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Promoter shape varies across populations and impacts promoter evolution and expression noise

Metazoan promoters initiate transcription either at precise positions (narrow promoters) or dispersed regions (broad promoters), a feature called promoter shape. Although highly conserved, the functional properties of promoters with different shapes and the genetic determinants of their evolution remain unclear. Here, we used natural genetic variation cross a panel of 81 Drosophila lines, to measure changes in transcriptional start site (TSS) usage, identifying thousands of genetic variants affecting transcript levels (strength) or the distribution of TSS within a promoter (shape). Our results identify promoter shape as a molecular trait, evolvable independently of promoter strength. Broad promoters typically harbor shape-associated variants, with signatures of adaptive selection. Single-cell measurements reveal that variants modulating promoter shape often increase expression noise, while heteroallelic interactions with other promoter variants alleviate these effects. These results uncover new functional properties of natural promoters, and suggest the minimization of expression noise as an important factor influencing promoter evolution.