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Series GSE138414 Query DataSets for GSE138414
Status Public on Oct 04, 2019
Title Genetic compensation in a stable slc25a46 mutant zebrafish
Organism Danio rerio
Experiment type Expression profiling by high throughput sequencing
Summary 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.
Overall design RNA-sequencing epxeriment of three groups with four biological replicates per group
Contributor(s) Buglo E, Danzi MC, Zuchner S, Dallman J
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Submission date Oct 03, 2019
Last update date Oct 04, 2019
Contact name Matt C Danzi
Organization name University of Miami
Street address 1095 NW 14th Terrace, Lois Pope LIFE Center 4-26
City Miami
State/province FL
ZIP/Postal code 33136
Country USA
Platforms (1)
GPL24995 Illumina NovaSeq 6000 (Danio rerio)
Samples (12)
GSM4107694 Control rep1
GSM4107695 Control rep2
GSM4107696 Control rep3
BioProject PRJNA575769

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE138414_slc25a46_readCountsPerGene.txt.gz 636.9 Kb (ftp)(http) TXT
Raw data are available in SRA
Processed data are available on Series record

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