Selection on noise constrains variation in a eukaryotic promoter

Abstract

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 selection1–4. When evidence of selection exists, such comparisons can identify properties of mutations that are most likely to persist in natural populations2. 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 (i.e., variability in expression among genetically identical cells5) 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 and provides rare empirical evidence of selection acting on expression noise.

Ancient trans-Acting siRNAs Confer Robustness and Sensitivity onto the Auxin Response

“…Both the increased sensitivity and robustness lent to the auxin response by the tasiRNA pathway promote the faithful transfer of information through a signaling network. Evidence that selection may indeed act on such network properties has been identified across the tree of life, and includes examples of selection acting on regulatory mutations that minimize expression noise in yeast (Metzger et al, 2015), as well as the conservation of shadow enhancers that maintain robust gene expression in animal systems (Frankel et al, 2010; Hong et al, 2008). The network properties lent to the auxin response by the tasiARF-ARFb module uncovered in this work thus provide a compelling explanation for the repeated cooption of this module throughout land plant evolution.…”

Next-generation analysis of gene expression regulation – comparing the roles of synthesis and degradation

“…Interestingly, recent work suggests that gene expression noise is subject to purifying selection for at least one yeast gene 49 . Thus, “Nothing in Biology Makes Sense Except in the Light of Evolution” (Theodosius Dobzhansky, 1973) may also apply to the evolution of different rates of synthesis and degradation – and the time is ripe for models and hypotheses that explain these selection processes.…”

Conserved non-AUG uORFs revealed by a novel regression analysis of ribosome profiling data

“…A dual fluorescence reporter plasmid was generated by cloning YFP (Metzger et al 2015) into the vector PTH761 (Chu et al 2013), such that UTR sequences could be inserted upstream of YFP using XmaI and BglII restriction sites (Supplemental Methods). Transcript leaders were cloned between the GPM1 transcription start site and YFP.…”