Disentangling the Contribution of Each Descriptive Characteristic of Every Single Mutation to Its Functional Effects

Mutational effects predictions continue to improve in accuracy as advanced artificial intelligence (AI) algorithms are trained on exhaustive experimental data. The next natural questions to ask are if it is possible to gain insights into which attribute of the mutation contributes how much to the mutational effects and if one can develop universal rules for mapping the descriptors to mutational effects. In this work, we mainly address the former aspect using a framework of interpretable AI. Relations between the physicochemical descriptors and their contributions to the mutational effects are extracted by analyzing the data on 29,832 variants from eight systematic deep mutational scan studies. An opposite trend in the dependence of fitness and solubility on the distance of the amino acid from the catalytic sites could be extracted and quantified. The dependence of the mutational effect contributions on the position-specific scoring matrix (PSSM) score for the amino acid after mutation or the BLOSUM score of the substitution showed universal trends. Our attempts in the present work to explain the quantitative differences in the dependence on conservation and SASA across proteins were not successful. The work nevertheless brings transparency into the predictions and development of rules, and will hopefully lead to empirically uncovering the universalities among these rules.

Automated summary

Predictions of mutational effects are improving in accuracy through advanced AI algorithms trained on experimental data. This study aimed to gain insights into the contributions of different mutation attributes to the effects, and to develop universal rules for mapping descriptors to mutational effects. The research extracted relationships between physicochemical descriptors and mutational effects, and identified universal trends in the contributions of certain factors to the effects.