Contrasting Frequencies and Effects of<i>cis</i>- and<i>trans</i>-Regulatory Mutations Affecting Gene Expression

Metzger, Brian P. H.; Duveau, Fabien; Yuan, Dorothy; Tryban, Stephen; Yang, Bing; Wittkopp, Patricia J.

doi:10.1093/molbev/msw011

Cited by 107 publications

(227 citation statements)

References 76 publications

Supporting

Mentioning

208

Contrasting

Order By: Relevance

“…To determine whether natural selection has impacted trans ‐regulatory variation affecting TDH3 promoter activity, we constructed models of neutral evolution using the effects of new mutations defined in prior work (Metzger et al. ). These mutations were generated with the mutagen EMS (Metzger et al.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Compensatorytrans-regulatory alleles minimizing variation inTDH3expression are common withinSaccharomyces cerevisiae

Metzger

Wittkopp

2019

Evolution Letters

Self Cite

View full text Add to dashboard Cite

Heritable variation in gene expression is common within species. Much of this variation is due to genetic differences outside of the gene with altered expression and is trans‐acting. This trans‐regulatory variation is often polygenic, with individual variants typically having small effects, making the genetic architecture and evolution of trans‐regulatory variation challenging to study. Consequently, key questions about trans‐regulatory variation remain, including the variability of trans‐regulatory variation within a species, how selection affects trans‐regulatory variation, and how trans‐regulatory variants are distributed throughout the genome and within a species. To address these questions, we isolated and measured trans‐regulatory differences affecting TDH3 promoter activity among 56 strains of Saccharomyces cerevisiae, finding that trans‐regulatory backgrounds varied approximately twofold in their effects on TDH3 promoter activity. Comparing this variation to neutral models of trans‐regulatory evolution based on empirical measures of mutational effects revealed that despite this variability in the effects of trans‐regulatory backgrounds, stabilizing selection has constrained trans‐regulatory differences within this species. Using a powerful quantitative trait locus mapping method, we identified ∼100 trans‐acting expression quantitative trait locus in each of three crosses to a common reference strain, indicating that regulatory variation is more polygenic than previous studies have suggested. Loci altering expression were located throughout the genome, and many loci were strain specific. This distribution and prevalence of alleles is consistent with recent theories about the genetic architecture of complex traits. In all mapping experiments, the nonreference strain alleles increased and decreased TDH3 promoter activity with similar frequencies, suggesting that stabilizing selection maintained many trans‐acting variants with opposing effects. This variation may provide the raw material for compensatory evolution and larger scale regulatory rewiring observed in developmental systems drift among species.

show abstract

Section: Resultsmentioning

confidence: 99%

“…These mutations were generated with the mutagen EMS (Metzger et al. ), which mimics the most common type of point mutation in yeast (Zhu et al. ) and the most common type of polymorphism found among natural yeast strains (G→A and C→T; MacLean et al.…”

Section: Resultsmentioning

confidence: 99%

Compensatorytrans-regulatory alleles minimizing variation inTDH3expression are common withinSaccharomyces cerevisiae

Metzger

Wittkopp

2019

Evolution Letters

Self Cite

View full text Add to dashboard Cite

show abstract

“…Other experimental studies on yeast (Gruber et al. 2012; Metzger et al. 2016) showed that cis -regulatory mutations arose less frequently with more moderate effects on phenotypic trait than other type of mutations potentially explaining their higher contribution to adaptive divergence over a longer period of time.…”

