The Individual and Population Genetics of Antibody Immunity
Authors: Corey T. Watson, Jacob Glanville, Wayne A. Marasco
Journal: Trends in Immunology (2017)

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. 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. 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. Antibodies (Abs) have long been appreciated as key constituents of the adaptive immune response. Their function is to enable selective recognition and mediate immune responses to novel foreign antigens. This is accomplished through the somatic generation of vast repertoires of hundreds of millions of unique Ab receptors that can be selected, matured, and ultimately participate in the formation of long-term memory during B-cell development and activation. As a consequence of this diversity, even after nearly a century of research, the complexity of the Ab response within and between individuals is only beginning to be delineated at the molecular and genetic levels. Hundreds of variable (V) and dozens of diversity (D) and joining (J) immunoglobulin (IG) germ-line gene segments across three primary loci in the human genome comprise the necessary building blocks of the expressed Ab heavy- and light-chain repertoires [1Lefranc M.-P. Lefranc G. The Immunoglobulin Factsbook. Academic Press, 2001Google Scholar]. Whereas the heavy chain is encoded by genes at the IG heavy-chain locus (IGH), the light chain can be encoded by genes at either the IG kappa (IGK) or IG lambda (IGL) chain loci [1Lefranc M.-P. Lefranc G. The Immunoglobulin Factsbook. Academic Press, 2001Google Scholar]. The naïve Ab repertoire is formed by assembling variants of these building blocks using a specialized V(D)J recombination process that somatically joins various V, D, and J segments (or V and J at IGK and IGL). The introduction and deletion of P and N nucleotides at V(D)J junctions and the pairing of different heavy and light chains dramatically increase diversity (Figure 1) [2Tonegawa S. Somatic generation of antibody diversity.Nature. 1983; 302: 575-581Crossref PubMed Scopus (3428) Google Scholar]. Considering these processes alone, a given baseline or primary naïve repertoire can theoretically sample from 1015 different Abs [3Schroeder H.W. Similarity and divergence in the development and expression of the mouse and human antibody repertoires.Dev. Comp. Immunol. 2006; 30: 119-135Crossref PubMed Scopus (115) Google Scholar]. The extraordinary diversity of the naïve repertoire ensures that it will likely contain a naïve Ab with at least weak initial binding against a vast array of antigens. Even so, this impressive baseline diversity can be subsequently augmented when a B cell encounters and is stimulated by an antigen to undergo somatic hypermutation (SHM; Figure 1), resulting in lineages of tens of thousands of clonally derived affinity maturation variants of the initial Ab. Specifically, SHM introduces somatic mutations throughout the variable portion of the Ab, including targeted hotspots residing within the antigen-contacting hypervariable complementarity-determining regions (CDRs). This process ultimately increases the affinity and specificity of the Ab for binding the target epitope, facilitating a highly focused antigen-specific response. While the prevailing paradigm for investigating B-cell and Ab-mediated responses has placed emphasis on the importance of the unique molecular mechanisms cited earlier in the generation of key functional Abs, there is a growing appreciation for the fact that IG genes are highly variable at the germ-line level, exhibiting extreme allelic polymorphism and gene copy number variation (CNV) between individuals and across populations [4Chimge N.-O. et al.Determination of gene organization in the human IGHV region on single chromosomes.Genes Immun. 