Pleiotropic effects of trans-regulatory mutations on gene expression and fitness
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ABSTRACT:
PROVIDER: PRJNA732302 | ENA |
REPOSITORIES: ENA
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Project description:Variation in gene expression arises from cis- and trans-regulatory mutations, which contribute differentially to expression divergence. Here, we compare the impacts on gene expression and fitness for cis- and trans-regulatory mutations affecting expression of the TDH3 gene in Saccharomyces cerevisiae. We use the effects of cis-regulatory mutations to isolate effects of trans-regulatory mutations caused by impacts on TDH3 from pleiotropic impacts on other genes, providing a rare distribution of pleiotropic effects. These pleiotropic effects were often, but not always, deleterious. For cis- and trans-regulatory mutations with similar effects on TDH3, trans-regulatory mutations had more widespread effects on gene expression, with distinct impacts on expression of genes downstream of TDH3. These differences between cis-and trans-regulatory mutations help explain their different contributions to regulatory evolution.
2021-05-25 | GSE175398 | GEO
Project description:Collateral fitness effects of mutations
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Project description:The abundance of transposable elements and DNA repeat sequences in mammalian genomes raises the question whether such insertions represent passive evolutionary baggage or may influence the expression of complex traits. We addressed this question in Drosophila melanogaster where the effects of single transposable elements on complex traits can be assessed in genetically identical individuals reared in controlled environments. Here we demonstrate that single P-element insertions in the intergenic region between the Gustatory receptor 5a (Gr5a) and Trapped in endoderm 1 (Tre1), which encodes an orphan receptor, exert complex pleiotropic effects on fitness traits, including selective nutrient intake, resistance to starvation and heat stress, and life span. Mutations in this region interact epistatically with downstream components of the insulin signaling pathway. Transposon-induced sex-specific and sex-antagonistic effects further accentuate the complex influences intergenic transposable elements can contribute to complex phenotypes. SUBMITTER_CITATION: Rollmann SM, Magwire MM, Morgan TJ, Ozsoy ED, Yamamoto A, Mackay TF, Anholt RR. Pleiotropic fitness effects of the Tre1-Gr5a region in Drosophila melanogaster. Nat Genet. 2006 Jul;38(7):824-9. Experiment Overall Design: BG02514, BG02257 and Canton S (B) lines were reared simultaneously at 25 C under a 12 h light/dark cycle and 70% humidity. At 5-7 days post-eclosion, we removed the heads of two replicate groups of 100 males and 100 females for each line. Total RNA was isolated from each replicate and biotinylated cRNA probes were hybridized to high density oligonucleotide microarrays (Affymetrix, Inc.) and visualized with a streptavidin-phycoerythrin conjugate, as described in the Affymetrix GeneChip Expression Analysis Technical Manual (2000), using internal references for quantification. The quantitative estimate of expression of each probe set is the Signal (Sig) metric, as described in the Affymetrix Microarray Suite, Version 5.0. Sig values were analyzed by two-way ANOVA according to the model Y = μ + L + S + LxS + E, where L is the effect of line, S is the effect of sex and E the error variance
2008-06-13 | E-GEOD-4789 | biostudies-arrayexpress
Project description:The abundance of transposable elements and DNA repeat sequences in mammalian genomes raises the question whether such insertions represent passive evolutionary baggage or may influence the expression of complex traits. We addressed this question in Drosophila melanogaster where the effects of single transposable elements on complex traits can be assessed in genetically identical individuals reared in controlled environments. Here we demonstrate that single P-element insertions in the intergenic region between the Gustatory receptor 5a (Gr5a) and Trapped in endoderm 1 (Tre1), which encodes an orphan receptor, exert complex pleiotropic effects on fitness traits, including selective nutrient intake, resistance to starvation and heat stress, and life span. Mutations in this region interact epistatically with downstream components of the insulin signaling pathway. Transposon-induced sex-specific and sex-antagonistic effects further accentuate the complex influences intergenic transposable elements can contribute to complex phenotypes. Keywords: Transcriptional profiles of P-element insertion lines in the Tre1/GR5a region of Drosophila
2006-05-31 | GSE4789 | GEO
Project description:Pleiotropic Fitness Effects of the lncRNA Uhg4 in Drosophila melanogaster
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Project description:We performed RNA-seq experiments to compare the gene expression profiles of cells expressing TEM-1 beta-lactamase with single-codon substitutions in the absence of beta-lactam antibiotics. Mutations with deleterious fitness effects in the absense of antibiotics also caused significant changes in gene expression, primarily in the induction of specific outer envelope stress response pathways and, in some cases, the mild-induction of a few genes in the heat-shock response pathway.
