Promoter sequence and architecture determine expression variability and confer robustness to genetic variants
- University of Copenhagen, Denmark
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
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GTEx Analysis V8 (dbGaP Accession phs000424.v8.p2)dbGaP Accession phs000424.v8.p2.
Article and author information
Author details
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.
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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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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