Deep Mutational Scanning in Disease-related Genes with Saturation Mutagenesis-Reinforced Functional Assays (SMuRF)
Ma, K.; Ng, K. K.; Huang, S.; Lake, N. J.; Xu, J.; Lek, A.; Ge, L.; Woodman, K. G.; Koczwara, K. E.; Ho, V.; O'Connor, C. L.; Joseph, S.; Brindley, M. A.; Campbell, K. P.; Lek, M.
Show abstract
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.
Matching journals
The top 3 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Detection of isoforms and genomic alterations by high-throughput full-length single-cell RNA sequencing in ovarian cancer 97%
- Overloading And unpacKing (OAK) - droplet-based combinatorial indexing for ultra-high throughput single-cell multiomic profiling 97%
- TAD Evolutionary and functional characterization reveals diversity in mammalian TAD boundary properties and function 97%
Similar papers in this journal
- Genome-wide CRISPR screens identify PTGES3 as a novel AR modulator 97%
- Dynamic network-guided CRISPRi screen reveals CTCF loop-constrained nonlinear enhancer-gene regulatory activity in cell state transitions 97%
- Synchronized long-read genome, methylome, epigenome, and transcriptome for resolving a Mendelian condition 96%
Similar papers in this journal
Similar papers in this journal
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.