title: Promoter shape varies across populations and affects promoter evolution and expression noise.
abstract: Animal promoters initiate transcription either at precise positions (narrow promoters) or dispersed regions (broad promoters), a distinction referred to as promoter shape. Although highly conserved, the functional properties of promoters with different shapes and the genetic basis of their evolution remain unclear. Here we used natural genetic variation across 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 TSSs within a promoter (shape). Our results identify promoter shape as a molecular trait that can evolve independently of promoter strength. Broad promoters typically harbor shape-associated variants, with signatures of adaptive selection. Single-cell measurements demonstrate that variants modulating promoter shape often increase expression noise, whereas 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 in promoter evolution.
authors.affiliation: European Molecular Biology Laboratory (EMBL) Genome Biology Unit, Heidelberg, Germany.
authors.forename: Ignacio E
authors.initials: IE
authors.lastname: Schor
authors.affiliation: European Molecular Biology Laboratory (EMBL) Genome Biology Unit, Heidelberg, Germany.
authors.forename: Jacob F
authors.initials: JF
authors.lastname: Degner
authors.affiliation: European Molecular Biology Laboratory (EMBL) Genome Biology Unit, Heidelberg, Germany.
authors.forename: Dermot
authors.initials: D
authors.lastname: Harnett
authors.affiliation: European Molecular Biology Laboratory (EMBL) Genome Biology Unit, Heidelberg, Germany.
authors.forename: Enrico
authors.initials: E
authors.lastname: Cannavò
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton, UK.
authors.forename: Francesco P
authors.initials: FP
authors.lastname: Casale
authors.affiliation: Department of Statistics, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Heejung
authors.initials: H
authors.lastname: Shim
authors.affiliation: European Molecular Biology Laboratory (EMBL) Genome Biology Unit, Heidelberg, Germany.
authors.forename: David A
authors.initials: DA
authors.lastname: Garfield
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton, UK.
authors.forename: Ewan
authors.initials: E
authors.lastname: Birney
authors.affiliation: Department of Human Genetics, University of Chicago, Chicago, Illinois, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Stephens
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton, UK.
authors.forename: Oliver
authors.identifier: http://orcid.org/0000-0002-8818-7193
authors.initials: O
authors.lastname: Stegle
authors.affiliation: European Molecular Biology Laboratory (EMBL) Genome Biology Unit, Heidelberg, Germany.
authors.forename: Eileen E M
authors.identifier: http://orcid.org/0000-0002-9544-8339
authors.initials: EE
authors.lastname: Furlong
mesh_terms: D000818:Animals; D005075:Biological Evolution; D004330:Drosophila / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D009622:Noise; D011401:Promoter Regions, Genetic / Q000235:genetics*; D024363:Transcription Initiation Site / Q000502:physiology; D014158:Transcription, Genetic / Q000235:genetics