A multi-objective based clustering for inferring BCR clonal lineages from high-throughput B cell repertoire data.

ABSTRACT

The adaptive B cell response is driven by the expansion, somatic hypermutation, and selection of B cell clonal lineages. A high number of clonal lineages in a B cell population indicates a highly diverse repertoire, while clonal size distribution and sequence diversity reflect antigen selective pressure. Identifying clonal lineages is fundamental to many repertoire studies, including repertoire comparisons, clonal tracking, and statistical analysis. Several methods have been developed to group sequences from high-throughput B cell repertoire data. Current methods use clustering algorithms to group clonally-related sequences based on their similarities or distances. Such approaches create groups by optimizing a single objective that typically minimizes intra-clonal distances. However, optimizing several objective functions can be advantageous and boost the algorithm convergence rate. Here we propose MobiLLe, a new method based on multi-objective clustering. Our approach requires V(D)J annotations to obtain the initial groups and iteratively applies two objective functions that optimize cohesion and separation within clonal lineages simultaneously. We show that our method greatly improves clonal lineage grouping on simulated benchmarks with varied mutation rates compared to other tools. When applied to experimental repertoires generated from high-throughput sequencing, its clustering results are comparable to the most performing tools and can reproduce the results of previous publications. The method based on multi-objective clustering can accurately identify clonally-related antibody sequences and presents the lowest running time among state-of-art tools. All these features constitute an attractive option for repertoire analysis, particularly in the clinical context. MobiLLe can potentially help unravel the mechanisms involved in developing and evolving B cell malignancies.