2005; 6: 186-193Crossref PubMed Scopus (25) Google Scholar, 5Li H. et al.Genetic diversity of the human immunoglobulin heavy chain VH region.Immunol. Rev. 2002; 190: 53-68Crossref PubMed Scopus (28) Google Scholar, 6Kidd M.J. et al.The inference of phased haplotypes for the immunoglobulin H chain V region gene loci by analysis of VDJ gene rearrangements.J. Immunol. 2012; 188: 1333-1340Crossref PubMed Scopus (73) Google Scholar, 7Watson C.T. et al.Complete haplotype sequence of the human immunoglobulin heavy-chain variable, diversity, and joining genes and characterization of allelic and copy-number variation.Am. J. Hum. Genet. 2013; 92: 530-546Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar, 8Sasso E.H. et al.Ethnic differences in polymorphism of an immunoglobulin VH3 gene.J. Clin. Invest. 1995; 96: 1591-1600Crossref PubMed Scopus (45) Google Scholar, 9Scheepers C. et al.Ability to develop broadly neutralizing HIV-1 antibodies is not restricted by the germline IG gene repertoire.J. Immunol. 2015; 194: 4371-4378Crossref PubMed Scopus (57) Google Scholar]. Recent studies have begun to highlight that, in addition to diversity introduced during V(D)J recombination, heavy- and light-chain pairing, and SHM, IG germ-line variation (e.g., allelic variation; Figure 1) plays a vital part in determining the development of the naïve repertoire, with downstream impacts on signatures observed in the memory compartment, and the capacity of an individual to mount an Ab response to specific epitopes [10Glanville J. et al.Naive antibody gene-segment frequencies are heritable and unaltered by chronic lymphocyte ablation.Proc. Natl. Acad. Sci. U. S. A. 2011; 108: 20066-20071Crossref PubMed Scopus (135) Google Scholar, 11Boyd S.D. et al.Individual variation in the germline Ig gene repertoire inferred from variable region gene rearrangements.J. Immunol. 2010; 184: 6986-6992Crossref PubMed Scopus (202) Google Scholar, 12Kidd M.J. et al.DJ pairing during VDJ recombination shows positional biases that vary among individuals with differing IGHD locus immunogenotypes.J. Immunol. 2015; 196: 1158-1164Crossref PubMed Scopus (23) Google Scholar, 13Wang C. et al.B-cell repertoire responses to varicella-zoster vaccination in human identical twins.Proc. Natl. Acad. Sci. U. S. A. 2015; 112: 500-505Crossref PubMed Scopus (74) Google Scholar, 14Rubelt F. et al.Individual heritable differences result in unique lymphocyte receptor repertoires of naïve and antigen-experienced cells.Nat. Commun. 2016; 6: 1-12Google Scholar, 15Avnir Y. et al.IGHV1-69 polymorphism modulates anti-influenza antibody repertoires, correlates with IGHV utilization shifts and varies by ethnicity.Sci. Rep. 2016; 6: 20842Crossref PubMed Scopus (120) Google Scholar, 16Wheatley A.K. et al.H5N1 vaccine-elicited memory B cells are genetically constrained by the IGHV locus in the recognition of a neutralizing epitope in the hemagglutinin stem.J. Immunol. 2015; 195: 602-610Crossref PubMed Scopus (73) Google Scholar]. Recent genomic sequencing indicates that IG loci, specifically IGH, may be among the most polymorphic in the human genome [17Watson C.T. et al.Sequencing of the human IG light chain loci from a hydatidiform mole BAC library reveals locus-specific signatures of genetic diversity.Genes Immun. 2014; 16: 24-34Crossref PubMed Scopus (26) Google Scholar]. Across IGH, IGK, and IGL, there are currently >420 alleles cataloged in the ImMunoGeneTics information system database (IMGT) [18Pallarès N. et al.The human immunoglobulin heavy variable genes.Exp. Clin. Immunogenet. 1999; 16: 36-60Crossref PubMed Scopus (73) Google Scholar, 19Lefranc M.-P. et al.IMGT®, the international ImMunoGeneTics information system® 25 years on.Nucleic Acids Res. 2014; 43: D413-D422Crossref PubMed Scopus (375) Google Scholar, 20Pallarés N. et al.The human immunoglobulin lambda variable (IGLV) genes and joining (IGLJ) segments.Exp. Clin. Immunogenet. 1998; 15: 8-18Crossref PubMed Scopus (65) Google Scholar, 21Barbié V. Lefranc M.P. The human immunoglobulin kappa variable (IGKV) genes and joining (IGKJ) segments.Exp. Clin. Immunogenet. 