Gain-of-Function Variomics and Multi-omics Network Biology for Precision Medicine

Li, M; Awasthi, Sharad; Ghosh, Sumanta Kumar; Bisht, Deepa; Akdemir, Zeynep H. Coban; Sheynkman, Gloria; Sahni, Nidhi; Yi, S. Stephen

doi:10.1007/978-1-0716-3163-8_24

Methods in Molecular Biology

2023

DOI: 10.1007/978-1-0716-3163-8_24

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Gain-of-Function Variomics and Multi-omics Network Biology for Precision Medicine

M Li

Sharad Awasthi

Sumanta Kumar Ghosh

et al.

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2024

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FiTMuSiC: leveraging structural and (co)evolutionary data for protein fitness prediction

Tsishyn,

Cia,

Hermans

et al. 2024

Hum Genomics

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Systematically predicting the effects of mutations on protein fitness is essential for the understanding of genetic diseases. Indeed, predictions complement experimental efforts in analyzing how variants lead to dysfunctional proteins that in turn can cause diseases. Here we present our new fitness predictor, FiTMuSiC, which leverages structural, evolutionary and coevolutionary information. We show that FiTMuSiC predicts fitness with high accuracy despite the simplicity of its underlying model: it was among the top predictors on the hydroxymethylbilane synthase (HMBS) target of the sixth round of the Critical Assessment of Genome Interpretation challenge (CAGI6) and performs as well as much more complex deep learning models such as AlphaMissense. To further demonstrate FiTMuSiC’s robustness, we compared its predictions with in vitro activity data on HMBS, variant fitness data on human glucokinase (GCK), and variant deleteriousness data on HMBS and GCK. These analyses further confirm FiTMuSiC’s qualities and accuracy, which compare favorably with those of other predictors. Additionally, FiTMuSiC returns two scores that separately describe the functional and structural effects of the variant, thus providing mechanistic insight into why the variant leads to fitness loss or gain. We also provide an easy-to-use webserver at https://babylone.ulb.ac.be/FiTMuSiC, which is freely available for academic use and does not require any bioinformatics expertise, which simplifies the accessibility of our tool for the entire scientific community.

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FiTMuSiC: leveraging structural and (co)evolutionary data for protein fitness prediction

Tsishyn,

Cia,

Hermans

et al. 2024

Hum Genomics

View full text Add to dashboard Cite

show abstract

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Gain-of-Function Variomics and Multi-omics Network Biology for Precision Medicine

Cited by 1 publication

References 72 publications

FiTMuSiC: leveraging structural and (co)evolutionary data for protein fitness prediction

FiTMuSiC: leveraging structural and (co)evolutionary data for protein fitness prediction

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