Polygenic and directional regulatory evolution across pathways in Saccharomyces

Abstract

The search to understand how genomes innovate in response to selection dominates the field of evolutionary biology. Powerful molecular evolution approaches have been developed to test individual loci for signatures of selection. In many cases, however, an organism's response to changes in selective pressure may be mediated by multiple genes, whose products function together in a cellular process or pathway. Here we assess the prevalence of polygenic evolution in pathways in the yeasts Saccharomyces cerevisiae and S. bayanus. We first established short-read sequencing methods to detect cis-regulatory variation in a diploid hybrid between the species. We then tested for the scenario in which selective pressure in one species to increase or decrease the activity of a pathway has driven the accumulation of cis-regulatory variants that act in the same direction on gene expression. Application of this test revealed a variety of yeast pathways with evidence for directional regulatory evolution. In parallel, we also used population genomic sequencing data to compare protein and cis-regulatory variation within and between species. We identified pathways with evidence for divergence within S. cerevisiae, and we detected signatures of positive selection between S. cerevisiae and S. bayanus. Our results point to polygenic, pathway-level change as a common evolutionary mechanism among yeasts. We suggest that pathway analyses, including our test for directional regulatory evolution, will prove to be a relevant and powerful strategy in many evolutionary genomic applications.A main challenge of evolutionary biology is to understand the influence of selection on genetic variation within and between species. Classically, molecular evolution methods have targeted individual genes or loci for tests of selection. Their successes have uncovered both protein-coding and regulatory variants with signatures of non-neutral evolution (1-3). However, decades of quantitative genetic mapping studies indicate that in most cases, variation in phenotype between individuals is the result of multiple sequence changes at unlinked loci (4). The genetic response to changes in selective pressure is likely to follow the same pattern, but, to date, methods for identifying cases of polygenic evolution have been at a premium.Some of the strongest evidence for polygenic adaptation has emerged from the study of protein-coding variants between phylogenetic lineages. Signatures of positive selection can be detected in the protein-coding sequences of groups of genes of related function (5-8), suggestive of a coherent series of genetic changes accumulated by a population in response to selection. Additionally, genetic variation in gene expression represents a rich data source for signatures of selection, both positive (9, 10) and purifying (11,12), although the mechanisms that govern regulatory evolution are not fully understood. Regulatory variants can act in cis, to impact the expression of a neighboring gene, or in trans, targeting the expression of genes el...

Ribosome profiling reveals post-transcriptional buffering of divergent gene expression in yeast

“…In F1 hybrids, differences in allele-specific translation efficiency reflect divergence of their cis-regulatory sequences. The effects of trans-regulatory divergence can then be inferred by comparing interspecies expression differences with F1 hybrid allelespecific expression (Wittkopp et al 2004;Tirosh et al 2009;Bullard et al 2010;McManus et al 2010). This approach is feasible with our strains, as S. cerevisiae and S. paradoxus are sufficiently divergent to allow proper allele assignment for 71% of sequence reads (Supplemental Table S1).…”

Gene regulation and speciation in house mice

“…To test for lineage-specific selection on genes with divergent cis-acting variants between the subspecies, a gene-set approach was employed (Bullard et al 2010;Fraser et al 2010Fraser et al , 2011. Under a neutral model, an equal number of genes will be up-and down-regulated by cis variants.…”

“…We test this prediction. Third, the identification of cis-eQTL allows us to ask whether differences in expression are driven by positive selection (Bullard et al 2010;Fraser et al 2010Fraser et al , 2011 and, if so, to identify classes of genes that are under selection. Fourth, we identify misexpression (i.e., changes >1.25-fold on a log 2 scale between the hybrid and both parents) in sterile and fertile hybrids.…”

Coordinated Functional Divergence of Genes after Genome Duplication in Arabidopsis thaliana

“…These authors also postulated that such duplicated functional networks or modules-representing functional pathways or parts thereof-would lead to an increase in biological complexity and/or morphology. Another argument that coordinated evolution might follow WGD is the observation that the evolution of traits often involves mutations in multiple genes (Bullard et al, 2010;Fraser et al, 2011;He et al, 2016;Roop et al, 2016), which makes sense given that many traits are polygenic in nature. Inquiries into the existence of such patterns of coordinated divergence in Arabidopsis thaliana (Blanc and Wolfe, 2004a;Ruprecht et al, 2016) and Saccharomyces cerevisiae (Pereira-Leal and Teichmann, 2005;Conant and Wolfe, 2006;Wapinski et al, 2007), which were mainly assessed at the expression level, have reported such cases to be rare.…”