1998; 15: 171-183Crossref PubMed Scopus (67) Google Scholar] that have been described from germ-line DNA in the human population, with an enrichment of nonsynonymous variants (Table 1). Although the validity of some alleles in IMGT has been called into question [22Wang Y. et al.Many human immunoglobulin heavy-chain IGHV gene polymorphisms have been reported in error.Immunol. Cell Biol. 2008; 86: 111-115Crossref PubMed Scopus (46) Google Scholar], the number of polymorphic alleles continues to grow [11Boyd S.D. et al.Individual variation in the germline Ig gene repertoire inferred from variable region gene rearrangements.J. Immunol. 2010; 184: 6986-6992Crossref PubMed Scopus (202) Google Scholar, 23Gadala-Maria D. et al.Automated analysis of high-throughput B-cell sequencing data reveals a high frequency of novel immunoglobulin V gene segment alleles.Proc. Natl. Acad. Sci. U. S. A. 2015; 112: E862-E870Crossref PubMed Scopus (140) Google Scholar, 24Corcoran M.M. et al.Production of individualized V gene databases reveals high levels of immunoglobulin genetic diversity.Nat. Commun. 2016; 7: 13642Crossref PubMed Scopus (130) Google Scholar], especially as IG gene sequencing is conducted in increasing numbers of non-Caucasian samples [7Watson C.T. et al.Complete haplotype sequence of the human immunoglobulin heavy-chain variable, diversity, and joining genes and characterization of allelic and copy-number variation.Am. J. Hum. Genet. 2013; 92: 530-546Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar, 9Scheepers C. et al.Ability to develop broadly neutralizing HIV-1 antibodies is not restricted by the germline IG gene repertoire.J. Immunol. 2015; 194: 4371-4378Crossref PubMed Scopus (57) Google Scholar, 25Wang Y. et al.Genomic screening by 454 pyrosequencing identifies a new human IGHV gene and sixteen other new IGHV allelic variants.Immunogenetics. 2011; 63: 259-265Crossref PubMed Scopus (47) Google Scholar]. A recent study conducted in 28 indigenous South Africans identified 122 non-IMGT IGHV alleles [9Scheepers C. et al.Ability to develop broadly neutralizing HIV-1 antibodies is not restricted by the germline IG gene repertoire.J. Immunol. 2015; 194: 4371-4378Crossref PubMed Scopus (57) Google Scholar]. In addition to IG allelic variation and single nucleotide polymorphisms (SNPs), CNVs, including large deletions, insertions, and duplications (∼8–75 Kb in length), are also prevalent in IG regions (Table 1). Using IGH as an example, up to 29 of the 58 functional/open reading frame (ORF) IGHV genes may vary in genomic copy number [4Chimge N.-O. et al.Determination of gene organization in the human IGHV region on single chromosomes.Genes Immun. 2005; 6: 186-193Crossref PubMed Scopus (25) Google Scholar, 6Kidd M.J. et al.The inference of phased haplotypes for the immunoglobulin H chain V region gene loci by analysis of VDJ gene rearrangements.J. Immunol. 2012; 188: 1333-1340Crossref PubMed Scopus (73) Google Scholar, 7Watson C.T. et al.Complete haplotype sequence of the human immunoglobulin heavy-chain variable, diversity, and joining genes and characterization of allelic and copy-number variation.Am. J. Hum. Genet. 2013; 92: 530-546Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar, 11Boyd S.D. et al.Individual variation in the germline Ig gene repertoire inferred from variable region gene rearrangements.J. Immunol. 2010; 184: 6986-6992Crossref PubMed Scopus (202) Google Scholar, 26Watson C.T. Breden F. The immunoglobulin heavy chain locus: genetic variation, missing data, and implications for human disease.Genes Immun. 2012; 13: 363-373Crossref PubMed Scopus (124) Google Scholar, 27Milner E.C. et al.Polymorphism and utilization of human VH genes.Ann. N. Y. Acad. Sci. 1995; 764: 50-61Crossref PubMed Scopus (48) Google Scholar, 28Shin E.K. et al.Polymorphism of the human immunoglobulin variable region segment V1-4.1.Immunogenetics. 