scholarly journals Complex polymorphic genetic architecture underlies trans-regulatory variation among strains of Saccharomyces cerevisiae

2019 ◽  
Author(s):  
Brian P. H. Metzger ◽  
Patricia J. Wittkopp
Keyword(s):  
Gene Expression ◽  
Saccharomyces Cerevisiae ◽  
Genetic Architecture ◽  
Promoter Activity ◽  
Reference Strain ◽  
Stabilizing Selection ◽  
Empirical Measures ◽  
Regulatory Variation ◽  
Multiple Strains ◽  
Opposing Effects

AbstractHeritable variation in gene expression is common within species. Much of this variation is due to genetic changes at loci other than the affected gene and is thus trans-acting. This trans-regulatory variation is often polygenic, with individual variants typically having small effects, making the genetic architecture of trans-regulatory variation challenging to study. Consequently, key questions about trans-regulatory variation remain, including how selection affects this variation and how trans-regulatory variants are distributed throughout the genome and within species. Here, we show that trans-regulatory variation affecting TDH3 promoter activity is common among strains of Saccharomyces cerevisiae. Comparing this variation to neutral models of trans-regulatory evolution based on empirical measures of mutational effects revealed that stabilizing selection has constrained this variation. Using a powerful quantitative trait locus (QTL) mapping method, we identified ∼100 loci altering expression between a reference strain and each of three genetically distinct strains. In all three cases, the non-reference strain alleles increased and decreased TDH3 promoter activity with similar frequencies, suggesting that stabilizing selection maintained many trans-acting variants with opposing effects. Loci altering expression were located throughout the genome, with many loci being strain specific and others being shared among multiple strains. These findings are consistent with theory showing stabilizing selection for quantitative traits can maintain many alleles with opposing effects, and the wide-spread distribution of QTL throughout the genome is consistent with the omnigenic model of complex trait variation. Furthermore, the prevalence of alleles with opposing effects might provide raw material for compensatory evolution and developmental systems drift.Significance statementGene expression varies among individuals in a population due to genetic differences in regulatory components. To determine how this variation is distributed within genomes and species, we used a powerful genetic mapping approach to examine multiple strains of Saccharomyces cerevisiae. Despite evidence of stabilizing selection maintaining gene expression levels among strains, we find hundreds of loci that affect expression of a single gene. These loci vary among strains and include similar frequencies of alleles that increase and decrease expression. As a result, each strain contains a unique set of compensatory alleles that lead to similar levels of gene expression among strains. This regulatory variation might form the basis for large scale regulatory rewiring observed between distantly related species.

scholarly journals Response of Regulatory Genetic Variation in Gene Expression to Environmental Change in Drosophila melanogaster

2020 ◽  
Author(s):  
Wen Huang ◽  
Mary Anna Carbone ◽  
Richard F. Lyman ◽  
Robert H. H. Anholt ◽  
Trudy F. C. Mackay
Keyword(s):  
Gene Expression ◽  
Drosophila Melanogaster ◽  
Genetic Architecture ◽  
Genetic Variance ◽  
Network Connectivity ◽  
Genotype By Environment Interaction ◽  
Stabilizing Selection ◽  
Environment Interaction ◽  
Genotype By Environment ◽  
Phenotypic Responses

AbstractThe genetics of phenotypic responses to changing environments remains elusive. Using whole genome quantitative gene expression as a model, we studied how the genetic architecture of regulatory variation in gene expression changed in a population of fully sequenced inbred Drosophila melanogaster strains when flies developed at different environments (25 °C and 18 °C). We found a substantial fraction of the transcriptome exhibited genotype by environment interaction, implicating environmentally plastic genetic architecture of gene expression. Genetic variance in expression increased at 18 °C relative to 25 °C for most genes that had a change in genetic variance. Although the majority of expression quantitative trait loci (eQTLs) for the gene expression traits in the two environments were shared and had similar effects, analysis of the environment-specific eQTLs revealed enrichment of binding sites for two transcription factors. Finally, although genotype by environment interaction in gene expression could potentially disrupt genetic networks, the co-expression networks were highly conserved across environments. Genes with higher network connectivity were under stronger stabilizing selection, suggesting that stabilizing selection on expression plays an important role in promoting network robustness.

scholarly journals Genotype by environment interaction for gene expression in Drosophila melanogaster

