Abstract
The human immune system depends on a highly diverse collection of antibody-making B cells. B cell receptor sequence diversity is generated by a random recombination process called “rearrangement” forming progenitor B cells, then a Darwinian process of lineage diversification and selection called “affinity maturation.” The resulting receptors can be sequenced in high throughput for research and diagnostics. Such a collection of sequences contains a mixture of various lineages, each of which may be quite numerous, or may consist of only a single member. As a step to understanding the process and result of this diversification, one may wish to reconstruct lineage membership, i.e. to cluster sampled sequences according to which came from the same rearrangement events. We call this clustering problem “clonal family inference.” In this paper we describe and validate a likelihood-based framework for clonal family inference based on a multi-hidden Markov Model (multi-HMM) framework for B cell receptor sequences. We describe an agglomerative algorithm to find a maximum likelihood clustering, two approximate algorithms with various trade-offs of speed versus accuracy, and a third, fast algorithm for finding specific lineages. We show that under simulation these algorithms greatly improve upon existing clonal family inference methods, and that they also give significantly different clusters than previous methods when applied to two real data sets.
Highlights
B cells effect the antibody-mediated component of the adaptive immune system
In this paper we describe and validate a likelihood-based framework for clonal family inference based on a multi-hidden Markov Model framework for B cell receptor sequences
The binding properties of antibodies are determined by the DNA sequences of their corresponding B cell receptors (BCRs)
Summary
B cells effect the antibody-mediated component of the adaptive immune system. The antigenbinding properties of B cells are defined by their B cell receptor, or BCR. The light chain process is slightly simpler, in that only a V and J recombine, but proceeds via similar trimming and joining processes These processes form the third complementarity determining region (CDR3) in each of the heavy and the light chain, which are important determinants of antibody binding properties. A series of checkpoints on the BCRs ensure that the resulting immunoglobulin is functional and not self-reactive through negative selection (reviewed in [1]) This process results in naive B cells with fully functioning receptors. When stimulated by binding to antigen in a germinal center, naive cells reproduce and mutate by via the process of somatic hypermutation, and are selected on the basis of antigen binding and presentation to T follicular helper cells [2] It is possible to sequence B cell receptors in high throughput, which in principle describes the collections of antigens to which the immune system is ready to react, and implicitly narrates how they came to be
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