1993; 38: 304-306Crossref PubMed Scopus (10) Google Scholar]; CNVs of IGH D (diversity) and constant (C) region genes are also known [11Boyd S.D. et al.Individual variation in the germline Ig gene repertoire inferred from variable region gene rearrangements.J. Immunol. 2010; 184: 6986-6992Crossref PubMed Scopus (202) Google Scholar, 12Kidd M.J. et al.DJ pairing during VDJ recombination shows positional biases that vary among individuals with differing IGHD locus immunogenotypes.J. Immunol. 2015; 196: 1158-1164Crossref PubMed Scopus (23) Google Scholar, 29Bottaro A. et al.Pulsed-field electrophoresis screening for immunoglobulin heavy-chain constant-region (IGHC) multigene deletions and duplications.Am. J. Hum. Genet. 1991; 48: 745-756PubMed Google Scholar]. Until recently, primarily due to technical difficulties associated with the complex genomic architecture of the IG loci, none of the known CNVs in IGHV had been sequenced at nucleotide resolution [7Watson C.T. et al.Complete haplotype sequence of the human immunoglobulin heavy-chain variable, diversity, and joining genes and characterization of allelic and copy-number variation.Am. J. Hum. Genet. 2013; 92: 530-546Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar]; many likely remain undescribed at the genomic level.Table 1Allelic, Copy Number, and Amino Acid Variation for IG Functional and Open Reading Frame Genes Cataloged in IMGTaData accessed from IMGT February 2017. NS, nonsynonymous; S, synonymous.FamilyGenesAllelesNS variantsS variantsCDR-H1 NS variantsCDR-H2 NS variantsGenes in CNVIGHV111401913236IGHV2423269311IGHV327109825791712IGHV4107892711188IGHV52944001IGHV61201000IGHV72640001Subtotal58267227155252929IGKV120353317411IGKV21118144110IGKV3818249210IGKV411NANANANA0IGKV511NANANANA0IGKV63520000IGKV700NANANANA0Subtotal44787330731IGLV171242021IGLV2620138230IGLV31118145330IGLV43621000IGLV551032001IGLV61220000IGLV72310000IGLV81311001IGLV91302000IGLV101341100IGLV111211000Subtotal39824523683Total141427345208384033a Data accessed from IMGT February 2017. NS, nonsynonymous; S, synonymous. Open table in a new tab The high prevalence of IG allelic and locus structural diversity translates into extreme levels of inter-individual haplotype variation [4Chimge N.-O. et al.Determination of gene organization in the human IGHV region on single chromosomes.Genes Immun. 2005; 6: 186-193Crossref PubMed Scopus (25) Google Scholar, 5Li H. et al.Genetic diversity of the human immunoglobulin heavy chain VH region.Immunol. Rev. 2002; 190: 53-68Crossref PubMed Scopus (28) Google Scholar, 6Kidd M.J. et al.The inference of phased haplotypes for the immunoglobulin H chain V region gene loci by analysis of VDJ gene rearrangements.J. Immunol. 2012; 188: 1333-1340Crossref PubMed Scopus (73) Google Scholar, 7Watson C.T. et al.Complete haplotype sequence of the human immunoglobulin heavy-chain variable, diversity, and joining genes and characterization of allelic and copy-number variation.Am. J. Hum. Genet. 2013; 92: 530-546Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar]. For example, recent comparisons of the two available completed assemblies for the IGHV gene region (∼1 Mb in length) revealed that two human chromosomes can vary by >100 Kb of sequence, with >2,800 SNPs, and CNVs of 10 IGHV functional/ORF genes [7Watson C.T. et al.Complete haplotype sequence of the human immunoglobulin heavy-chain variable, diversity, and joining genes and characterization of allelic and copy-number variation.Am. J. Hum. Genet. 2013; 92: 530-546Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar, 17Watson C.T. et al.Sequencing of the human IG light chain loci from a hydatidiform mole BAC library reveals locus-specific signatures of genetic diversity.Genes Immun. 