Immunoglobulin heavy chains are sufficient to determine most B cell clonal relationships1

B cell clonal expansion is vital for adaptive immunity. High-throughput B cell receptor (BCR) sequencing enables investigating this process, but requires computational inference to identify clonal relationships. This inference usually relies on only the BCR heavy chain, as most current protocols do not preserve heavy:light chain pairing. The extent to which paired light chains aids inference is unknown. Using human single-cell paired BCR datasets, we assessed the ability of heavy chain-based clonal clustering to identify clones. Of the expanded clones identified, <20% grouped cells expressing inconsistent light chains. Heavy chains from these misclustered clones contained more distant junction sequences and shared fewer V segment mutations than the accurate clones. This suggests that additional heavy chain information could be leveraged to refine clonal relationships. Conversely, light chains were insufficient to refine heavy chain-based clonal clusters. Overall, the BCR heavy chain alone is sufficient to identify clonal relationships with confidence.