Genetic compensation in a stable slc25a46 mutant zebrafish
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA575769 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10230303.fastq.gz | Fastqsanger.gz | |||
| SRR10230304.fastq.gz | Fastqsanger.gz | |||
| SRR10230305.fastq.gz | Fastqsanger.gz | |||
| SRR10230306.fastq.gz | Fastqsanger.gz | |||
| SRR10230307.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 12 |
Similar Datasets
Project description:A phenomenon of genetic compensation is commonly observed when an organism with a disease-bearing mutation does not show phenotypic penetrance due to compensatory gene expression changes. Reports have spread showing the absence of disease phenotypes in stable knockout models, but not in transient knockdown models. As such, these incidents present a challenge for the disease modeling field, although a deeper understanding of genetic compensation may also hold the key for novel therapeutic interventions. In our study we created a knockout model of slc25a46 gene, which is a recently discovered important player in mitochondrial dynamics and deleterious mutations in which are known to cause peripheral neuropathy, optic atrophy and cerebellar ataxia. We report a case of genetic compensation in the fourth generation (F4) of slc25a46 knockout zebrafish mutant, in contrast to a penetrant disease phenotype in the first generation (F0) slc25a46 mosaic mutant (crispant), generated with CRISPR/Cas-9 technology. We show that F0 crispant phenotype is specific and rescuable. By performing mRNA sequencing, we define significant changes in slc25a46 F4 mutant’s gene expression profile, which are nearly not present in F0 crispants. We find that among the top candidates for the phenotypic compensation anxa6 gene stands out as a functionally relevant player in mitochondrial dynamics. We also find that our genetic compensation case does not arise from previously identified mechanisms driven by mutant mRNA decay. Our study serves as an important contribution to the understanding of phenomenon of genetic compensation and presents novel insights on Slc25a46 function. Furthermore, our study provides the evidence for the efficiency of F0 CRISPR screens for disease candidate genes, which may advance the field of functional genetics.
2019-10-04 | GSE138414 | GEO
Project description:Investigation of genetic compensation in tdp1-/- zebrafish embryos
| PRJNA626551 | ENA
Project description:Genetic compensation is triggered by mutant mRNA degradation
| PRJNA470582 | ENA
Project description:Tdp1, tyrosyl-DNA phosphodiesterase 1, is an enzyme responsible for the repair of DNA breaks resulting from aberrant topoisomerase 1 activity, called Top1 cleavage complexes (Top1-CCs). Mutation of Tdp1 leads to a progressive neurodegenerative disorder spinocerebellar ataxia with axonal neuropathy 1 (SCAN1). We have generated tdp1-/- zebrafish as a model for SCAN1. The adult fish have a behavioral defect and hypersensitivity to camptothecin (CPT), a Top1 poison. Strikingly, the embryos do not show increased sensitivity to CPT, unlike any other reported vertebrate models, suggesting genetic compensation is at play at this stage. We thus carried out microarray analysis in CPT-treated zebrafish embryos to compare the gene expression profiles of tdp1WT and tdp1-/- genotypes. Gene expression analysis revealed 1,8111 genes that were differentially expressed: 1,071 were upregulated and 740 were downregulated. Sprtn and neil1, two potential compensation candidates were upregulated in the tdp1-/- embryos.
2022-04-19 | GSE148923 | GEO
Project description:Genetic compensation by transcriptional modulation of related gene(s) (also known as transcriptional adaptation) has been reported in numerous systems1-3; however, whether and how such a response can be activated in the absence of protein feedback loops is unknown. Here, we develop and analyze several models of transcriptional adaptation in zebrafish and mouse that we show are not caused by loss of protein function. We find that the increase in transcript levels is due to enhanced transcription, and observe a correlation between the levels of mutant mRNA decay and transcriptional upregulation of related genes. To assess the role of mutant mRNA degradation in triggering transcriptional adaptation, we use genetic and pharmacological approaches and find that mRNA degradation is indeed required for this process. Notably, uncapped RNAs, themselves subjected to rapid degradation, can also induce transcriptional adaptation. Next, we generate alleles that fail to transcribe the mutated gene and find that they do not show transcriptional adaptation, and exhibit more severe phenotypes than those observed in alleles displaying mutant mRNA decay. Transcriptome analysis of these different alleles reveals the upregulation of hundreds of genes with enrichment for those showing sequence similarity with the mutated gene's mRNA, suggesting a model whereby mRNA degradation products induce the response via sequence similarity. These results expand the role of the mRNA surveillance machinery in buffering against mutations by triggering the transcriptional upregulation of related genes. Besides implications for our understanding of disease-causing mutations, our findings will help design mutant alleles with minimal transcriptional adaptation-derived compensation.
