A Sitewise Model of Natural Selection on Individual Antibodies via a Transformer–Encoder

During affinity maturation, antibodies are selected for their ability to fold and to bind a target antigen between rounds of somatic hypermutation. Previous studies have identified patterns of selection in antibodies using B cell repertoire sequencing data. However, these studies are constrained by needing to group many sequences or sites to make aggregate predictions. In this paper, we develop a transformer-encoder selection model of maximum resolution: given a single antibody sequence, it predicts the strength of selection on each amino acid site. Specifically, the model predicts for each site whether evolution will be slower than expected relative to a model of the neutral mutation process (purifying selection) or faster than expected (diversifying selection). We show that the model does an excellent job of modeling the process of natural selection on held out data, and does not need to be enormous or trained on vast amounts of data to perform well. The patterns of purifying vs diversifying natural selection do not neatly partition into the complementarity-determining vs framework regions: for example, there are many sites in framework that experience strong diversifying selection. There is a weak correlation between selection factors and solvent accessibility. When considering evolutionary shifts down a tree of antibody evolution, affinity maturation generally shifts sites towards purifying natural selection, however this effect depends on the region, with the biggest shifts toward purifying selection happening in the third complementarity-determining region. We observe distinct evolution between gene families but a limited relationship between germline diversity and selection strength.