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1. Contributions of mutation and selection to regulatory variation: lessons from the Saccharomyces cerevisiae TDH3 gene

   https://doi.org/10.1098/rstb.2022.0057  

   Wittkopp, Patricia J. (May 2023, Philosophical Transactions of the Royal Society B: Biological Sciences)

   Heritable variation in gene expression is common within and among species and contributes to phenotypic diversity. Mutations affecting eithercis- ortrans-regulatory sequences controlling gene expression give rise to variation in gene expression, and natural selection acting on this variation causes some regulatory variants to persist in a population for longer than others. To understand how mutation and selection interact to produce the patterns of regulatory variation we see within and among species, my colleagues and I have been systematically determining the effects of new mutations on expression of theTDH3gene inSaccharomyces cerevisiaeand comparing them to the effects of polymorphisms segregating within this species. We have also investigated the molecular mechanisms by which regulatory variants act. Over the past decade, this work has revealed properties ofcis- andtrans-regulatory mutations including their relative frequency, effects, dominance, pleiotropy and fitness consequences. Comparing these mutational effects to the effects of polymorphisms in natural populations, we have inferred selection acting on expression level, expression noise and phenotypic plasticity. Here, I summarize this body of work and synthesize its findings to make inferences not readily discernible from the individual studies alone. This article is part of the theme issue ‘Interdisciplinary approaches to predicting evolutionary biology’. 

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2. Hybrid Epigenomes Reveal Extensive Local Genetic Changes to Chromatin Accessibility Contribute to Divergence in Embryonic Gene Expression Between Species

   https://doi.org/10.1093/molbev/msad222  

   Devens, Hannah R; Davidson, Phillip L; Byrne, Maria; Wray, Gregory A (November 2023, Molecular Biology and Evolution)

   Wittkopp, Patricia (Ed.)

   Abstract Chromatin accessibility plays an important role in shaping gene expression, yet little is known about the genetic and molecular mechanisms that influence the evolution of chromatin configuration. Both local (cis) and distant (trans) genetic influences can in principle influence chromatin accessibility and are based on distinct molecular mechanisms. We, therefore, sought to characterize the role that each of these plays in altering chromatin accessibility in 2 closely related sea urchin species. Using hybrids of Heliocidaris erythrogramma and Heliocidaris tuberculata, and adapting a statistical framework previously developed for the analysis of cis and trans influences on the transcriptome, we examined how these mechanisms shape the regulatory landscape at 3 important developmental stages, and compared our results to similar analyses of the transcriptome. We found extensive cis- and trans-based influences on evolutionary changes in chromatin, with cis effects generally larger in effect. Evolutionary changes in accessibility and gene expression are correlated, especially when expression has a local genetic basis. Maternal influences appear to have more of an effect on chromatin accessibility than on gene expression, persisting well past the maternal-to-zygotic transition. Chromatin accessibility near gene regulatory network genes appears to be distinctly regulated, with trans factors appearing to play an outsized role in the configuration of chromatin near these genes. Together, our results represent the first attempt to quantify cis and trans influences on evolutionary divergence in chromatin configuration in an outbred natural study system and suggest that chromatin regulation is more genetically complex than was previously appreciated. 

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3. Diverse gene regulatory mechanisms alter rattlesnake venom gene expression at fine evolutionary scales

   https://doi.org/10.1093/gbe/evae110  

   Gopalan, Siddharth S; Perry, Blair W; Francioli, Yannick Z; Schield, Drew R; Guss, Hannah D; Bernstein, Justin M; Ballard, Kaas; Smith, Cara F; Saviola, Anthony J; Adams, Richard H; et al (May 2024, Genome Biology and Evolution)

   Gossmann, Toni (Ed.)