2014; 16: 24-34Crossref PubMed Scopus (26) Google Scholar]. In population sequencing experiments, extreme examples of heterozygosity have been noted, with evidence of some individuals carrying more than one allele at every IGHV coding gene [9Scheepers C. et al.Ability to develop broadly neutralizing HIV-1 antibodies is not restricted by the germline IG gene repertoire.J. Immunol. 2015; 194: 4371-4378Crossref PubMed Scopus (57) Google Scholar]. Supporting earlier genetic mapping data [4Chimge N.-O. et al.Determination of gene organization in the human IGHV region on single chromosomes.Genes Immun. 2005; 6: 186-193Crossref PubMed Scopus (25) Google Scholar, 5Li H. et al.Genetic diversity of the human immunoglobulin heavy chain VH region.Immunol. Rev. 2002; 190: 53-68Crossref PubMed Scopus (28) Google Scholar], more recent analysis of inferred haplotypes from Ab repertoire data surveyed in nine individuals revealed that all 18 haplotypes characterized were unique [6Kidd M.J. et al.The inference of phased haplotypes for the immunoglobulin H chain V region gene loci by analysis of VDJ gene rearrangements.J. Immunol. 2012; 188: 1333-1340Crossref PubMed Scopus (73) Google Scholar]. Furthermore, at the population level, of the few SNPs and CNVs screened within IGH, allele and genotype frequencies have been shown to vary considerably between ethnic backgrounds [7Watson C.T. et al.Complete haplotype sequence of the human immunoglobulin heavy-chain variable, diversity, and joining genes and characterization of allelic and copy-number variation.Am. J. Hum. Genet. 2013; 92: 530-546Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar, 8Sasso E.H. et al.Ethnic differences in polymorphism of an immunoglobulin VH3 gene.J. Clin. Invest. 1995; 96: 1591-1600Crossref PubMed Scopus (45) Google Scholar, 9Scheepers C. et al.Ability to develop broadly neutralizing HIV-1 antibodies is not restricted by the germline IG gene repertoire.J. Immunol. 2015; 194: 4371-4378Crossref PubMed Scopus (57) Google Scholar, 15Avnir Y. et al.IGHV1-69 polymorphism modulates anti-influenza antibody repertoires, correlates with IGHV utilization shifts and varies by ethnicity.Sci. Rep. 2016; 6: 20842Crossref PubMed Scopus (120) Google Scholar], with evidence of selection [7Watson C.T. et al.Complete haplotype sequence of the human immunoglobulin heavy-chain variable, diversity, and joining genes and characterization of allelic and copy-number variation.Am. J. Hum. Genet. 2013; 92: 530-546Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar]. Despite the evidence for elevated germ-line diversity, genomic resources for IG loci continue to lag behind other regions of the genome [26Watson C.T. Breden F. The immunoglobulin heavy chain locus: genetic variation, missing data, and implications for human disease.Genes Immun. 2012; 13: 363-373Crossref PubMed Scopus (124) Google Scholar]. Because of this, the comprehensive and accurate genotyping of IG polymorphisms remains a significant challenge [26Watson C.T. Breden F. The immunoglobulin heavy chain locus: genetic variation, missing data, and implications for human disease.Genes Immun. 2012; 13: 363-373Crossref PubMed Scopus (124) Google Scholar, 30Luo S. et al.Estimating copy number and allelic variation at the immunoglobulin heavy chain locus using short reads.PLoS Comput. Biol. 2016; 12: 1-21Crossref Scopus (16) Google Scholar], and as a result, the full extent of IG polymorphism and the implications for human health are yet to be uncovered [26Watson C.T. Breden F. The immunoglobulin heavy chain locus: genetic variation, missing data, and implications for human disease.Genes Immun. 2012; 13: 363-373Crossref PubMed Scopus (124) Google Scholar]. However, it is plausible that population-level diversity in the IG loci, particularly in IGH, will rival that of other complex immune gene families, such as the human leukocyte antigen (HLA) and killer cell IG-like receptor (KIR) genes. These genes are also characterized by extreme haplotype diversity, due to CNV and coding region variation [31Trowsdale J. Knight J.C. Major histocompatibility complex genomics and human disease.Annu. Rev. Genomics Hum. Genet. 