Section: Introductionmentioning

confidence: 99%

No excess of cis -regulatory variation associated with intra-specific selection in wild pearl millet ( Cenchrus americanus )

et al. 2017

View full text Add to dashboard Cite

Several studies suggest that cis-regulatory mutations are the favorite target of evolutionary changes, one reason being that cis-regulatory mutations might have fewer deleterious pleiotropic effects than protein-coding mutations. A review of the process also suggests that this bias towards adaptive cis-regulatory variation might be less pronounced at the intraspecific level compared with the interspecific level. In this study, we assessed the contribution of cis-regulatory variation to adaptation at the intraspecific level using populations of wild pearl millet (Cenchrus americanus ssp. monodii) sampled along an environmental gradient in Niger. From RNA sequencing of hybrids to assess allele-specific expression, we identified genes with cis-regulatory divergence between two parental accessions collected in contrasted environmental conditions. This revealed that ∼15% of transcribed genes showed cis-regulatory variation. Intersecting the gene set exhibiting cis-regulatory variation with the gene set identified as targets of selection revealed no excess of cis-acting mutations among the selected genes. We additionally found no excess of cis-regulatory variation among genes associated with adaptive traits. As our approach relied on methods identifying mainly genes submitted to strong selection pressure or with high phenotypic effect, the contribution of cis-regulatory changes to soft selection or polygenic adaptive traits remains to be tested. However our results favor the hypothesis that enrichment of adaptive cis-regulatory divergence builds up over time. For short evolutionary time-scales, cis-acting mutations are not predominantly involved in adaptive evolution associated with strong selective signal.

show abstract

“…Cis -regulatory changes are expected to be important drivers of local adaptation (Wray, 2007), while trans -regulatory variation is considered more likely to be under purifying selection (Schaefke et al 2013 but see also Landry et al 2005 for discussion of cis–trans coevolution). Correspondingly, trans -regulatory polymorphisms tend to affect gene expression less strongly than cis polymorphisms, and their effects are more likely to be nonadditive (Zhang et al 2011; Gruber et al 2012; Schaefke et al 2013; Meiklejohn et al 2014; Metzger et al 2016). Nevertheless, work in multiple species has demonstrated an important role for both cis and trans polymorphism in shaping expression variation (Cubillos et al 2012; Meiklejohn et al 2014; Guerrero et al 2016), and the role of trans variation may have been underestimated due to the higher statistical power required to detect it (Mackay et al 2009; Clément-Ziza et al 2014).…”

mentioning

confidence: 99%

Regulatory Architecture of Gene Expression Variation in the Threespine Stickleback Gasterosteus aculeatus

Pritchard

Viitaniemi

McCairns

et al. 2017

G3 Genes|Genomes|Genetics

View full text Add to dashboard Cite

Much adaptive evolutionary change is underlain by mutational variation in regions of the genome that regulate gene expression rather than in the coding regions of the genes themselves. An understanding of the role of gene expression variation in facilitating local adaptation will be aided by an understanding of underlying regulatory networks. Here, we characterize the genetic architecture of gene expression variation in the threespine stickleback (Gasterosteus aculeatus), an important model in the study of adaptive evolution. We collected transcriptomic and genomic data from 60 half-sib families using an expression microarray and genotyping-by-sequencing, and located expression quantitative trait loci (eQTL) underlying the variation in gene expression in liver tissue using an interval mapping approach. We identified eQTL for several thousand expression traits. Expression was influenced by polymorphism in both cis- and trans-regulatory regions. Trans-eQTL clustered into hotspots. We did not identify master transcriptional regulators in hotspot locations: rather, the presence of hotspots may be driven by complex interactions between multiple transcription factors. One observed hotspot colocated with a QTL recently found to underlie salinity tolerance in the threespine stickleback. However, most other observed hotspots did not colocate with regions of the genome known to be involved in adaptive divergence between marine and freshwater habitats.

show abstract

Contrasting Frequencies and Effects ofcis- andtrans-Regulatory Mutations Affecting Gene Expression

Cited by 107 publications

References 76 publications

Compensatorytrans-regulatory alleles minimizing variation inTDH3expression are common withinSaccharomyces cerevisiae

Compensatorytrans-regulatory alleles minimizing variation inTDH3expression are common withinSaccharomyces cerevisiae

No excess of cis -regulatory variation associated with intra-specific selection in wild pearl millet ( Cenchrus americanus )

Regulatory Architecture of Gene Expression Variation in the Threespine Stickleback Gasterosteus aculeatus

Contact Info

Product

Resources

About