   Abstract Understanding and predicting the relationships between genotype and phenotype is often challenging, largely due to the complex nature of eukaryotic gene regulation. A step towards this goal is to map how phenotypic diversity evolves through genomic changes that modify gene regulatory interactions. Using the Prairie Rattlesnake (Crotalus viridis) and related species, we integrate mRNA-seq, proteomic, ATAC-seq and whole genome resequencing data to understand how specific evolutionary modifications to gene regulatory network components produce differences in venom gene expression. Through comparisons within and between species, we find a remarkably high degree of gene expression and regulatory network variation across even a shallow level of evolutionary divergence. We use these data to test hypotheses about the roles of specific trans-factors and cis-regulatory elements, how these roles may vary across venom genes and gene families, and how variation in regulatory systems drive diversity in venom phenotypes. Our results illustrate that differences in chromatin and genotype at regulatory elements play major roles in modulating expression. However, we also find that enhancer deletions, differences in transcription-factor expression, and variation in activity of the insulator protein CTCF also likely impact venom phenotypes. Our findings provide insight into the diversity and gene-specificity of gene regulatory features and highlight the value of comparative studies to link gene regulatory network variation to phenotypic variation. 

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4. Parallel and population-specific gene regulatory evolution in cold-adapted fly populations

   https://doi.org/10.1093/genetics/iyab077  

   Huang, Yuheng; Lack, Justin B; Hoppel, Grant T; Pool, John E (May 2021, Genetics)

   Begun, D (Ed.)

   Abstract Changes in gene regulation at multiple levels may comprise an important share of the molecular changes underlying adaptive evolution in nature. However, few studies have assayed within- and between-population variation in gene regulatory traits at a transcriptomic scale, and therefore inferences about the characteristics of adaptive regulatory changes have been elusive. Here, we assess quantitative trait differentiation in gene expression levels and alternative splicing (intron usage) between three closely related pairs of natural populations of Drosophila melanogaster from contrasting thermal environments that reflect three separate instances of cold tolerance evolution. The cold-adapted populations were known to show population genetic evidence for parallel evolution at the SNP level, and here we find evidence for parallel expression evolution between them, with stronger parallelism at larval and adult stages than for pupae. We also implement a flexible method to estimate cis- vs trans-encoded contributions to expression or splicing differences at the adult stage. The apparent contributions of cis- vs trans-regulation to adaptive evolution vary substantially among population pairs. While two of three population pairs show a greater enrichment of cis-regulatory differences among adaptation candidates, trans-regulatory differences are more likely to be implicated in parallel expression changes between population pairs. Genes with significant cis-effects are enriched for signals of elevated genetic differentiation between cold- and warm-adapted populations, suggesting that they are potential targets of local adaptation. These findings expand our knowledge of adaptive gene regulatory evolution and our ability to make inferences about this important and widespread process. 

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5. The quantitative genetics of gene expression in Mimulus guttatus

   https://doi.org/10.1371/journal.pgen.1011072  

   Veltsos, Paris; Kelly, John K. (April 2024, PLOS Genetics)

   Lasky, Jesse R. (Ed.)

   Gene expression can be influenced by genetic variants that are closely linked to the expressed gene (cis eQTLs) and variants in other parts of the genome (trans eQTLs). We created a multiparental mapping population by sampling genotypes from a single natural population ofMimulus guttatusand scored gene expression in the leaves of 1,588 plants. We find that nearly every measured gene exhibits cis regulatory variation (91% have FDR < 0.05). cis eQTLs are usually allelic series with three or more functionally distinct alleles. The cis locus explains about two thirds of the standing genetic variance (on average) but varies among genes and tends to be greatest when there is high indel variation in the upstream regulatory region and high nucleotide diversity in the coding sequence. Despite mapping over 10,000 trans eQTL / affected gene pairs, most of the genetic variance generated by trans acting loci remains unexplained. This implies a large reservoir of trans acting genes with subtle or diffuse effects. Mapped trans eQTLs show lower allelic diversity but much higher genetic dominance than cis eQTLs. Several analyses also indicate that trans eQTLs make a substantial contribution to the genetic correlations in expression among different genes. They may thus be essential determinants of “gene expression modules,” which has important implications for the evolution of gene expression and how it is studied by geneticists. 

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