Inferring processes underlying B-cell repertoire diversity.

Abstract

One contribution of 13 to a theme issue 'The dynamics of antibody repertoires'. 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, owing 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.

Systems Analysis Reveals High Genetic and Antigen-Driven Predetermination of Antibody Repertoires throughout B Cell Development

“…Ever since its first implementation in 2009 (Weinstein et al, 2009), highthroughput sequencing of immunoglobulin/antibody repertoires (Ig-seq) has enabled unprecedented quantitative insight into the diversity of humoral immunity. Several studies have reported deterministic convergence in multiple components of repertoire structure: germline gene usage (Avnir et al, 2016;Galson et al, 2015a;Glanville et al, 2011;Rubelt et al, 2016;Tr€ uck et al, 2014;Wang et al, 2015), clonal expansion (Greiff et al, 2015b;Mora et al, 2010;Weinstein et al, 2009), clonal sequence diversity (Henry Dunand and Wilson, 2015;Elhanati et al, 2015;Galson et al, 2015b;Jackson et al, 2013;McHeyzer-Williams et al, 1993;Mora et al, 2010;Parameswaran et al, 2013;Reddy et al, 2010;Tr€ uck et al, 2014;Vollmers et al, 2013;Weinstein et al, 2009;Yang et al, 2015) and repertoire size (Elhanati et al, 2015;Glanville et al, 2009).…”

Learning the High-Dimensional Immunogenomic Features That Predict Public and Private Antibody Repertoires

“…As a result of the enormous theoretical diversity of Ab and TCR repertoires (.10 13 ) (8-11) and technological limitations (Sanger sequencing), it was long believed that clonal repertoires were, to an overwhelming extent, private to each individual (12,13). However, as a result of recent advances in high-throughput immune repertoire sequencing, it has been observed that a considerable fraction (.1%) of CDR3s is shared across individuals (1,5,(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). Thus, these shared clones (hereafter referred to as "public clones") are refining our view of adaptive immune repertoire diversity.…”

Assessing human B cell repertoire diversity and convergence

“…Estimates of the theoretical diversity of the human B cell repertoire range from 10 12 to 10 18 . However, several factors limit the actual size.…”

“…Firstly, the upper range of the theoretical number of BCRs is larger than the number of available B cells in the organism at any given time. Secondly, not all Ig gene segments are rearranged at the same frequency . Consequently, pairings of IgH and IgL chains encoded by specific V gene segments will be generated at higher likelihood than others.…”

“…It remains unclear, to what extent inter‐ and intra‐individual diversity in naive and memory B cell repertoires is driven by genetic factors or by antigen exposure, respectively. To obtain insights in the development of naive and antigen‐experienced B cell repertoires statistical inference approaches have been used to investigate overall repertoire diversity and to identify selection patterns . From these analyses, it has become apparent that not all recombination events occur with the same likelihood and that the transition from the naive to the memory B cell repertoire enhances these effects by selecting sequences with higher generation probabilities .…”