2019-10-28 | GSE137362 | GEO
Project description:Synonymous mutations do not change the sequence of the polypeptide but they may still influence fitness. We investigated in Salmonella enterica how four synonymous mutations in the rpsT gene (encoding ribosomal protein S20) reduce fitness (i.e. growth rate) and the mechanisms by which this cost can be genetically compensated. The reduced growth rates of the synonymous mutants were correlated with reduced levels of the rpsT transcript and S20 protein. In an adaptive evolution experiment these fitness impairments could be compensated by mutations that either caused up-regulation of S20 through increased gene dosage (due to duplications), increased transcription of the rpsT gene (due to an rpoD mutation or mutations in rpsT), or increased translation from the rpsT transcript (due to rpsT mutations). We suggest that the reduced levels of S20 in the synonymous mutants result in production of a defective subpopulation of 30S subunits lacking S20 that reduce protein synthesis and bacterial growth and that the compensatory mutations restore S20 levels and the number of functional ribosomes. Our results demonstrate how specific synonymous mutations can cause substantial fitness reductions and that many different types intra- and extragenic compensatory mutations can efficiently restore fitness. Furthermore, our study highlights that also synonymous sites can be under strong selection, which may have implications for the use of dN/dS ratios as signature for selection.
2016-03-11 | PXD003495 | Pride
Project description:Long noncoding RNAs (lncRNAs) are a diverse class of RNAs that are critical for gene regulation, DNA repair and splicing, and have been implicated in cancer, stress response, and development. However, the function of many lncRNAs remains unknown. In Drosophila melanogaster, U snoRNA host gene 4 (Uhg4) encodes an antisense long noncoding RNA that is host to seven small nucleolar RNAs (snoRNAs). Uhg4 is expressed ubiquitously during development and in all adult fly tissues with maximal expression in ovaries; however, it has no annotated function(s). Here, we used CRISPR-Cas9 germline gene editing to generate multiple deletions spanning the promoter region and first exon of Uhg4. Mutant flies were sterile, showed delayed development and decreased viability, and changes in sleep and responses to stress. Whole genome RNA sequencing of Uhg4 deletion flies and their controls identified coregulated genes and genetic interaction networks. Gene ontology analyses highlighted a broad spectrum of biological processes, including morphogenesis, stress response, and regulation of transcription and translation. Thus, Uhg4 is a lncRNA essential for reproduction with pleiotropic effects on multiple fitness traits.
2022-04-26 | GSE199865 | GEO
Project description:We performed RNA-seq experiments to compare the gene expression profiles of cells expressing single-codon substitutions in the antibiotic resistance genes NDM-1, CAT-I, or aadB in the absence of antibiotics. Mutations with deleterious fitness effects in the absense of antibiotics also caused significant changes in gene expression in a number of genes related to stress-response pathways including the regulator of colanic acid capsule synthesis (Rcs) response, the phage shock protein response (Psp), and the oxidative stress response. Fold differences in gene expression were mutation- and gene-dependent.
2022-12-31 | GSE199248 | GEO
Project description:The prevalence of clonal haematopoiesis of indeterminate potential (CHIP) in healthy individuals increases rapidly from age 60 onwards and has been associated with increased risk for malignancy, heart disease and ischemic stroke. CHIP is driven by somatic mutations in stem cells that are also drivers of myeloid malignancies. Since mutations in stem cells often drive leukaemia, we hypothesised that stem cell fitness substantially contributes to transformation from CHIP to leukaemia. Stem cell fitness is defined as the proliferative advantage over cells carrying no or only neutral mutations. It is currently unknown whether mutations in different CHIP genes lead to distinct fitness advantages that could form the basis for patient stratification. We set out to quantify the fitness effects of CHIP drivers over a 12-year timespan in older age, using longitudinal error-corrected sequencing data. Two key results support the possibility for individualised clinical monitoring of CHIP: (i) We developed a new filtering method to extract fitness effects from longitudinal data using Bayesian inference, while taking into account individual mutational context and co-occurrence of mutations, and thus quantify the growth potential of variants within each individual. (ii) We show that gene-specific fitness differences can outweigh inter-individual variation and therefore could form the basis for personalised clinical management in the future.
2022-05-03 | GSE178936 | GEO