Prediction of impacts of mutations on protein structure and interactions: SDM, a statistical approach, and mCSM, using machine learning
Why this work is in the frame
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Bibliographic record
Abstract
Next-generation sequencing methods have not only allowed an understanding of genome sequence variation during the evolution of organisms but have also provided invaluable information about genetic variants in inherited disease and the emergence of resistance to drugs in cancers and infectious disease. A challenge is to distinguish mutations that are drivers of disease or drug resistance, from passengers that are neutral or even selectively advantageous to the organism. This requires an understanding of impacts of missense mutations in gene expression and regulation, and on the disruption of protein function by modulating protein stability or disturbing interactions with proteins, nucleic acids, small molecule ligands, and other biological molecules. Experimental approaches to understanding differences between wild-type and mutant proteins are most accurate but are also time-consuming and costly. Computational tools used to predict the impacts of mutations can provide useful information more quickly. Here, we focus on two widely used structure-based approaches, originally developed in the Blundell lab: site-directed mutator (SDM), a statistical approach to analyze amino acid substitutions, and mutation cutoff scanning matrix (mCSM), which uses graph-based signatures to represent the wild-type structural environment and machine learning to predict the effect of mutations on protein stability. Here, we describe DUET that uses machine learning to combine the two approaches. We discuss briefly the development of mCSM for understanding the impacts of mutations on interfaces with other proteins, nucleic acids, and ligands, and we exemplify the wide application of these approaches to understand human genetic disorders and drug resistance mutations relevant to cancer and mycobacterial infections. STATEMENT FOR A BROADER AUDIENCE: Genetic or somatic changes in genes can lead to mutations in human proteins, which give rise to genetic disorders or cancer, or to genes of pathogens leading to drug resistance. Computer software described here, using statistical approaches or machine learning, uses the information from genome sequencing of humans and pathogens, together with experimental or modeled 3D structures of gene products, the proteins, to predict impacts of mutations in genetic disease, cancer and drug resistance.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it