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1. 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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2. Learning gene networks under SNP perturbation using SNP and allele-specific expression data

   https://doi.org/10.1101/2023.10.23.563661  

   Yoon, Jun Ho; Kim, Seyoung (October 2023, bioRxiv)

   Abstract Allele-specific expression quantification from RNA-seq reads provides opportunities to study the control of gene regulatory networks bycis-acting andtrans-acting genetic variants. Many existing methods performed a single-gene and single-SNP association analysis to identify expression quantitative trait loci (eQTLs), and placed the eQTLs against known gene networks for functional interpretation. Instead, we view eQTL data as a capture of the effects of perturbation of gene regulatory system by a large number of genetic variants and reconstruct a gene network perturbed by eQTLs. We introduce a statistical framework called CiTruss for simultaneously learning a gene network andcis-acting andtrans-acting eQTLs that perturb this network, given population allele-specific expression and SNP data. CiTruss uses a multi-level conditional Gaussian graphical model to modeltrans-acting eQTLs perturbing the expression of both alleles in gene network at the top level andcis-acting eQTLs perturbing the expression of each allele at the bottom level. We derive a transformation of this model that allows efficient learning for large-scale human data. Our analysis of the GTEx and LG×SM advanced intercross line mouse data for multiple tissue types with CiTruss provides new insights into genetics of gene regulation. CiTruss revealed that gene networks consist of local subnetworks over proximally located genes and global subnetworks over genes scattered across genome, and that several aspects of gene regulation by eQTLs such as the impact of genetic diversity, pleiotropy, tissue-specific gene regulation, and local and long-range linkage disequilibrium among eQTLs can be explained through these local and global subnetworks. 

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3. Genome-wide association mapping of transcriptome variation in Mimulus guttatus indicates differing patterns of selection on cis - versus trans -acting mutations

   https://doi.org/10.1093/genetics/iyab189  

   Brown, Keely_E; Kelly, John_K; Wright, ed., S. (November 2021, Genetics)

   Abstract We measured the floral bud transcriptome of 151 fully sequenced lines of Mimulus guttatus from one natural population. Thousands of single nucleotide polymorphisms (SNPs) are implicated as transcription regulators, but there is a striking difference in the allele frequency spectrum of cis-acting and trans-acting mutations. Cis-SNPs have intermediate frequencies (consistent with balancing selection) while trans-SNPs exhibit a rare-alleles model (consistent with purifying selection). This pattern only becomes clear when transcript variation is normalized on a gene-to-gene basis. If a global normalization is applied, as is typically in RNAseq experiments, asymmetric transcript distributions combined with “rarity disequilibrium” produce a superabundance of false positives for trans-acting SNPs. To explore the cause of purifying selection on trans-acting mutations, we identified gene expression modules as sets of coexpressed genes. The extent to which trans-acting mutations influence modules is a strong predictor of allele frequency. Mutations altering expression of genes with high “connectedness” (those that are highly predictive of the representative module expression value) have the lowest allele frequency. The expression modules can also predict whole-plant traits such as flower size. We find that a substantial portion of the genetic (co)variance among traits can be described as an emergent property of genetic effects on expression modules. 

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4. Trans -regulatory loci shape natural variation of gene expression plasticity in Arabidopsis

   https://doi.org/10.1093/genetics/iyaf116  

   Lensink, Mariele; Monroe, Grey; Kliebenstein, Daniel_J; Birchler, ed., J. (June 2025, GENETICS)

   Abstract Organisms regulate gene expression in response to environmental cues, a process known as plasticity, to adjust to changing environments. Research into natural variation and the evolution of plasticity frequently studies cis-regulatory elements with theory suggesting they are more important evolutionarily than trans-regulatory elements. Genome-wide association (GWA) studies have supported this idea, observing a predominance of cis-loci affecting plasticity. However, studies in structured populations provide a contrasting image, raising questions about the genetic architecture of natural variation in plasticity. To circumvent potential statistical difficulties present in GWA studies, we mapped loci underlying transcriptomic plasticity in response to salicylic acid (SA) using recombinant inbred lines generated from 2 random Arabidopsis thaliana accessions. We detected extensive transgressive segregation in the SA response, suggesting that plasticity to salicylate in Arabidopsis is polygenic. Most loci (>75%) underlying this variation act in trans, especially for loci influencing plasticity. Trans-acting loci were enriched in genome hotspots, with predominantly small-effect sizes distributed across many genes. This could potentially explain their under-discovery in GWA studies. This work reveals a potentially important role for trans-acting loci in plastic expression responses, with implications for understanding plant adaptation to different environments. 

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5. 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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