Abstract
Adaptive immune receptor repertoire sequencing (AIRR-Seq) offers the possibility of identifying and tracking B cell clonal expansions during adaptive immune responses. Members of a B cell clone are descended from a common ancestor and share the same initial V(D)J rearrangement, but their B cell receptor (BCR) sequence may differ due to the accumulation of somatic hypermutations (SHMs). Clonal relationships are learned from AIRR-seq data by analyzing the BCR sequence, with the most common methods focused on the highly diverse junction region. However, clonally related cells often share SHMs which have been accumulated during affinity maturation. Here, we investigate whether shared SHMs in the V and J segments of the BCR can be leveraged along with the junction sequence to improve the ability to identify clonally related sequences. We develop independent distance functions that capture junction similarity and shared mutations, and combine these in a spectral clustering framework to infer the BCR clonal relationships. Using both simulated and experimental data, we show that this model improves both the sensitivity and specificity for identifying B cell clones. Source code for this method is freely available in the SCOPer (Spectral Clustering for clOne Partitioning) R package (version 0.2 or newer) in the Immcantation framework: www.immcantation.org under the AGPLv3 license.
Highlights
B cells recognize pathogens through their B cell receptor (BCR)
Antigen-specific B cells undergo intense proliferation. This B cell clonal expansion is coupled with a process of somatic hypermutations (SHMs), which results in the accumulation of mutations in the DNA encoding the BCR
Successful binding leads to repeated cycles of proliferation, SHM and affinitydependent selection resulting in the generation of high-affinity memory and antibody-secreting plasma cells
Summary
B cells recognize pathogens through their BCR. The ability to recognize and initiate a response to a wide variety of pathogens depends upon a large population of B cell lymphocytes each of which expresses a particular receptor for antigen. For IGH-chains, diversity is initially created in the germline via recombination of variable IGHV, diversity IGHD, and joining IGHJ genes (termed the V(D)J recombination process [1]). For IGL-chains, the IGLV gene is rearranged directly to IGLJ gene. The region where IGHV, IGHD and IGHJ come together in IGH (or IGLV and IGLJ for IGL) is termed the CDR3 (the junction region is defined as the CDR3 plus the prefix and suffix conserved flanking amino acid residues), and this high diversity region is often involved in antigen-binding [5]
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