Changes in gene expression predictably shift and switch genetic interactions
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA506414 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8234150_1.fastq.gz | Fastqsanger.gz | |||
| SRR8234150_2.fastq.gz | Fastqsanger.gz | |||
| SRR8234160_1.fastq.gz | Fastqsanger.gz | |||
| SRR8234160_2.fastq.gz | Fastqsanger.gz | |||
| SRR8234170_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 62 |
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Project description:An important goal in disease genetics and evolutionary biology is to understand how mutations combine together to alter phenotypes and fitness. Non-additive genetic (epistatic) interactions between mutations occur extensively within and between genes, which makes accurate genetic prediction a difficult challenge. Moreover, for unclear reasons, the interactions between mutations change quite extensively across conditions, cell types, and species, with important consequences for both evolution and precision medicine such as the exploitation of synthetic lethality in cancer. To better understand the plasticity of genetic interactions, we reduced the problem to a minimal system where we combined mutations within a single protein performing a single cellular function. The only perturbation to the system was a change in the expression level of the mutated gene itself. Even in this minimal system, the interactions between mutations were highly plastic, with interactions changing in both magnitude and sign when the expression level was altered. Mathematical modelling revealed the cause of this as the non-linear relationship between the concentration of the protein and the cellular phenotype.These non-linearities are widespread in biology and transform expression level-independent effects of mutations on protein folding and stability into mutation outcomes and interactions that shift and switch as gene expression changes. This plasticity of mutation effects and genetic interactions has important implications for human disease and evolutionary theory.
2019-07-31 | GSE122806 | GEO
Project description:Non-additive interactions between mutations occur extensively and also change across conditions, making genetic prediction a difficult challenge. To better understand the plasticity of genetic interactions (epistasis), we combine mutations in a single protein performing a single function (a transcriptional repressor inhibiting a target gene). Even in this minimal system, genetic interactions switch from positive (suppressive) to negative (enhancing) as the expression of the gene changes. These seemingly complicated changes can be predicted using a mathematical model that propagates the effects of mutations on protein folding to the cellular phenotype. More generally, changes in gene expression should be expected to alter the effects of mutations and how they interact whenever the relationship between expression and a phenotype is nonlinear, which is the case for most genes. These results have important implications for understanding genotype-phenotype maps and illustrate how changes in genetic interactions can often-but not always-be predicted by hierarchical mechanistic models.
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Project description:A central question in genetics and evolution is the extent to which mutations have outcomes that change depending on the genetic context in which they occur. Pairwise interactions between mutations have been systematically mapped within and between genes, and contribute substantially to phenotypic variation amongst individuals. However, the extent to which genetic interactions themselves are stable or dynamic across genotypes is unclear. Here we quantify >45,000 genetic interactions between the same 87 pairs of mutations across >500 closely related genotypes of a yeast tRNA. Strikingly, all pairs of mutations interacted in at least 9% of genetic backgrounds and all pairs switched from interacting positively to interacting negatively in different genotypes (FDR<0.1). Higher order interactions are also abundant and dynamic across genotypes. The epistasis in this molecule means that all individual mutations switch from detrimental to beneficial in even closely-related genotypes. As a consequence, accurate genetic prediction requires mutation effects to be measured across different genetic backgrounds and the use of higher order epistatic terms.
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Project description:Programmed genetic rearrangements in lymphocytes require transcription at antigen receptor genes to promote accessibility for initiating double-strand break (DSB) formation critical for DNA recombination and repair. Here we show that activated B cells deficient in the PTIP component of the MLL3 (mixed-lineage leukemia 3) /MLL4 complex display impaired histone methylation (H3K4me3) and transcription initiation of downstream switch regions at the immunoglobulin heavy-chain (Igh) locus leading to defective immunoglobulin class-switching. We also show that PTIP accumulation at DSBs contributes to class-switch recombination (CSR) and genome stability independently from Igh switch transcription. These results demonstrate that PTIP promotes specific chromatin changes that control the accessibility of the Igh locus to CSR, and suggest a non-redundant role for the MLL3/MLL4 complex in altering antibody effector function. Genome-wide analysis of histone modifications, PTIP, and Pol II in PTIP-WT and PTIP-KO mouse activated B cells.
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Project description:Gardner2000 - genetic toggle switch in E.coli
The behaviour of the genetic toggle switch and the conditions for bistability has been studies using a synthetic, bistable gene circuit.
This model is described in the article:
Construction of a genetic toggle switch in Escherichia coli.
Gardner TS, Cantor CR, Collins JJ
Nature. 2000 Jan 20;403(6767):339-42.
Abstract:
It has been proposed' that gene-regulatory circuits with virtually any desired property can be constructed from networks of simple regulatory elements. These properties, which include multistability and oscillations, have been found in specialized gene circuits such as the bacteriophage lambda switch and the Cyanobacteria circadian oscillator. However, these behaviours have not been demonstrated in networks of non-specialized regulatory components. Here we present the construction of a genetic toggle switch-a synthetic, bistable gene-regulatory network-in Escherichia coli and provide a simple theory that predicts the conditions necessary for bistability. The toggle is constructed from any two repressible promoters arranged in a mutually inhibitory network. It is flipped between stable states using transient chemical or thermal induction and exhibits a nearly ideal switching threshold. As a practical device, the toggle switch forms a synthetic, addressable cellular memory unit and has implications for biotechnology, biocomputing and gene therapy.
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2024-09-02 | BIOMD0000000507 | BioModels
Project description:A coregulator shift, rather than the canonical switch, underlies thyroid hormone action in liver
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Project description:Environmental and Genetic Modifiers of squint Penetrance during Zebrafish Embryogenesis. Gene expression changes due to temperature shift during devlopment in homozygous squint mutants and wild_type embryos
2006-07-24 | E-MEXP-775 | biostudies-arrayexpress
Project description:Programmed genetic rearrangements in lymphocytes require transcription at antigen receptor genes to promote accessibility for initiating double-strand break (DSB) formation critical for DNA recombination and repair. Here we show that activated B cells deficient in the PTIP component of the MLL3 (mixed-lineage leukemia 3) /MLL4 complex display impaired histone methylation (H3K4me3) and transcription initiation of downstream switch regions at the immunoglobulin heavy-chain (Igh) locus leading to defective immunoglobulin class-switching. We also show that PTIP accumulation at DSBs contributes to class-switch recombination (CSR) and genome stability independently from Igh switch transcription. These results demonstrate that PTIP promotes specific chromatin changes that control the accessibility of the Igh locus to CSR, and suggest a non-redundant role for the MLL3/MLL4 complex in altering antibody effector function.
2010-08-25 | GSE20852 | GEO
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