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Wen Huang ◽  
Mary Anna Carbone ◽  
Richard F. Lyman ◽  
Robert R. H. Anholt ◽  
Trudy F. C. Mackay
Keyword(s):  
Gene Expression ◽  
Drosophila Melanogaster ◽  
Genetic Architecture ◽  
Genetic Variance ◽  
Network Connectivity ◽  
Genotype By Environment Interaction ◽  
Stabilizing Selection ◽  
Environment Interaction ◽  
Genotype By Environment ◽  
Phenotypic Responses

Abstract The genetics of phenotypic responses to changing environments remains elusive. Using whole-genome quantitative gene expression as a model, here we study how the genetic architecture of regulatory variation in gene expression changed in a population of fully sequenced inbred Drosophila melanogaster strains when flies developed in different environments (25 °C and 18 °C). We find a substantial fraction of the transcriptome exhibited genotype by environment interaction, implicating environmentally plastic genetic architecture of gene expression. Genetic variance in expression increases at 18 °C relative to 25 °C for most genes that have a change in genetic variance. Although the majority of expression quantitative trait loci (eQTLs) for the gene expression traits in the two environments are shared and have similar effects, analysis of the environment-specific eQTLs reveals enrichment of binding sites for two transcription factors. Finally, although genotype by environment interaction in gene expression could potentially disrupt genetic networks, the co-expression networks are highly conserved across environments. Genes with higher network connectivity are under stronger stabilizing selection, suggesting that stabilizing selection on expression plays an important role in promoting network robustness.

scholarly journals Empirical measures of mutational effects define neutral models of regulatory evolution in Saccharomyces cerevisiae

2019 ◽  
Vol 116 (42) ◽  
pp. 21085-21093 ◽  
Author(s):  
Andrea Hodgins-Davis ◽  
Fabien Duveau ◽  
Elizabeth A. Walker ◽  
Patricia J. Wittkopp
Keyword(s):  
Gene Expression ◽  
Saccharomyces Cerevisiae ◽  
Phenotypic Variation ◽  
Natural Populations ◽  
Point Mutations ◽  
Regulatory Evolution ◽  
Empirical Measures ◽  
Expression Variation ◽  
Neutral Models ◽  
New Mutations

Understanding how phenotypes evolve requires disentangling the effects of mutation generating new variation from the effects of selection filtering it. Tests for selection frequently assume that mutation introduces phenotypic variation symmetrically around the population mean, yet few studies have tested this assumption by deeply sampling the distributions of mutational effects for particular traits. Here, we examine distributions of mutational effects for gene expression in the budding yeast Saccharomyces cerevisiae by measuring the effects of thousands of point mutations introduced randomly throughout the genome. We find that the distributions of mutational effects differ for the 10 genes surveyed and are inconsistent with normality. For example, all 10 distributions of mutational effects included more mutations with large effects than expected for normally distributed phenotypes. In addition, some genes also showed asymmetries in their distribution of mutational effects, with new mutations more likely to increase than decrease the gene’s expression or vice versa. Neutral models of regulatory evolution that take these empirically determined distributions into account suggest that neutral processes may explain more expression variation within natural populations than currently appreciated.

UBE2L6 is Involved in Cisplatin Resistance by Regulating the Transcription of ABCB6

2020 ◽  
Vol 20 (12) ◽  
pp. 1487-1496 ◽  
Author(s):  
Midori Murakami ◽  
Hiroto Izumi ◽  
Tomoko Kurita ◽  
Chiho Koi ◽  
Yasuo Morimoto ◽  
...  
Keyword(s):  
Gene Expression ◽  
Promoter Activity ◽  
Anticancer Agent ◽  
Cisplatin Resistance ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Molecular Target ◽  
Transcriptional Level ◽  
And Control ◽  
Resistant Cells

