Mosaic deletion patterns of the human antibody heavy chain gene locus shown by Bayesian haplotyping

Gidoni, Moriah; Snir, Omri; Peres, Ayelet; Polak, Pazit; Lindeman, Ida; Mikocziova, Ivana; Sarna, Vikas Kumar; Lundin, Knut E.A.; Clouser, Christopher R.; Vigneault, François; Collins, Andrew M.; Sollid, Ludvig M.; Yaari, Gur

doi:10.1038/s41467-019-08489-3

Cited by 93 publications

(193 citation statements)

References 41 publications

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“…One measure of diversity is provided by consideration of heterozygous loci in individuals who have been genotyped by the analysis of VDJ rearrangements. When heterozygosity was explored at 50 IGHV gene loci in 98 individuals, only 5 genes were heterozygous in more than 50% of individuals, while 19 genes were heterozygous in more than 20% of individuals 20 . Homozygosity was a conspicuous feature of individual genotypes, with heterozygosity being seen at fewer than ