Trans-acting regulatory variation in Saccharomyces cerevisiae and the role of transcription factors

Yvert, Gaël; Brem, Rachel B.; Whittle, Jacqueline; Akey, Joshua M.; Foss, Eric J.; Smith, Erin N.; Mackelprang, Rachel; Kruglyak, Leonid

doi:10.1038/ng1222

Cited by 578 publications

(665 citation statements)

References 39 publications

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“…Recently, a yeast intercross study showed a notable absence of over-represented gene categories near trans eQTLs, suggesting no hierarchy of functional classes 36 . We investigated whether the same conclusion was true for our radiation hybrid data.…”

Section: Functional Categorization Of Trans Ceqtlsmentioning

confidence: 99%

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Fine mapping of regulatory loci for mammalian gene expression using radiation hybrids

et al. 2008

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We mapped regulatory loci for nearly all protein-coding genes in mammals using comparative genomic hybridization and expression array measurements from a panel of mouse-hamster radiation hybrid cell lines. The large number of breaks in the mouse chromosomes and the dense genotyping of the panel allowed extremely sharp mapping of loci. As the regulatory loci result from extra gene dosage, we call them copy number expression quantitative trait loci, or ceQTLs. The −2log 10 P support interval for the ceQTLs was <150 kb, containing an average of <2-3 genes. We identified 29,769 trans ceQTLs with −log 10 P > 4, including 13 hotspots each regulating >100 genes in trans. Further, this work identifies 2,761 trans ceQTLs harboring no known genes, and provides evidence for a mode of gene expression autoregulation specific to the X chromosome.

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Section: Functional Categorization Of Trans Ceqtlsmentioning

confidence: 99%

“…The absence of Gene Ontology category enrichment near trans ceQTLs in the yeast intercross study 36 may represent lack of naturally occurring polymorphisms for genes at network hubs. This relative deficiency might arise because of selective pressure.…”

Section: Functional Categorization Of Trans Ceqtlsmentioning

confidence: 99%

Fine mapping of regulatory loci for mammalian gene expression using radiation hybrids

et al. 2008

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“…Following the ''gold rush'' ushered in by the sequencing of the S. cerevisiae genome, efforts are being made to revisit this natural diversity. Phenotypic analyses of diverse yeast strains [1,2] and the application of microarray technology to the analysis of allelic variation [3][4][5][6][7][8] and population genetic variation in gene expression [9][10][11] are providing new insights into the ecology and diversity of the species. Such analyses should also be applicable to the elucidation of pathways that face strong diversifying selection, such as those governing uptake and metabolism of nutrients.…”

Section: Introductionmentioning

confidence: 99%

Harnessing Natural Diversity to Probe Metabolic Pathways

Homann¹,

Cai²,

Becker³

et al. 2005

PLoS Genet

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Analyses of cellular processes in the yeast Saccharomyces cerevisiae rely primarily upon a small number of highly domesticated laboratory strains, leaving the extensive natural genetic diversity of the model organism largely unexplored and unexploited. We asked if this diversity could be used to enrich our understanding of basic biological processes. As a test case, we examined a simple trait: the utilization of di/tripeptides as nitrogen sources. The capacity to import small peptides is likely to be under opposing selective pressures (nutrient utilization versus toxin vulnerability) and may therefore be sculpted by diverse pathways and strategies. Hitherto, dipeptide utilization in S. cerevisiae was solely ascribed to the activity of a single protein, the Ptr2p transporter. Using high-throughput phenotyping and several genetically diverse strains, we identified previously unknown cellular activities that contribute to this trait. We find that the Dal5p allantoate/ureidosuccinate permease is also capable of facilitating di/ tripeptide transport. Moreover, even in the absence of Dal5p and Ptr2p, an additional activity-almost certainly the periplasmic asparaginase II Asp3p-facilitates the utilization of dipeptides with C-terminal asparagine residues by a different strategy. Another, as-yet-unidentified activity enables the utilization of dipeptides with C-terminal arginine residues. The relative contributions of these activities to the utilization of di/tripeptides vary among the strains analyzed, as does the vulnerability of these strains to a toxic dipeptide. Only by sampling the genetic diversity of multiple strains were we able to uncover several previously unrecognized layers of complexity in this metabolic pathway. High-throughput phenotyping facilitates the rapid exploration of the molecular basis of biological complexity, allowing for future detailed investigation of the selective pressures that drive microbial evolution.Citation: Homann OR, Cai H, Becker JM, Lindquist SL (2005) Harnessing natural diversity to probe metabolic pathways. PLoS Genet 1(6): e80.

