Deep Mutational Scanning in Disease-related Genes with Saturation Mutagenesis-Reinforced Functional Assays (SMuRF).

Autor:	Ma K; Department of Genetics, Yale School of Medicine, New Haven, CT, USA., Huang S; Department of Genetics, Yale School of Medicine, New Haven, CT, USA.; Equal second authors., Ng KK; Department of Genetics, Yale School of Medicine, New Haven, CT, USA.; Equal second authors., Lake NJ; Department of Genetics, Yale School of Medicine, New Haven, CT, USA., Joseph S; Howard Hughes Medical Institute, Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, Department of Molecular Physiology and Biophysics and Department of Neurology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA, USA., Xu J; Yale University, New Haven, CT, USA., Lek A; Department of Genetics, Yale School of Medicine, New Haven, CT, USA.; Muscular Dystrophy Association, Chicago, IL, USA., Ge L; Department of Genetics, Yale School of Medicine, New Haven, CT, USA.; Department of Neurology, National Center for Children's Health, Beijing Children's Hospital, Capital Medical University, Beijing, China., Woodman KG; Department of Genetics, Yale School of Medicine, New Haven, CT, USA., Koczwara KE; Department of Genetics, Yale School of Medicine, New Haven, CT, USA., Cohen J; Department of Genetics, Yale School of Medicine, New Haven, CT, USA., Ho V; Department of Genetics, Yale School of Medicine, New Haven, CT, USA., O'Connor CL; Department of Genetics, Yale School of Medicine, New Haven, CT, USA., Brindley MA; Department of Infectious Diseases, Department of Population Health, University of Georgia, Athens, GA, USA.; Senior Authors., Campbell KP; Howard Hughes Medical Institute, Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, Department of Molecular Physiology and Biophysics and Department of Neurology, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, IA, USA.; Senior Authors., Lek M; Department of Genetics, Yale School of Medicine, New Haven, CT, USA.; Senior Authors.; Lead Contact.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Jun 25. Date of Electronic Publication: 2024 Jun 25.
DOI:	10.1101/2023.07.12.548370
Abstrakt:	Interpretation of disease-causing genetic variants remains a challenge in human genetics. Current costs and complexity of deep mutational scanning methods hamper crowd-sourcing approaches toward genome-wide resolution of variants in disease-related genes. Our framework, Saturation Mutagenesis-Reinforced Functional assays (SMuRF), addresses these issues by offering simple and cost-effective saturation mutagenesis, as well as streamlining functional assays to enhance the interpretation of unresolved variants. Applying SMuRF to neuromuscular disease genes FKRP and LARGE1 , we generated functional scores for all possible coding single nucleotide variants, which aid in resolving clinically reported variants of uncertain significance. SMuRF also demonstrates utility in predicting disease severity, resolving critical structural regions, and providing training datasets for the development of computational predictors. Our approach opens new directions for enabling variant-to-function insights for disease genes in a manner that is broadly useful for crowd-sourcing implementation across standard research laboratories. Competing Interests: Declaration of interests The authors declare no competing interests. Declaration of generative AI and AI-assisted technologies We used ChatGPT 3.5 and Gemini to improve the readability and language in this manuscript. The manuscript was first drafted by us and polished with the tools sentence-by-sentence where we deemed necessary. We then reviewed and finalized the text. We take full responsibility for the contents of this manuscript.
Databáze:	MEDLINE
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