Selection on noise constrains variation in a eukaryotic promoter

• Published in: Nature (London) Vol. 521; no. 7552; pp. 344 - 347
• Main Authors: Metzger, Brian P. H., Yuan, David C., Gruber, Jonathan D., Duveau, Fabien, Wittkopp, Patricia J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.05.2015; Nature Publishing Group
• Subjects: 13; 13/31; 38; 38/35; 38/47; 38/70; 631/181/2474; 631/181/457; 631/208/199; 631/208/480; Binding sites; Evolution, Molecular; Gene Expression Regulation, Fungal - genetics; Genes; Genetic diversity; Genetic drift; Genomes; Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) - genetics; Haplotypes; Humanities and Social Sciences; letter; multidisciplinary; Mutation; Mutation - genetics; Phenotype; Polymorphism, Genetic - genetics; Promoter Regions, Genetic - genetics; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae Proteins - genetics; Science; Selection, Genetic - genetics
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/nature14244

Quantifying activity of cis -regulatory sequences controlling gene expression shows that selection on expression noise has a greater impact on sequence variation than selection on mean expression level. Transcriptional noise a target of natural selection Patricia Wittkopp and colleagues measure and compare the effects of 236 mutations in a cis -regulatory region from Saccharomyces cerevisiae to the effects of natural polymorphisms observed in the same region among 85 isolates of this species. They find that selection on variability in expression among genetically identical cells appears to have had a greater effect on sequence variation than selection on mean expression level, at their promoter. This may not be because variation in expression noise affects fitness more than variation in mean expression level; rather, it may be due to differences in the distributions of mutational effects for these two phenotypes. Genetic variation segregating within a species reflects the combined activities of mutation, selection, and genetic drift. In the absence of selection, polymorphisms are expected to be a random subset of new mutations; thus, comparing the effects of polymorphisms and new mutations provides a test for selection 1 , 2 , 3 , 4 . When evidence of selection exists, such comparisons can identify properties of mutations that are most likely to persist in natural populations 2 . Here we investigate how mutation and selection have shaped variation in a cis -regulatory sequence controlling gene expression by empirically determining the effects of polymorphisms segregating in the TDH3 promoter among 85 strains of Saccharomyces cerevisiae and comparing their effects to a distribution of mutational effects defined by 236 point mutations in the same promoter. Surprisingly, we find that selection on expression noise (that is, variability in expression among genetically identical cells 5 ) appears to have had a greater impact on sequence variation in the TDH3 promoter than selection on mean expression level. This is not necessarily because variation in expression noise impacts fitness more than variation in mean expression level, but rather because of differences in the distributions of mutational effects for these two phenotypes. This study shows how systematically examining the effects of new mutations can enrich our understanding of evolutionary mechanisms. It also provides rare empirical evidence of selection acting on expression noise.