Promoter sequence and architecture determine expression variability and confer robustness to genetic variants
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Promoter sequence and architecture determine expression variability and confer robustness to genetic variants. / Einarsson, Hjorleifur; Salvatore, Marco; Vaagenso, Christian; Alcaraz, Nicolas; Lange, Jette Bornholdt; Rennie, Sarah; Andersson, Robin.
In: eLife, Vol. 2022, 2022.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Promoter sequence and architecture determine expression variability and confer robustness to genetic variants
AU - Einarsson, Hjorleifur
AU - Salvatore, Marco
AU - Vaagenso, Christian
AU - Alcaraz, Nicolas
AU - Lange, Jette Bornholdt
AU - Rennie, Sarah
AU - Andersson, Robin
PY - 2022
Y1 - 2022
N2 - 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.
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 transcription start site regions within a promoter.
U2 - 10.7554/eLife.80943
DO - 10.7554/eLife.80943
M3 - Journal article
C2 - 36377861
VL - 2022
JO - eLife
JF - eLife
SN - 2050-084X
ER -
ID: 327464562