Promoter sequence and architecture determine expression variability and confer robustness to genetic variants

Abstract

Genetic and environmental exposures cause variability in gene expression. Although most genes are affected in a population, their effect sizes vary greatly, indicating the existence of regulatory mechanisms that could amplify or attenuate expression variability. Here, we investigate the relationship between the sequence and transcription start site architectures of promoters and their expression variability across human individuals. We find that expression variability can be largely explained by a promoter's DNA sequence and its binding sites for specific transcription factors. We show that promoter expression variability reflects the biological process of a gene, demonstrating a selective trade-off between stability for metabolic genes and plasticity for responsive genes and those involved in signaling. Promoters with a rigid transcription start site architecture are more prone to have variable expression and to be associated with genetic variants with large effect sizes, while a flexible usage of transcription start sites within a promoter attenuates expression variability and limits genotypic effects. Our work provides insights into the variable nature of responsive genes and reveals a novel mechanism for supplying transcriptional and mutational robustness to essential genes through multiple transcription start site regions within a promoter.

Data availability

Sequencing data have been deposited into the GEO database: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE188131

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Hjorleifur Einarsson

    Department of Biology, University of Copenhagen, Copenhagen N, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  2. Marco Salvatore

    Department of Biology, University of Copenhagen, Copenhagen N, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  3. Christian Vaagenso

    Department of Biology, University of Copenhagen, Copenhagen N, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  4. Nicolas Alcaraz

    Department of Biology, University of Copenhagen, Copenhagen N, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  5. Jette Bornholdt Lange

    Department of Biology, University of Copenhagen, Copenhagen N, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  6. Sarah Rennie

    Department of Biology, University of Copenhagen, Copenhagen N, Denmark
    Competing interests
    The authors declare that no competing interests exist.
  7. Robin Andersson

    Department of Biology, University of Copenhagen, Copenhagen N, Denmark
    For correspondence
    robin@binf.ku.dk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1516-879X

Funding

Danmarks Frie Forskningsfond (6108-00038)

  • Robin Andersson

European Research Council (638173)

  • Robin Andersson

Novo Nordisk Fonden (NNF18OC0052570)

  • Robin Andersson

Novo Nordisk Fonden (NNF20OC0059796)

  • Robin Andersson

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Eduardo Eyras, Australian National University, Australia

Publication history

  1. Received: June 10, 2022
  2. Accepted: November 14, 2022
  3. Accepted Manuscript published: November 15, 2022 (version 1)

Copyright

© 2022, Einarsson et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Hjorleifur Einarsson
  2. Marco Salvatore
  3. Christian Vaagenso
  4. Nicolas Alcaraz
  5. Jette Bornholdt Lange
  6. Sarah Rennie
  7. Robin Andersson
(2022)
Promoter sequence and architecture determine expression variability and confer robustness to genetic variants
eLife 11:e80943.
https://doi.org/10.7554/eLife.80943
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