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

Abstract
Data availability
Article and author information
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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

1. Einarsson H
2. et al
(2021) Promoter sequence and architecture determine expression variability and confer robustness of genetic variation
NCBI Gene Expression Omnibus, GSE188131.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE188131

The following previously published data sets were used

1. Osorio D
2. Yu X
3. Yu P
4. Serpedin E
5. Cai JJ
(2019) Single-cell RNA sequencing of lymphoblastoid cell lines of European and African ancestries
NCBI Gene Expression Omnibus, GSE126321.

https://cdn.elifesciences.org/articles/80943/ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE126321
1. Collado-Torres L
2. Nellore A
3. Kammers K
4. Ellis SE
5. Taub MA
6. Hansen KD
7. Jaffe AE
8. Langmead B
9. Leek JT
(2017) Reproducible RNA-seq analysis using recount2
ERP001942.

https://jhubiostatistics.shinyapps.io/recount/
1. GTEx Consortium
(2017) GTEx Analysis V8 (dbGaP Accession phs000424.v8.p2)
dbGaP Accession phs000424.v8.p2.

https://www.gtexportal.org/home/datasets

Article and author information

Author details

Hjorleifur Einarsson

Department of Biology, University of Copenhagen, Copenhagen N, Denmark

Competing interests
The authors declare that no competing interests exist.
Marco Salvatore

Department of Biology, University of Copenhagen, Copenhagen N, Denmark

Competing interests
The authors declare that no competing interests exist.
Christian Vaagenso

Department of Biology, University of Copenhagen, Copenhagen N, Denmark

Competing interests
The authors declare that no competing interests exist.
Nicolas Alcaraz

Department of Biology, University of Copenhagen, Copenhagen N, Denmark

Competing interests
The authors declare that no competing interests exist.
Jette Bornholdt Lange

Department of Biology, University of Copenhagen, Copenhagen N, Denmark

Competing interests
The authors declare that no competing interests exist.
Sarah Rennie

Department of Biology, University of Copenhagen, Copenhagen N, Denmark

Competing interests
The authors declare that no competing interests exist.
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.

"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.

Copyright

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.