Functional clustering of B cell receptors using sequence and structural features

摘要

The repertoires of B cell receptors (BCRs), which can be captured by single cell-resolution sequencing technologies, contain a personal history of a donor's antigen exposure. One of the current challenges in analyzing such BCR sequence data is to assign sequences to groups with similar antigen and epitope bind- ing specificity. This is a non-trivial task given the paucity of experimentally-determined antibody-antigen structures and the fact that different gene combinations in B cells can lead to receptors that target the same antigen and epitope. Here, we describe a method for clustering BCRs based on sequence and pre- dicted structural features in order to predict groups with similar antigen and epitope binding specificity. We show that all known experimentally-determined structures of antibody-antigen complexes can be clus- tered accurately (AUC 0.981) and that use of predicted structural features improved the accuracy of the epitope classification. We next show that an independent and non-redundant set of 104 anti-HIV antibody sequences could be clustered corresponding to manually-assigned epitopes with a specificity of 99.7% and a sensitivity of 61.93%, with the imbalance in sensitivity due almost entirely to one group of antibodies— those that target the gp120 V3 loop, which do not form a single, well-defined cluster. We next examined a diverse set of anti-hemagglutinin BCR sequences from humans and mice. We observed clusters that in- cluded human or mouse sequences with anti-hemagglutinin antibodies of known structure. We also ob- served clusters that included both human and mouse sequences. Importantly, to the extent that the epi- topes have been experimentally characterized, none of the observed clusters erroneously grouped different hemagglutinin binding regions. Taken together, these results demonstrate that the proposed clus- tering method provides high-throughput prediction of BCRs with common binding specificity across clonal lineages, donors and even species.