Background: Cisplatin is an important anticancer agent in cancer chemotherapy, but when resistant cells appear, treatment becomes difficult, and the prognosis is poor. Objective: In this study, we investigated the gene expression profile in cisplatin sensitive and resistant cells, and identified the genes involved in cisplatin resistance. Methods: Comparison of gene expression profiles revealed that UBE2L6 mRNA is highly expressed in resistant cells. To elucidate whether UBE2L6 is involved in the acquisition of cisplatin resistance, UBE2L6- overexpressing cells established from cisplatin-sensitive cells and UBE2L6-silenced cells developed from cisplatin- resistant cells were generated, and the sensitivity of cisplatin was examined. Results: The sensitivity of the UBE2L6-overexpressing cells did not change compared with the control cells, but the UBE2L6-silenced cells were sensitized to cisplatin. To elucidate the mechanism of UBE2L6 in cisplatin resistance, we compared the gene expression profiles of UBE2L6-silenced cells and control cells and found that the level of ABCB6 mRNA involved in cisplatin resistance was decreased. Moreover, ABCB6 promoter activity was partially suppressed in UBE2L6-silenced cells. Conclusion: These results suggest that cisplatin-resistant cells have upregulated UBE2L6 expression and contribute to cisplatin resistance by regulating ABCB6 expression at the transcriptional level. UBE2L6 might be a molecular target that overcomes cisplatin resistance.

scholarly journals Mot3, a Zn Finger Transcription Factor That Modulates Gene Expression and Attenuates Mating Pheromone Signaling in Saccharomyces cerevisiae

Genetics ◽  
1998 ◽  
Vol 149 (2) ◽  
pp. 879-892 ◽  
Author(s):  
Anatoly V Grishin ◽  
Michael Rothenberg ◽  
Maureen A Downs ◽  
Kendall J Blumer
Keyword(s):  
Gene Expression ◽  
Saccharomyces Cerevisiae ◽  
Signaling Pathway ◽  
G Protein ◽  
Binding Sites ◽  
Dependent Manner ◽  
Pheromone Response ◽  
Mating Pheromone ◽  
Pheromone Signaling ◽  
Yeast Genes

Abstract In the yeast Saccharomyces cerevisiae, mating pheromone response is initiated by activation of a G protein- and mitogen-activated protein (MAP) kinase-dependent signaling pathway and attenuated by several mechanisms that promote adaptation or desensitization. To identify genes whose products negatively regulate pheromone signaling, we screened for mutations that suppress the hyperadaptive phenotype of wild-type cells overexpressing signaling-defective G protein β subunits. This identified recessive mutations in MOT3, which encodes a nuclear protein with two Cys2-His2 Zn fingers. MOT3 was found to be a dosage-dependent inhibitor of pheromone response and pheromone-induced gene expression and to require an intact signaling pathway to exert its effects. Several results suggested that Mot3 attenuates expression of pheromone-responsive genes by mechanisms distinct from those used by the negative transcriptional regulators Cdc36, Cdc39, and Mot2. First, a Mot3-lexA fusion functions as a transcriptional activator. Second, Mot3 is a dose-dependent activator of several genes unrelated to pheromone response, including CYC1, SUC2, and LEU2. Third, insertion of consensus Mot3 binding sites (C/A/T)AGG(T/C)A activates a promoter in a MOT3-dependent manner. These findings, and the fact that consensus binding sites are found in the 5′ flanking regions of many yeast genes, suggest that Mot3 is a globally acting transcriptional regulator. We hypothesize that Mot3 regulates expression of factors that attenuate signaling by the pheromone response pathway.

scholarly journals Screening and Genetic Network Analysis of Genes Involved in Freezing and Thawing Resistance in DaMDHAR—Expressing Saccharomyces cerevisiae Using Gene Expression Profiling

Genes ◽  
2021 ◽  
Vol 12 (2) ◽  
pp. 219
Author(s):  
Il-Sup Kim ◽  
Woong Choi ◽  
Jonghyeon Son ◽  
Jun Hyuck Lee ◽  
Hyoungseok Lee ◽  
...  
Keyword(s):  
Gene Expression ◽  
Saccharomyces Cerevisiae ◽  
Transcription Factors ◽  
Stress Tolerance ◽  
Genetic Network ◽  
Yeast Cells ◽  
Enzymatic Antioxidants ◽  
Freezing And Thawing ◽  
Metal Ion Homeostasis ◽  
Transgenic Yeast

