Journal
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
Volume 20, Issue -, Pages 117-127Publisher
ELSEVIER
DOI: 10.1016/j.csbj.2021.12.007
Keywords
Genomics; Protein science; Data interpretation; RAS mutation; Structural bioinformatics; Functional genomics
Funding
- Medical College of Wisconsin
- Advancing a Healthier Wisconsin Endowment at the Medical College of Wisconsin
- Genomic Sciences and Precision Medicine Center of Medical College of Wisconsin
- NIH [R01-DK52913]
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This study reports computational scores for interpreting disease-associated genomic variation in the RAS family of genes. By using a combination of experimental datasets and computational methods, the research found a high correlation between 3D structure-based scores and experimental measures, indicating the impact of biochemical scores on the functional behavior of variants.
In the current study, we report computational scores for advancing genomic interpretation of disease-associated genomic variation in members of the RAS family of genes. For this purpose, we applied 31 sequence-and 3D structure-based computational scores, chosen by their breadth of biophysical properties. We parametrized our data by assembling a numerically homogenized experimentally-derived dataset, which when use in our calculations reveal that computational scores using 3D structure highly correlate with experimental measures (e.g., GAP-mediated hydrolysis R-Spearman = 0.80 and RAF affinity R-spearman = 0.82), while sequence-based scores are discordant with this data. Performing all-against-all comparisons, we applied this parametrized modeling approach to the study of 935 RAS variants from 7 RAS genes, which led us to identify 4 groups of mutations according to distinct biochemical scores within each group. Each group was comprised of hotspot and non-hotspot KRAS variants, indicating that poorly characterized variants could functionally behave like pathogenic mutations. Combining computational scores using dimensionality reduction indicated that changes to local unfolding propensity associate with changes in enzyme activity by genomic variants. Hence, our systematic approach, combining methodologies from both clinical genomics and 3D structural bioinformatics, represents an expansion for interpreting genomic data, provides information of mechanistic value, and that is transferable to other proteins. (C) 2021 The Author(s). Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology.
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