2019-01-17 | GSE114212 | GEO
Project description:Mutations in CEP290, a large multidomain coiled coil protein, are associated with multiple cilia-associated syndromes. Over 130 CEP290 mutations have been linked to a wide spectrum of human ciliopathies, raising the question of how mutations in a single gene cause different disease syndromes. In zebrafish the expressivity of cep290 deficiencies were linked to the type of genetic ablation: acute cep290 morpholino knockdown caused severe cilia-related phenotypes while defects in a Crispr/Cas9 genetic mutant were restricted to photoreceptor defects. Here we show that milder phenotypes in genetic mutants were associated with upregulation of genes encoding the cilia-associated small GTPases arl3, arl13b, and unc119b. Upregulation of UNC119b was also observed in urine-derived renal epithelial cells from human JBTS CEP290 patients. Ectopic expression of arl3, arl13b and unc119b in cep290 morphant zebrafish embryos rescued Kupffer's vesicle cilia and partially rescued photoreceptor outer segment defects. The results suggest that genetic compensation by upregulation of genes involved in a common subcellular process, lipidated protein trafficking to cilia, may be a conserved mechanism contributing to genotype-phenotype variations observed in CEP290 deficiencies.
2021-05-26 | GSE175491 | GEO
Project description:Understanding buffering mechanisms for various perturbations is essential for understanding robustness in cellular systems. Protein-level dosage compensation, which arises when changes in gene copy number do not translate linearly into protein level, is one mechanism for buffering against genetic perturbations. Here, we present an approach to identify genes with dosage compensation by increasing the copy number of individual genes using the genetic tug-of-war technique. Our screen of chromosome I suggests that dosage-compensated genes constitute approximately 10% of the genome and consist predominantly of subunits of multi-protein complexes. Importantly, because subunit levels are regulated in a stoichiometry-dependent manner, dosage compensation plays a crucial role in maintaining subunit stoichiometries. Indeed, we observed changes in the levels of a complex when its subunit stoichiometries were perturbed. We further analyzed compensation mechanisms using a proteasome-defective mutant as well as ribosome profiling, which provided strong evidence for compensation by ubiquitin-dependent degradation but not reduced translational efficiency. Thus, our study provides a systematic understanding of dosage compensation and highlights that this post-translational regulation is a critical aspect of robustness in cellular systems.
2016-12-30 | GSE85036 | GEO
Project description:A phenomenon of genetic compensation is commonly observed when an organism with a disease-bearing mutation shows incomplete penetrance of the disease phenotype. Such incomplete phenotypic penetrance, or genetic compensation, is more commonly found in stable knockout models, rather than transient knockdown models. As such, these incidents present a challenge for the disease modeling field, although a deeper understanding of genetic compensation may also hold the key for novel therapeutic interventions. In our study we created a knockout model of slc25a46 gene, which is a recently discovered important player in mitochondrial dynamics, and deleterious mutations in which are known to cause peripheral neuropathy, optic atrophy and cerebellar ataxia. We report a case of genetic compensation in a stable slc25a46 homozygous zebrafish mutant (hereafter referred as "mutant"), in contrast to a penetrant disease phenotype in the first generation (F0) slc25a46 mosaic mutant (hereafter referred as "crispant"), generated with CRISPR/Cas-9 technology. We show that the crispant phenotype is specific and rescuable. By performing mRNA sequencing, we define significant changes in slc25a46 mutant's gene expression profile, which are largely absent in crispants. We find that among the most significantly altered mRNAs, anxa6 gene stands out as a functionally relevant player in mitochondrial dynamics. We also find that our genetic compensation case does not arise from mechanisms driven by mutant mRNA decay. Our study contributes to the growing evidence of the genetic compensation phenomenon and presents novel insights about Slc25a46 function. Furthermore, our study provides the evidence for the efficiency of F0 CRISPR screens for disease candidate genes, which may be used to advance the field of functional genetics.
| S-EPMC7092968 | biostudies-literature
Project description:The zebrafish has proven to be a versatile and valuable model for investigating the molecular and cellular basis of Fragile X syndrome (FXS). Reduction of expression of the zebrafish FMR1-ortholgous gene, fmr1, causes developmental and behavioural phenotypes related to the human syndrome. The hu2787 nonsense mutation allele of fmr1 is now the most widely used zebrafish model of FXS, although the FXS-relevant phenotypes seen from morpholino antisense oligonucleotide (morpholino) suppression of fmr1 transcript translation were not observed when this allele was first described. The subsequent discovery of genetic compensation, whereby morpholino-directed knockdown can give a more “pure” loss-of-function phenotype while mutations causing nonsense mediated decay of transcripts cause compensatory upregulation of homologous transcripts, suggested an explanation for the differences observed. To test for molecular evidence of genetic compensation in fmr1hu2787 homozygous mutants, we compared the transcriptomes of homozygous mutant and wild type larvae at 2 days post fertilisation. We observed statistically significant changes in the expression of a number of gene transcripts, but none with sequence homology to fmr1. Curiously, the majority of differentially expressed genes are located, like fmr1, on chromosome 14. Quantitative PCR tests on genomic DNA did not support that the apparent expression differences were artefacts due to changes in relative chromosome abundance. The coordinate dysregulation of chromosome 14 genes due to mutation of fmr1 supports this gene’s involvement in a chromosome-wide gene regulation complex.
2020-05-30 | GSE151443 | GEO
Project description:We sought to identify new factors important for myeloid development. From a forward genetic screen in zebrafish we identified the transciptional repressor Zbtb11. To understand pathways regulated by Zbtb11 we profiled gene expression in 48 hpf WT and mne mutant zebrafish. We identified TP53 as a significantly upregulated gene in mne compared to WT.
2017-04-28 | GSE94532 | GEO