Inferring B Cell Phylogenies from Paired Heavy and Light Chain BCR Sequences with Dowser 9050

Abstract Description Antibodies are vital to immune responses and are composed of genetically variable heavy and light chains. These structures are initially expressed as B cell receptors (BCRs). BCR diversity is shaped through somatic hypermutation and selection during immune responses. This evolutionary process produces B cell clones, cells that descend from a common ancestor but differ by mutations. Phylogenetic trees inferred from BCR sequences can reconstruct the mutation history within a clone. Until recently, BCR sequencing technologies separated heavy and light chains, but advancements in single-cell sequencing now pair these chains from individual cells. However, it is unclear how these separate genes should be combined to infer B cell phylogenies. We investigated strategies for using paired heavy and light chain sequences to build phylogenies. We found that incorporating light chains significantly improved tree accuracy and reproducibility across all methods tested. This improvement was greater than the difference between tree-building methods and persisted even when mixing bulk and single-cell sequencing data. However, we also found that many phylogenetic methods estimated significantly biased branch lengths when some light chains were missing. Maximum likelihood methods can remove this bias by partitioning branch lengths for heavy and light chain genes. We recommend using maximum likelihood methods with separate heavy and light chain partitions, especially when mixing data types. Funding Sources NIH/NLM T15LM007056 Topic Categories Computational and Systems Immunology (COMP)