The cryoprotection of cell activity is a key determinant in frozen-dough technology. Although several factors that contribute to freezing tolerance have been reported, the mechanism underlying the manner in which yeast cells respond to freezing and thawing (FT) stress is not well established. Therefore, the present study demonstrated the relationship between DaMDHAR encoding monodehydroascorbate reductase from Antarctic hairgrass Deschampsia antarctica and stress tolerance to repeated FT cycles (FT2) in transgenic yeast Saccharomyces cerevisiae. DaMDHAR-expressing yeast (DM) cells identified by immunoblotting analysis showed high tolerance to FT stress conditions, thereby causing lower damage for yeast cells than wild-type (WT) cells with empty vector alone. To detect FT2 tolerance-associated genes, 3′-quant RNA sequencing was employed using mRNA isolated from DM and WT cells exposed to FT (FT2) conditions. Approximately 332 genes showed ≥2-fold changes in DM cells and were classified into various groups according to their gene expression. The expressions of the changed genes were further confirmed using western blot analysis and biochemical assay. The upregulated expression of 197 genes was associated with pentose phosphate pathway, NADP metabolic process, metal ion homeostasis, sulfate assimilation, β-alanine metabolism, glycerol synthesis, and integral component of mitochondrial and plasma membrane (PM) in DM cells under FT2 stress, whereas the expression of the remaining 135 genes was partially related to protein processing, selenocompound metabolism, cell cycle arrest, oxidative phosphorylation, and α-glucoside transport under the same condition. With regard to transcription factors in DM cells, MSN4 and CIN5 were activated, but MSN2 and MGA1 were not. Regarding antioxidant systems and protein kinases in DM cells under FT stress, CTT1, GTO, GEX1, and YOL024W were upregulated, whereas AIF1, COX2, and TRX3 were not. Gene activation represented by transcription factors and enzymatic antioxidants appears to be associated with FT2-stress tolerance in transgenic yeast cells. RCK1, MET14, and SIP18, but not YPK2, have been known to be involved in the protein kinase-mediated signalling pathway and glycogen synthesis. Moreover, SPI18 and HSP12 encoding hydrophilin in the PM were detected. Therefore, it was concluded that the genetic network via the change of gene expression levels of multiple genes contributing to the stabilization and functionality of the mitochondria and PM, not of a single gene, might be the crucial determinant for FT tolerance in DaMDAHR-expressing transgenic yeast. These findings provide a foundation for elucidating the DaMDHAR-dependent molecular mechanism of the complex functional resistance in the cellular response to FT stress.

scholarly journals Fibroblast Growth Factors Regulate Prolactin Transcription via an Atypical Rac-Dependent Signaling Pathway

2003 ◽  
Vol 17 (10) ◽  
pp. 1921-1930 ◽  
Author(s):  
Twila A. Jackson ◽  
David M. Koterwas ◽  
Melissa A. Morgan ◽  
Andrew P. Bradford
Keyword(s):  
Gene Expression ◽  
Growth Factors ◽  
Signaling Pathway ◽  
Promoter Activity ◽  
Fibroblast Growth Factors ◽  
Dominant Negative ◽  
Pituitary Cells ◽  
Dependent Manner ◽  
Fibroblast Growth ◽  
Prl Gene

Abstract Fibroblast growth factors (FGFs) play a critical role in pituitary development and in pituitary tumor formation and progression. We have previously characterized FGF signal transduction and regulation of the tissue-specific rat prolactin (rPRL) promoter in GH4 pituitary cells. FGF induction of rPRL transcription is independent of Ras, but mediated by a protein kinase C-δ (PKCδ)-dependent activation of MAPK (ERK). Here we demonstrate a functional role for the Rho family monomeric G protein, Rac1, in FGF regulation of PRL gene expression via an atypical signaling pathway. Expression of dominant negative Rac, but not RhoA or Cdc42, selectively inhibited FGF-induced rPRL promoter activity. Moreover, expression of dominant negative Rac also attenuated FGF-2 and FGF-4 stimulation of MAPK (ERK). However, in contrast to other Rac-dependent signaling pathways, FGF activation of rPRL promoter activity was independent of the c-Jun N-terminal kinase (JNK) and phosphoinositide 3-kinase/Akt cascades. FGFs failed to activate JNK1 or JNK2, and expression of dominant negative JNK or Akt constructs did not block FGF-induced PRL transcription. Consistent with the role of PKCδ in FGF regulation of PRL gene expression, activation of the rPRL promoter was blocked by an inhibitor of phospholipase Cγ (PLCγ) activity. FGF treatment also induced rapid tyrosine phosphorylation of PLCγ in a Rac-dependent manner. These results suggest that FGF-2 and FGF-4 activate PRL gene expression via a novel Rac1, PLCγ, PKCδ, and ERK cascade, independent of phosphoinositol-3-kinase and JNK.

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