "Misexpression of inactive genes in whole blood is associated with nearby rare structural variants",

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

author = "Thomas Vanderstichele and Burnham, {Katie L.} and {de Klein}, Niek and Manuel Tardaguila and Brittany Howell and Klaudia Walter and Kousik Kundu and Jonas Koeppel and Wanseon Lee and Alex Tokolyi and Elodie Persyn and Nath, {Artika P.} and Jonathan Marten and Slav{\'e} Petrovski and Roberts, {David J.} and {Di Angelantonio}, Emanuele and John Danesh and Alix Berton and Adam Platt and Butterworth, {Adam S.} and Nicole Soranzo and Leopold Parts and Michael Inouye and Paul, {Dirk S.} and Davenport, {Emma E.}",

note = "Publisher Copyright: {\textcopyright} 2024 The Authors",

year = "2024",

month = aug,

day = "8",

doi = "10.1016/j.ajhg.2024.06.017",

language = "English",

volume = "111",

pages = "1524--1543",

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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', American Journal of Human Genetics, vol. 111, no. 8, pp. 1524-1543. https://doi.org/10.1016/j.ajhg.2024.06.017

TY - JOUR

T1 - Misexpression of inactive genes in whole blood is associated with nearby rare structural variants

AU - Vanderstichele, Thomas

AU - Burnham, Katie L.

AU - de Klein, Niek

AU - Tardaguila, Manuel

AU - Howell, Brittany

AU - Walter, Klaudia

AU - Kundu, Kousik

AU - Koeppel, Jonas

AU - Lee, Wanseon

AU - Tokolyi, Alex

AU - Persyn, Elodie

AU - Nath, Artika P.

AU - Marten, Jonathan

AU - Petrovski, Slavé

AU - Roberts, David J.

AU - Di Angelantonio, Emanuele

AU - Danesh, John

AU - Berton, Alix

AU - Platt, Adam

AU - Butterworth, Adam S.

AU - Soranzo, Nicole

AU - Parts, Leopold

AU - Inouye, Michael

AU - Paul, Dirk S.

AU - Davenport, Emma E.

PY - 2024/8/8

Y1 - 2024/8/8

N2 - 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.

AB - 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.

KW - aberrant expression

KW - ectopic expression

KW - misexpression

KW - structural variants

KW - transcript fusion

KW - transcriptional readthrough

KW - transcriptomic outlier

UR - http://www.scopus.com/inward/record.url?scp=85200219230&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2024.06.017

DO - 10.1016/j.ajhg.2024.06.017

M3 - Article

C2 - 39053458

AN - SCOPUS:85200219230

SN - 0002-9297

VL - 111

SP - 1524

EP - 1543

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 8

ER -

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

Abstract

Bibliographical note

Keywords

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