Epistatic models predict mutable sites in SARS-CoV-2 proteins and epitopes

During the COVID pandemic, new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants emerge and spread, some being of major concern due to their increased infectivity or capacity to reduce vaccine efficiency. Anticipating mutations, which might give rise to new variants, would be of great interest. We construct sequence models predicting how mutable SARS-CoV-2 positions are, using a single SARS-CoV-2 sequence and databases of other coronaviruses. Predictions are tested against available mutagenesis data and the observed variability of SARS-CoV-2 proteins. Interestingly, predictions agree increasingly with observations, as more SARS-CoV-2 sequences become available. Combining predictions with immunological data, we find an overrepresentation of mutations in current variants of concern. The approach may become relevant for potential outbreaks of future viral diseases.The emergence of new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major concern given their potential impact on the transmissibility and pathogenicity of the virus as well as the efficacy of therapeutic interventions. Here, we predict the mutability of all positions in SARS-CoV-2 protein domains to forecast the appearance of unseen variants. Using sequence data from other coronaviruses, preexisting to SARS-CoV-2, we build statistical models that not only capture amino acid conservation but also more complex patterns resulting from epistasis. We show that these models are notably superior to conservation profiles in estimating the already observable SARS-CoV-2 variability. In the receptor binding domain of the spike protein, we observe that the predicted mutability correlates well with experimental measures of protein stability and that both are reliable mutability predictors (receiver operating characteristic areas under the curve \~0.8). Most interestingly, we observe an increasing agreement between our model and the observed variability as more data become available over time, proving the anticipatory capacity of our model. When combined with data concerning the immune response, our approach identifies positions where current variants of concern are highly overrepresented. These results could assist studies on viral evolution and future viral outbreaks and, in particular, guide the exploration and anticipation of potentially harmful future SARS-CoV-2 variants.To ensure reproducibility and access to our results we provide at https://giancarlocroce.github.io/DCA_SARS-CoV-2/ the data generated in the course of this research and a Jupyter notebook to reproduce key figures and guide data analysis. This notebook will also contain data updated as compared to the datasets used in this article. The code to generate the predictions for the IND and DCA models is available at https://github.com/juan-rodriguez-rivas/covmut. All other study data are included in the article and/or SI Appendix.