Trans-acting regulatory variation in Saccharomyces cerevisiae
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ABSTRACT:
ORGANISM(S): Saccharomyces cerevisiae
PROVIDER: GSE617 | GEO | 2003/09/03
SECONDARY ACCESSION(S): PRJNA87515
REPOSITORIES: GEO
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Project description:Natural genetic variation can cause significant differences in gene expression, but little is known about the polymorphisms that affect gene regulation. We analyzed regulatory variation in a cross between laboratory and wild strains of Saccharomyces cerevisiae. Clustering and linkage analysis defined groups of coregulated genes and the loci involved in their regulation. Most expression differences mapped to trans-acting loci. Positional cloning and functional assays showed that polymorphisms in GPA1 and AMN1 affect expression of genes involved in pheromone response and daughter cell separation, respectively. We also asked whether particular classes of genes were more likely to contain trans-regulatory polymorphisms. Notably, transcription factors showed no enrichment, and trans-regulatory variation seems to be broadly dispersed across classes of genes with different molecular functions
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Project description:Like protein coding genes, loci that produce microRNAs (miRNAs) are generally considered to be under purifying selection, consistent with miRNA polymorphisms being able to cause disease. Nevertheless, it has been hypothesized that variation in miRNA genes may contribute to phenotypic diversity. Here we demonstrate that a naturally occurring polymorphism in the MIR164A gene interacts epistatically with an unlinked locus to affect leaf shape and shoot architecture in Arabidopsis thaliana. A single-base pair substitution in the miRNA complementary sequence alters the stability of the miRNA:miRNA* duplex. It thereby interferes with processing of the precursor and greatly reduces miRNA accumulation. We demonstrate that this is not a rare exception, but that natural strains of Arabidopsis thaliana harbor dozens of similar polymorphisms that affect processing of a wide range of miRNA precursors. Our results suggest that natural variation in miRNA processability due to cis mutations is a common contributor to phenotypic variation in plants.
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Project description:Gene expression is regulated both by cis elements, which are DNA segments closely linked to the genes they regulate, and by trans activating factors, which are usually proteins capable of diffusing to unlinked genes. Understanding the patterns and sources of regulatory variation is crucial for understanding phenotypic and genome evolution. Here, we investigate the global patterns of gene expression evolution in Saccharomyces cerivisiae. We report statistical methods useful in quantifying cis and trans regulation using next generation sequencing data. Using these methods, measured genome-wide allele-specific expression by deep sequencing to investigate the genetic architecture of gene regulatory variation between two strains of Saccharomyces cerevisiae. We find that expression polymorphism in yeast is common for both cis and trans regulation, though trans variation is more common. Our detailed analyses of the effects of functional constraint on expression variation as indicated by measures such as protein connectivity, gene essentiality, and the ratio of nonsynonymous substitutions to synonymous substitutions clearly reveal that both classes of variation are under purifying selection, but trans variation is more sensitive to selective constraint. Comparing interspecific expression divergence between S. cerevisiae and S. paradoxus to our intraspecific variation suggests that natural selection strongly influences the patterns of variation we observe. Further analyses revealed that cis divergence is more frequently mediated by positive Darwinian selection than trans divergence, which is compatible with neutral evolution. Study the gene expression patterns in two strains of yeast (BY and RM)
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Project description:The pervasiveness of gene expression variation and its contribution to phenotypic variation and evolution is well known. This gene expression variation is context dependent, with differences in regulatory architecture often associated with intrinsic and environmental factors, and is modulated by regulatory elements that can act in cis (linked) or in trans (unlinked) relative to the genes they affect. So far, little is known about how this genetic variation affects the evolution of regulatory architecture among closely related tissues during population divergence. To address this question, we analyzed gene expression in the midgut, hindgut, and Malpighian tubule as well as microbiome composition in the two gut tissues in four Drosophila melanogaster strains and their F1 hybrids from two divergent populations: one from the derived, European range and one from the ancestral, African range. In both the transcriptome and microbiome data, we detected extensive tissue- and genetic background-specific effects, including effects of genetic background on overall tissue specificity. Tissue-specific effects were typically stronger than genetic background-specific effects, although the two gut tissues were not more similar to each other than to the Malpighian tubules. An examination of allele specific expression revealed that, while both cis and trans effects were more tissue-specific in genes expressed differentially between populations than genes with conserved expression, trans effects were more tissue-specific than cis effects. Despite there being highly variable regulatory architecture, this observation was robust across tissues and genetic backgrounds, suggesting that the expression of trans variation can be spatially fine-tuned as well as or better than cis variation during population divergence and yielding new insights into cis and trans regulatory evolution.
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Project description:Expression level polymorphisms (ELPs) often result in cis-acting expression quantitative trait loci (cis-eQTL), which are important QTL and association mapping tools and account significantly for phenotypic variability. Generally, it is assumed that such stably heritable ELP represent regulatory element polymorphisms in the respective genes. However, comprehensive genome-wide analyses linking expression level, regulatory sequence and gene structure variation are missing, preventing definite verification of this assumption. Here we analyzed heritability of ELP observed between Arabidopsis thaliana accessions Eil-0 and Lc-0 by comparing genotyped recombinant inbred lines (RIL) to their parents in microarray analyses. Keywords: expression level polymorphism, Arabidopsis thaliana accessions, recombinant inbred lines
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Project description:Clinical response to glucocorticoids (GCs), steroid hormones widely used as pharmaceuticals, varies extensively, with many patients (~30%) showing a weak response to treatment. Although little is known about the molecular basis of this variation, regulatory polymorphisms are likely to play a key role as GCs act largely through activation of a transcription factor, the GC receptor. In an effort to characterize the molecular basis of variation in GC sensitivity, we measured in vitro lymphocyte GC sensitivity (LGS) and transcriptome-wide response to GCs in peripheral blood mononuclear cells (PBMCs) from African-American healthy donors. We found that variation in LGS was correlated with transcriptional response at 27 genes (FDR<0.1). Furthermore, a genome-wide association scan revealed a quantitative trait locus (QTL) for LGS (rs11129354, P=4x10-8) that was also associated with transcriptional response at multiple genes, including many (14 of 27) where transcriptional response was correlated with LGS. Using allelic imbalance assays, we show that this QTL is a GC-dependent cis-regulatory polymorphism for RBMS3, which encodes an RNA-binding protein known as a tumor suppressor. We found that siRNA-mediated knockdown of RBMS3 expression increases cellular proliferation in PBMCs, consistent with the role of the gene as a negative regulator of proliferation. We propose that differences in LGS reflect variation in transcriptional response, which are influenced by a GC-dependent regulatory polymorphism that acts in cis relative to RBMS3 and in trans to affect the transcriptional response of multiple distant genes.
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