2013; 14: 301-323Crossref PubMed Scopus (477) Google Scholar, 32Parham P. Moffett A. Variable NK cell receptors and their MHC class I ligands in immunity, reproduction and human evolution.Nat. Rev. Immunol. 2013; 13: 133-144Crossref PubMed Scopus (373) Google Scholar]; HLA genes, for example, have thousands of known alleles [31Trowsdale J. Knight J.C. Major histocompatibility complex genomics and human disease.Annu. Rev. Genomics Hum. Genet. 2013; 14: 301-323Crossref PubMed Scopus (477) Google Scholar]. In contrast to IG genes, HLA and KIR have been studied more extensively across human populations, and have demonstrated critical roles in disease [31Trowsdale J. Knight J.C. Major histocompatibility complex genomics and human disease.Annu. Rev. Genomics Hum. Genet. 2013; 14: 301-323Crossref PubMed Scopus (477) Google Scholar, 32Parham P. Moffett A. Variable NK cell receptors and their MHC class I ligands in immunity, reproduction and human evolution.Nat. Rev. Immunol. 2013; 13: 133-144Crossref PubMed Scopus (373) Google Scholar]. Our limited knowledge of IG population diversity has hindered our ability to comprehensively test for direct connections between IG germ-line polymorphisms, variation in the repertoire generated after recombination, amino acid variation in the Ab produced, and ultimately Ab function. Advances in high-throughput sequencing technology now enable extensive characterization of the expressed Ab repertoire [33Georgiou G. et al.The promise and challenge of high-throughput sequencing of the antibody repertoire.Nat. Biotechnol. 2014; 32: 158-168Crossref PubMed Scopus (483) Google Scholar, 34Boyd S.D. Joshi S.A. High-throughput DNA sequencing analysis of antibody repertoires.Microbiol. Spectr. 2014; 2: 1-13Crossref Scopus (21) Google Scholar, 35Yaari G. Kleinstein S.H. Practical guidelines for B-cell receptor repertoire sequencing analysis.Genome Med. 2015; 7: 121Crossref PubMed Scopus (160) Google Scholar], creating opportunities for beginning to investigate the heritability of the Ab response at fine-scale resolution. Applications of these methods, collectively referred to as repertoire sequencing ('IgSeq' or 'RepSeq'), have already led to a wealth of new discoveries in a range of contexts [33Georgiou G. et al.The promise and challenge of high-throughput sequencing of the antibody repertoire.Nat. Biotechnol. 2014; 32: 158-168Crossref PubMed Scopus (483) Google Scholar, 36Jackson K.J.L. et al.The shape of the lymphocyte receptor repertoire: lessons from the B cell receptor.Front. Immunol. 2013; 4: 1-12Crossref PubMed Scopus (87) Google Scholar]. These include general observations that key features of the Ab repertoire show extensive variability between healthy individuals [10Glanville J. et al.Naive antibody gene-segment frequencies are heritable and unaltered by chronic lymphocyte ablation.Proc. Natl. Acad. Sci. U. S. A. 2011; 108: 20066-20071Crossref PubMed Scopus (135) Google Scholar, 11Boyd S.D. et al.Individual variation in the germline Ig gene repertoire inferred from variable region gene rearrangements.J. Immunol. 2010; 184: 6986-6992Crossref PubMed Scopus (202) Google Scholar, 13Wang C. et al.B-cell repertoire responses to varicella-zoster vaccination in human identical twins.Proc. Natl. Acad. Sci. U. S. A. 2015; 112: 500-505Crossref PubMed Scopus (74) Google Scholar, 14Rubelt F. et al.Individual heritable differences result in unique lymphocyte receptor repertoires of naïve and antigen-experienced cells.Nat. Commun. 2016; 6: 1-12Google Scholar, 37Galson J.D. et al.In-depth assessment of within-individual and inter-individual variation in the B cell receptor repertoire.Front. Immunol. 