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

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 is largely determined by a promoter9s DNA sequence and its binding sites for specific transcription factors. We further demonstrate that flexible usage of transcription start sites within a promoter attenuates variability, providing transcriptional and mutational robustness.