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The immunoglobulin heavy chain locus: genetic variation, missing data, and implications for human disease

Abstract

The immunoglobulin (IG) loci consist of repeated and highly homologous sets of genes of different types, variable (V), diversity (D) and junction (J), that rearrange in developing B cells to produce an individual’s highly variable repertoire of expressed antibodies, designed to bind to a vast array of pathogens. This repeated structure makes these loci susceptible to a high frequency of insertion and deletion events through evolutionary time, and also makes them difficult to characterize at the genomic level or assay with high-throughput techniques. Given the central role of antibodies in the adaptive immune system, it is not surprising that early candidate gene approaches showed that germline polymorphisms in these regions correlated with susceptibility to both infectious and autoimmune diseases. However, more recent studies, particularly those using high-throughput genome-wide arrays, have failed to implicate these loci in disease. In this review of the IG heavy chain variable gene cluster (IGHV), we examine how poorly we understand the distribution of haplotype variation in this genomic region, and we argue that this lack of information may mask candidate loci in the IGHV gene cluster as causative factors for infectious and autoimmune diseases.

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Acknowledgements

We would like to thank Dr Bernard Crespi for helpful comments on early drafts of this manuscript, as well as three anonymous reviewers for their many useful suggestions for improvement of our original submission. We would also like to thank Dr Marie-Paule Lefranc, founder and director of IMGT, for ongoing encouragement and support of our continued research efforts in the immunoglobulin regions.

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Watson, C., Breden, F. The immunoglobulin heavy chain locus: genetic variation, missing data, and implications for human disease. Genes Immun 13, 363–373 (2012). https://doi.org/10.1038/gene.2012.12

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Keywords

  • immunoglobulin heavy chain locus
  • copy number variation
  • SNP
  • antibody
  • human disease
  • GWAS

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