Variation in human antibody and T-cell receptor repertoires

Haplotype variation in immunoglobulin genes 

Very little information is available on the copy number and allelic variation of human immunoglobulin genes, which code for the huge antibody diversity critical to the adaptive immune system.  Thus it is not possible to design high-throughput genotyping tools, and we are missing disease connections at these highly variable loci. Watson, et al. 2012. The immunoglobulin heavy chain locus: genetic variation, missing data, and implications for human disease. Genes and Immunity 2012: 1-11. We therefore sequenced the first complete immunoglobulin haplotype from a single human chromosome, which is now the human genome reference. Watson, Willsey, et al. 2013. Complete haplotype of the human immunoglobulin heavy-chain variable, diversity, and joining genes and characterization of allelic and copy-number variation.  American Journal of Human Genetics 92:1-17. This article has had a major impact on the field by raising the question: how does variation in the germline repertoire affect disease-stimulated antibody responses? Avnir, Watson, et al. 2016. IGHV1-69 polymorphism modulates anti-influenza antibody repertoires, correlates with IGHV utilization shifts and varies by ethnicity.  Scientific Reports 6:20842.

Variation in expressed antibody repertoires 

In order to examine widely held assumptions about properties of broadly-neutralizing anti-HIV antibodies, we combined sequences from multiple studies. Breden, Lepik, et al. 2011. Comparison of antibody repertoires produced by HIV-1 infection, other chronic and acute infections, and systemic autoimmune disease. PLoS ONE 3:e16857. This led our lab to understand the need to integrate the massive databases of antibodies being generated by next generation sequencing technology, for vaccine, therapeutic antibody and anti-cancer therapy development.  iReceptor enables searches across a federated database system and will greatly improve biomedical research and patient care.  This effort won’t be successful without buy-in from the research community, and I am the main organizer of the Adaptive Immune Receptor Repertoire (AIRR) Community Initiative, which is developing common sets of metadata, protocols and standards of practice.  This initiative has been mentioned in overview articles in Nature, Nature Medicine, and Nature Biotechnology, and the 2016 Community Meeting in Rockville, MD was sponsored by NIH. 

Figure 1: Recombination of V,D, and J Germline Genes into a Functional Antibody (Market and F. Nina Papavasiliou, PLos Biology 1:24-27

Figure 2. Map of the 1Mb human Immunoglobulin heavy chain locus (IgH) showing the high density of homologous Variable (V), Diversity (D), and Joining (J) genes and pseudogenes. 
(Matsuda, et al. 1998, JEM 11:2151–2162)