Genetic compensation triggered by mutant mRNA degradation
Mohamed A. El-Brolosy,Zacharias Kontarakis,Andrea Rossi,Andrea Rossi,Carsten Kuenne,Stefan Günther,Nana Fukuda,Khrievono Kikhi,Giulia L. M. Boezio,Carter M. Takacs,Carter M. Takacs,Shih-Lei Lai,Shih-Lei Lai,Ryuichi Fukuda,Claudia Gerri,Claudia Gerri,Antonio J. Giraldez,Didier Y.R. Stainier +17 more
913
TL;DR: Transcriptional adaptation, a genetic compensation process by which organisms respond to mutations by upregulating related genes, is triggered by mRNA decay and involves a sequence-dependent mechanism.
read more
Abstract: Genetic robustness, or the ability of an organism to maintain fitness in the presence of harmful mutations, can be achieved via protein feedback loops. Previous work has suggested that organisms may also respond to mutations by transcriptional adaptation, a process by which related gene(s) are upregulated independently of protein feedback loops. However, the prevalence of transcriptional adaptation and its underlying molecular mechanisms are unknown. Here, by analysing several models of transcriptional adaptation in zebrafish and mouse, we uncover a requirement for mutant mRNA degradation. Alleles that fail to transcribe the mutated gene do not exhibit transcriptional adaptation, and these alleles give rise to more severe phenotypes than alleles displaying mutant mRNA decay. Transcriptome analysis in alleles displaying mutant mRNA decay reveals the upregulation of a substantial proportion of the genes that exhibit sequence similarity with the mutated gene's mRNA, suggesting a sequence-dependent mechanism. These findings have implications for our understanding of disease-causing mutations, and will help in the design of mutant alleles with minimal transcriptional adaptation-derived compensation.
read more
Chat with Paper
AI Agents for this Paper
Find similar papers on Google Scholar, PubMed and Arxiv
Write a critical review of this paper
Analyze citations of this paper to find unaddressed research gaps
Citations
Disease-Associated Variants in GRIN1, GRIN2A and GRIN2B genes: Insights into NMDA Receptor Structure, Function, and Pathophysiology
Michal Korinek,M C Serra,Fes Abdel Rahman,Mark Dobrovolski,Viktor Kuchtiak,В. В. Абрамова,Klevinda Fili,Eni Tomović,Barbora Hrčka Krausová,Jan Krůšek,Jiří Černý,Ladislav Vyklický,Ahmet A. Balık,Tereza Smejkalová +13 more
TL;DR: This review synthesizes functional evaluations of disease-associated variants in GRIN1, GRIN2A, and GRIN2B genes, examining receptor function, agonist affinity, and cell surface expression to classify variants as gain-of-function or loss-of-function.
7
CLN3 deficiency leads to neurological and metabolic perturbations during early development
Ursula Heins-Marroquin,Randolph R. Singh,Simon Perathoner,Floriane Gavotto,Carla Merino,Myrto Patraskaki,Gemma Gomez‐Giro,Felix Bruno Kleine Borgmann,Marc‐Etienne Meyer,Anaïs Carpentier,Marc O. Warmoes,Christian Jaeger,Michel Mittelbronn,Jens C. Schwamborn,María Lorena Cordero-Maldonado,Alexander D. Crawford,Emma Schymanski,Carole L. Linster +17 more
TL;DR: CLN3 deficiency leads to neurological and metabolic perturbations during early development, highlighting glycerophosphoinositol and BMP as potential biomarkers.
Validation of Candidate Sleep Disorder Risk Genes Using Zebrafish
Steven Tran,David A. Prober +1 more
TL;DR: Zebrafish (Danio rerio), an alternative vertebrate model for studying sleep, allows for the rapid and cost-effective generation of mutant lines using the CRISPR/Cas9 system, and identifies a gene associated with each GWAS hit that is likely responsible for the human sleep phenotype.
Considerations for the Use of Mutation as a Regulatory Endpoint in Risk Assessment.
TL;DR: With the current advent of predictive methods, new testing paradigms, mode‐of‐action/adverse outcome pathways, and quantitative risk assessment approaches, various stakeholders are starting to employ these state‐of-the‐science methodologies to further the conversation on decision making and advance the regulatory paradigm beyond the dominant LNT status quo.
7
Capillaries communicate with the arteriolar microvascular network by a pannexin/purinergic-dependent pathway in hamster skeletal muscle.
TL;DR: In this paper, a pannexin/purinergic-dependent intravascular communication pathway exists in skeletal muscle microvasculature that facilitates capillary communication with upstream arterioles that control their perfusion.
7
References
Basic Local Alignment Search Tool
TL;DR: A new approach to rapid sequence comparison, basic local alignment search tool (BLAST), directly approximates alignments that optimize a measure of local similarity, the maximal segment pair (MSP) score.
98.8K
Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2
TL;DR: This work presents DESeq2, a method for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates, which enables a more quantitative analysis focused on the strength rather than the mere presence of differential expression.
Trimmomatic: a flexible trimmer for Illumina sequence data
TL;DR: Timmomatic is developed as a more flexible and efficient preprocessing tool, which could correctly handle paired-end data and is shown to produce output that is at least competitive with, and in many cases superior to, that produced by other tools, in all scenarios tested.
57.9K
STAR: ultrafast universal RNA-seq aligner
Alexander Dobin,Carrie A. Davis,Felix Schlesinger,Jorg Drenkow,Chris Zaleski,Sonali Jha,Philippe Batut,Mark Chaisson,Thomas R. Gingeras +8 more
TL;DR: The Spliced Transcripts Alignment to a Reference (STAR) software based on a previously undescribed RNA-seq alignment algorithm that uses sequential maximum mappable seed search in uncompressed suffix arrays followed by seed clustering and stitching procedure outperforms other aligners by a factor of >50 in mapping speed.
Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2
TL;DR: This work presents DESeq2, a method for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates, which enables a more quantitative analysis focused on the strength rather than the mere presence of differential expression.