RT Journal Article
SR Electronic
T1 Promoter sequence and architecture determine expression variability and confer robustness to genetic variants
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.10.29.466407
DO 10.1101/2021.10.29.466407
A1 Einarsson, Hjörleifur
A1 Salvatore, Marco
A1 Vaagensø, Christian
A1 Alcaraz, Nicolas
A1 Bornholdt, Jette
A1 Rennie, Sarah
A1 Andersson, Robin
YR 2022
UL http://biorxiv.org/content/early/2022/06/09/2021.10.29.466407.abstract
AB 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 independent transcription start site regions within a promoter.Competing Interest StatementThe authors have declared no competing interest.