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“…(cis regulation refers to the control of expression by the gene itself whereas trans regulation refers to the influence of the genetic background.) Many studies have addressed this question at various levels of divergence (1)(2)(3)(4)(5)(6)(7)(8)(9). For example, one may measure the expressions of two alleles at the locus of interest in a common genetic background (usually F 1 s) (1,2,5).…”

mentioning

confidence: 99%

Complex genetic interactions underlying expression differences between Drosophila races: Analysis of chromosome substitutions

Wang

McPeek³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Regulation of gene expression is usually separated into cis and trans components. The separation may become artificial if much of the variation in expression is under multigenic and epistatic (e.g., cis-bytrans) control. There is hence a need to quantify the relative contribution of cis, trans, and cis-by-trans effects on expression divergence at different levels of evolution. To do so across the whole genome, we analyzed the full set of chromosome-substitution lines between the two behavioral races of Drosophila melanogaster. Our observations: (i) Only Ϸ3% of the genes with an expression difference are purely cis regulated. In fact, relatively few genes are governed by simple genetics because nearly 80% of expression differences are controlled by at least two chromosomes. (ii) For 14% of the genes, cis regulation does play a role but usually in conjunction with trans regulation. This joint action of cis and trans effects, either additive or epistatic, is referred to as inclusive cis effect. (iii) The percentage of genes with inclusive cis effect increases to 32% among genes that are strongly differentiated between the two races. (iv) We observed a nonrandom distribution of trans-acting factors, with a substantial deficit on the second chromosome. Between Drosophila racial groups, trans regulation of expression difference is extensive, and cis regulation often evolves in conjunction with trans effects.K nowledge of the genetics of complex traits is fundamental to modern medicine, agriculture, and evolutionary biology. Among all complex traits, gene expression as phenotype may be most amenable to genetic analysis. The first question about expression regulation naturally is whether there is a cis component and how strong the cis component is. (cis regulation refers to the control of expression by the gene itself whereas trans regulation refers to the influence of the genetic background.) Many studies have addressed this question at various levels of divergence (1-9). For example, one may measure the expressions of two alleles at the locus of interest in a common genetic background (usually F 1 s) (1, 2, 5). Because the collection of trans-acting factors in the same cellular environment is assumed to affect the two alleles equally, asymmetric allelic expression implies differences due to cis-regulatory divergence. Similarly, expression quantitative trait loci (eQTL) mapping permits inference of cis regulation if the eQTL is mapped closely to the expressed gene itself (6-10).A second question is how strong cis regulation is relative to trans regulation. In the extreme case where most expression variation is controlled by cis-trans interactions (e.g., joint actions of cis elements and transcription factors), the question would not be very meaningful because cis and trans components are both indispensable. It is desirable to explicitly model expression regulation to include cis, trans, and cis-by-trans control. Many kinds of data allow such explicit modeling. The use of large numbers of recombinant strains for express...

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Trans-acting regulatory variation in Saccharomyces cerevisiae and the role of transcription factors

Cited by 578 publications

References 39 publications

Fine mapping of regulatory loci for mammalian gene expression using radiation hybrids

Fine mapping of regulatory loci for mammalian gene expression using radiation hybrids

Harnessing Natural Diversity to Probe Metabolic Pathways

Complex genetic interactions underlying expression differences between Drosophila races: Analysis of chromosome substitutions

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