Genetic variation in the immunoglobulin heavy chain locus shapes the human antibody repertoire

Abstract

The contribution of heritable factors to antibody function and diversity is not fully understood, but has profound implications for delineating variation in the antibody response observed at the population-level. We performed matched long-read-based characterization of the immunoglobulin heavy chain (IGH) locus and expressed antibody repertoire profiling at population-scale to examine, for the first time, the impact of IGH genomic variation on the antibody repertoire. We characterized extensive IGH polymorphism, including novel structural variants (SVs), small insertion/deletions (indels), single nucleotide variants (SNVs), and IG genes and alleles. Countering models that antibody repertoire diversity is driven largely by stochastic processes, we demonstrate that IGH genetic factors make significant contributions to gene usage in both the naive and antigen-experienced repertoire. Specifically, the usage of 73% of IGH genes was associated with common polymorphisms, including those capable of explaining >70% of variance in gene usage. These variants were enriched in transcription factor binding sites and other functional elements associated with V(D)J recombination, and overlapped polymorphisms from genome-wide association studies. Furthermore, we found evidence for the coordinated regulation of IGH genes across the repertoire, demonstrating complex interactions between IGH variants and gene usage. These results refine our understanding of variation observed in the antibody repertoire, and will advance the study of antibody function in disease.

Functional antibodies exhibit light chain coherence

“…It is reasonable to assume that some sequences treated as naive in this study are in fact antigen-specific, as others have described in SARS-CoV-2 infection 49 . Conversely, although progress has been made in the identification of novel germline alleles 50,51 , some sequences treated as memory in this study may in fact be naive and produced by novel alleles not detected by our inference methods.…”

Characterisation of the immune repertoire of a humanised transgenic mouse through immunophenotyping and high-throughput sequencing

“…Kymice contain the Ig haplotype of a single human subject consistent with reduced diversity relative to outbred human B-cell repertoires where the considerable allelic and haplotypic diversity observed in human populations has significant effects on the expressed BCR repertoire ( Rodriguez et al, 2022 ). Given the Kymouse’s use of a single haplotype, and differences in the observed germline gene usages, it is likely that the BCR response to antigen stimulus in the Kymouse will represent only a subset of the possible diversity of the outbred human response and this should be in consideration in vaccine response modelling.…”

IGHV allele similarity clustering improves genotype inference from adaptive immune receptor repertoire sequencing data

“…Exploring naive repertoires is far from complete, as most studies focus on the same ethnic populations. As demonstrated by Rodriguez et al [32] different ethnicity influence the IGH composition (i.e genes, deletions, etc.). With more repertoire data curated with different ethnic background, the allele specific threshold might have to be tailored toward the ethnic population.…”