The effect of genetic variation at the immunoglobulin heavy chain variable region gene loci on biases in the generation of the human primary antibody repertoire

摘要

The human primary antibody repertoire must be incredibly diverse in order to combat a constantly evolving array of pathogens. Random events contribute to the repertoire diversity that is created within an individual on a daily basis. Similarly, much of the genetic variation existing between individuals and populations at the immunoglobulin loci has been generated via stochastic processes. However, deviations from randomness have been detected both during the processes that generate the primary repertoire within an individual and during the evolution of the immunoglobulin genes. This complex set of events and genes has been notoriously difficult to investigate. However, next-generation sequencing technologies have recently allowed the creation of datasets containing thousands of rearranged sequences. This has allowed great insight into the events taking place during the formation of a B cell in the bone marrow and into genetic diversity within and between human populations. The information contained in such large datasets allows many questions to be asked. Preferential IGHD-IGHJ pairing has been reported, but the mechanism involved is unclear. Using very large datasets and the fact that VDJ rearrangement is an intrachromosomal event, complex patterns were detected. These patterns changed in a predictable way in individuals carrying IGHD deletion polymorphisms, suggesting a strong positional influence and the involvement of other factors too. Results also suggest that the recombinase associates with an IGHJ gene before associating with an IGHD partner. Allele frequencies of structural IGH polymorphisms vary between different ethnic human populations. Differentiation of sequence variants of the IGH locus was investigated in individuals from six different ethnic backgrounds, including a rarely studied Amerindian population. Significant differentiation was observed between several pairs of populations. This work has important implications for a more personalised approach to vaccines and therapeutics. Analysis of these diverse populations suggested the existence of many novel unreported allelic variants. These alleles were then included into the repertoire used previously to study the evolution of the subregions of IGHV genes. The analysis produced remarkably similar results, suggesting that the implications for selection in these regions will not change regardless of the number of extra alleles that remain to be reported.