Evolutionary Dynamics of Regulatory Changes Underlying Gene Expression Divergence among Saccharomyces Species

Abstract

Heritable changes in gene expression are important contributors to phenotypic differences within and between species and are caused by mutations in cis-regulatory elements and trans-regulatory factors. Although previous work has suggested that cis-regulatory differences preferentially accumulate with time, technical restrictions to closely related species and limited comparisons have made this observation difficult to test. To address this problem, we used allele-specific RNA-seq data from Saccharomyces species and hybrids to expand both the evolutionary timescale and number of species in which the evolution of regulatory divergence has been investigated. We find that as sequence divergence increases, cis-regulatory differences do indeed become the dominant type of regulatory difference between species, ultimately becoming a better predictor of expression divergence than trans-regulatory divergence. When both cis- and trans-regulatory differences accumulate for the same gene, they more often have effects in opposite directions than in the same direction, indicating widespread compensatory changes underlying the evolution of gene expression. The frequency of compensatory changes within and between species and the magnitude of effect for the underlying cis- and trans-regulatory differences suggests that compensatory changes accumulate primarily due to selection against divergence in gene expression as a result of weak stabilizing selection on gene expression levels. These results show that cis-regulatory differences and compensatory changes in regulation play increasingly important roles in the evolution of gene expression as time increases.

Compensatorytrans-regulatory alleles minimizing variation inTDH3expression are common withinSaccharomyces cerevisiae

“…Although it might seem counterintuitive to find such extensive genetic variation affecting a trait whose variance appears to have been limited by stabilizing selection, theoretical work has previously shown that stabilizing selection acting on quantitative traits can maintain abundant cryptic genetic variation with offsetting effects (Lande 1976;Dover and Flavell 1984;Turelli 1984;Barton 1986Barton , 1989. The pervasiveness of genetic variants with opposing effects on expression is consistent with the recurrent observation of compensatory evolution in genomic comparisons of gene expression within and among species (Goncalves et al 2012;Schaefke et al 2013;Coolon et al 2014;Mack et al 2016;Verta et al 2016;Metzger et al 2017). This variation may form the basis for developmental systems drift in which phenotypes stay stable over evolutionary time, but the molecular components responsible for the phenotype change (True and Haag 2001;Brachi et al 2010;Gordon and Ruvinsky 2012;Pavlicev and Wagner 2012): with many combinations of alleles available that can produce the same trait value, changes in the regulation of a trait that do not alter the trait value might be common.…”

“…; Metzger et al. ). This variation may form the basis for developmental systems drift in which phenotypes stay stable over evolutionary time, but the molecular components responsible for the phenotype change (True and Haag ; Brachi et al.…”

Complex polymorphic genetic architecture underlies trans-regulatory variation among strains of Saccharomyces cerevisiae

“…These observations are consistent with the recently described "omnigenic model" of complex traits, which predicts that many quantitative trait loci with small, often opposing effects, are located throughout the genome and segregate within a population (62). The pervasiveness of genetic variants with opposing effects on expression might also explain the recurrent observation of compensatory evolution in genomic comparisons of gene expression within and between species (7,9,(63)(64)(65)(66). In addition, this variation might also form the basis for developmental systems drift in which phenotypes stay stable over evolutionary time, but the molecular components responsible for the phenotype change (67)(68)(69)(70): with many combinations of alleles available that can produce the same trait value, changes in the regulation of a trait that do not alter the trait value might be common.…”

Inferring the genetic architecture of expression variation from replicated high throughput allele-specific expression experiments

“…The cis effect parameter (e cis ) for a gene is defined as the ratio of the expression from allele 1 and allele 2 Schaefke et al 2013). However, previous allele-specific expression studies using RNA-seq for cis-effect typically employed 1-3 hybrid replicates in binomial framework Schaefke et al 2013;Metzger, Wittkopp, and Coolon 2017;Rhoné et al 2017;Mack, Campbell, and Nachman 2016;McManus et al 2014;Bell et al 2013), which assumes that the read counts for each allele among replicates can be modeled as a Poisson random variable.…”