2015; 6: 1-13Crossref PubMed Scopus (63) Google Scholar], and a limited overlap of B-cell receptor clones between individuals, even monozygotic (MZ) twins [10Glanville J. et al.Naive antibody gene-segment frequencies are heritable and unaltered by chronic lymphocyte ablation.Proc. Natl. Acad. Sci. U. S. A. 2011; 108: 20066-20071Crossref PubMed Scopus (135) Google Scholar, 13Wang C. et al.B-cell repertoire responses to varicella-zoster vaccination in human identical twins.Proc. Natl. Acad. Sci. U. S. A. 2015; 112: 500-505Crossref PubMed Scopus (74) Google Scholar, 14Rubelt F. et al.Individual heritable differences result in unique lymphocyte receptor repertoires of naïve and antigen-experienced cells.Nat. Commun. 2016; 6: 1-12Google Scholar]. However, RepSeq studies have also revealed that these inter-individual differences are not necessarily random, but likely have a strong underlying genetic component, providing initial support for the importance of germ-line IG polymorphism in determining the naïve and Ag-stimulated Ab repertoire. For example, several recent studies have revealed that V, D, and J gene usage in the naïve repertoire is much more highly correlated between MZ twins than between unrelated individuals [10Glanville J. et al.Naive antibody gene-segment frequencies are heritable and unaltered by chronic lymphocyte ablation.Proc. Natl. Acad. Sci. U. S. A. 2011; 108: 20066-20071Crossref PubMed Scopus (135) Google Scholar, 13Wang C. et al.B-cell repertoire responses to varicella-zoster vaccination in human identical twins.Proc. Natl. Acad. Sci. U. S. A. 2015; 112: 500-505Crossref PubMed Scopus (74) Google Scholar, 14Rubelt F. et al.Individual heritable differences result in unique lymphocyte receptor repertoires of naïve and antigen-experienced cells.Nat. Commun. 2016; 6: 1-12Google Scholar], and that IG gene usage patterns are consistent across time points within a given individual [38Laserson U. et al.High-resolution antibody dynamics of vaccine-induced immune responses.Proc. Natl. Acad. Sci. U. S. A. 2014; 111: 4928-4933Crossref PubMed Scopus (136) Google Scholar]. A role for genetic factors can be seen for other repertoire features in twins as well, including the degree of SHM [13Wang C. et al.B-cell repertoire responses to varicella-zoster vaccination in human identical twins.Proc. Natl. Acad. Sci. U. S. A. 2015; 112: 500-505Crossref PubMed Scopus (74) Google Scholar], and the distribution of CDR-H3 length and clone convergence [10Glanville J. et al.Naive antibody gene-segment frequencies are heritable and unaltered by chronic lymphocyte ablation.Proc. Natl. Acad. Sci. U. S. A. 2011; 108: 20066-20071Crossref PubMed Scopus (135) Google Scholar, 13Wang C. et al.B-cell repertoire responses to varicella-zoster vaccination in human identical twins.Proc. Natl. Acad. Sci. U. S. A. 2015; 112: 500-505Crossref PubMed Scopus (74) Google Scholar, 14Rubelt F. et al.Individual heritable differences result in unique lymphocyte receptor repertoires of naïve and antigen-experienced cells.Nat. Commun. 2016; 6: 1-12Google Scholar]. Intriguingly, although existing data suggest that features in the memory compartment are more stochastic, likely reflective of random recruitment and transient proliferation, certain genes and repertoire features exhibit predictable patterns even in memory B cells [10Glanville J. et al.Naive antibody gene-segment frequencies are heritable and unaltered by chronic lymphocyte ablation.Proc. Natl. Acad. Sci. U. S. A. 2011; 108: 20066-20071Crossref PubMed Scopus (135) Google Scholar, 13Wang C. et al.B-cell repertoire responses to varicella-zoster vaccination in human identical twins.Proc. Natl. Acad. Sci. U. S. A. 2015; 112: 500-505Crossref PubMed Scopus (74) Google Scholar, 14Rubelt F. et al.Individual heritable differences result in unique lymphocyte receptor repertoires of naïve and antigen-experienced cells.Nat. Commun. 2016; 6: 1-12Google Scholar, 39Vollmers C. et al.Genetic measurement of memory B-cell recall using antibody repertoire sequencing.Proc. Natl. Acad. Sci. U. S. A. 2013; 110: 13463-13468Crossref PubMed Scopus (183) Google Scholar]. Studies of