B cell Variable genes have evolved their codon usage to focus the targeted patterns of somatic mutation on the complementarity determining regions

Abstract

The exceptional ability of B cells to diversify through somatic mutation and improve affinity of the repertoire towards the antigens is the cornerstone of adaptive immunity. Somatic mutation is not evenly distributed and exhibits certain micro-sequence specificities. We show here that the combination of somatic mutation targeting and the codon usage in human B cell receptor (BCR) Variable (V) genes create expected patterns of mutation and post mutation changes that are focused on their complementarity determining regions (CDR). T cell V genes are also skewed in targeting mutations but to a lesser extent and are lacking the codon usage bias observed in BCRs. This suggests that the observed skew in T cell receptors is due to their amino acid usage, which is similar to that of BCRs. The mutation targeting and the codon bias allow B cell CDRs to diversify by specifically accumulating nonconservative changes. We counted the distribution of mutations to CDR in 4 different human datasets. In all four cases we found that the number of actual mutations in the CDR correlated significantly with the V gene mutation biases to the CDR predicted by our models. Finally, it appears that the mutation bias in V genes indeed relates to their long-term survival in actual human repertoires. We observed that resting repertoires of B cells overexpressed V genes that were especially biased towards focused mutation and change in the CDR. This bias in V gene usage was somewhat relaxed at the height of the immune response to a vaccine, presumably because of the need for a wider diversity in a primary response. However, older patients did not retain this flexibility and were biased towards using only highly skewed V genes at all stages of their response.

Eye on the B-ALL: B-cell receptor repertoires reveal persistence of numerous B-lymphoblastic leukemia subclones from diagnosis to relapse

“…43 Indeed, the mutations within these clusters are enriched within the CDR1-3 regions compared with FWR1-3 regions (Supplementary Figure S4) and in AID mutational motifs (Supplementary Table S10), suggestive of AID activity. 44, 45, 46 These mutations can be used to infer the hierarchical structure and extent of BCR diversification from a leukemia-initiating B-cell to bulk leukemia. To investigate the effect of treatment on the population structure of B-ALL, we studied diagnostic-relapse pairs exhibiting related BCRs, thus permitting sequence comparisons (patients A, C–F).…”

The evolution within us

“…Naive B cells, which have not encountered antigen, show extensive diversity arising from several sources: polymorphism in the receptor-coding genes, recombination between these genes, insertions and deletions [52,53]. The receptor genes themselves show selection for mutational hotspots and coldspots in structurally beneficial areas [54,55]. Precursors of naive B cells are further selected for non-autoreactivity [56].…”

Immunoglobulin gene analysis as a tool for investigating human immune responses

“…28 With the later determination of mutational hotspots, 29,30 that are the result of AID targeting and other DNA repair biases, 31,32 incorporation of targeting data into more complex algorithms enable improved prediction of whether a repertoire of antibodies has been selected or not. 33 Other nuances, such as positional effects with respect to transcription initiation sites, 34 intrinsic codon bias toward those more susceptible to amino acid change in CDRs 35 or individual codon mapping across the repertoire, 36 can also be taken into consideration. Analysis of hypermutation in the context of gene families, where the evolution of a B cell clone can be mapped by a phylogenetic study of hypermutation, can provide further insights and inferences to understand B cell biology (see Section 4.3 below).…”