title: Contrasting Frequencies and Effects of cis- and trans-Regulatory Mutations Affecting Gene Expression.
abstract: Heritable differences in gene expression are caused by mutations in DNA sequences encoding cis-regulatory elements and trans-regulatory factors. These two classes of regulatory change differ in their relative contributions to expression differences in natural populations because of the combined effects of mutation and natural selection. Here, we investigate how new mutations create the regulatory variation upon which natural selection acts by quantifying the frequencies and effects of hundreds of new cis- and trans-acting mutations altering activity of the TDH3 promoter in the yeast Saccharomyces cerevisiae in the absence of natural selection. We find that cis-regulatory mutations have larger effects on expression than trans-regulatory mutations and that while trans-regulatory mutations are more common overall, cis- and trans-regulatory changes in expression are equally abundant when only the largest changes in expression are considered. In addition, we find that cis-regulatory mutations are skewed toward decreased expression while trans-regulatory mutations are skewed toward increased expression. We also measure the effects of cis- and trans-regulatory mutations on the variability in gene expression among genetically identical cells, a property of gene expression known as expression noise, finding that trans-regulatory mutations are much more likely to decrease expression noise than cis-regulatory mutations. Because new mutations are the raw material upon which natural selection acts, these differences in the frequencies and effects of cis- and trans-regulatory mutations should be considered in models of regulatory evolution.
authors.affiliation: Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor.
authors.forename: Brian P H
authors.initials: BP
authors.lastname: Metzger
authors.affiliation: Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor.
authors.forename: Fabien
authors.initials: F
authors.lastname: Duveau
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor Department of Biology, Stanford University.
authors.forename: David C
authors.initials: DC
authors.lastname: Yuan
authors.affiliation: Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor.
authors.forename: Stephen
authors.initials: S
authors.lastname: Tryban
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor.
authors.forename: Bing
authors.initials: B
authors.lastname: Yang
authors.affiliation: Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor wittkopp@umich.edu.
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Wittkopp
mesh_terms: D000483:Alleles; D001483:Base Sequence; D019143:Evolution, Molecular; D015870:Gene Expression; D015966:Gene Expression Regulation, Fungal; D005816:Genetic Complementation Test / Q000379:methods*; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D011401:Promoter Regions, Genetic; D012045:Regulatory Sequences, Nucleic Acid; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism; D012641:Selection, Genetic
chemical_list: D029701:Saccharomyces cerevisiae Proteins; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); C465226:TDH3 protein, S cerevisiae
keywords: TDH3.; distribution of mutational effects; expression noise; mutational target size; neutral evolution