The Individual and Population Genetics of Antibody Immunity

Antibodies (Abs) produced by immunoglobulin (IG) genes are the most diverse proteins expressed in humans. While part of this diversity is generated by recombination during B-cell development and mutations during affinity maturation, the germ-line IG loci are also diverse across human populations and ethnicities. Recently, proof-of-concept studies have demonstrated genotype–phenotype correlations between specific IG germ-line variants and the quality of Ab responses during vaccination and disease. However, the functional consequences of IG genetic variation in Ab function and immunological outcomes remain underexplored. In this opinion article, we outline interconnections between IG genomic diversity and Ab-expressed repertoires and structure. We further propose a strategy for integrating IG genotyping with functional Ab profiling data as a means to better predict and optimize humoral responses in genetically diverse human populations, with immediate implications for personalized medicine. Genetic variation in human populations affects how individuals are able to mount functional antibody responses. Different alleles can encode convergent binding motifs that result in successful Ab responses against specific infections and vaccinations. Given the complexity of the IG loci and the diversity of the antibody repertoire, links between IG polymorphism and antibody repertoire variability have not been thoroughly explored. We present a strategy to mine genotype–repertoire–disease associations.