Inferring processes underlying B-cell repertoire diversity

TL;DR

This paper uses probabilistic inference to analyze the processes generating human B-cell receptor diversity, revealing key differences from T-cell repertoires and detailed mutation patterns.

Contribution

It introduces a probabilistic framework to quantify VDJ recombination and hypermutation processes in human B-cells, providing new insights into repertoire diversity and mutation mechanisms.

Findings

B-cell repertoire is more diverse than T-cell repertoire due to longer junctional insertions.

Sequences passing initial selection have higher generation probabilities.

Hypermutations are non-uniformly distributed along V genes, explained by an independent site model.

Abstract

We quantify the VDJ recombination and somatic hypermutation processes in human B-cells using probabilistic inference methods on high-throughput DNA sequence repertoires of human B-cell receptor heavy chains. Our analysis captures the statistical properties of the naive repertoire, first after its initial generation via VDJ recombination and then after selection for functionality. We also infer statistical properties of the somatic hypermutation machinery (exclusive of subsequent effects of selection). Our main results are the following: the B-cell repertoire is substantially more diverse than T-cell repertoires, due to longer junctional insertions; sequences that pass initial selection are distinguished by having a higher probability of being generated in a VDJ recombination event; somatic hypermutations have a non-uniform distribution along the V gene that is well explained by an independent site model for the sequence context around the hypermutation site.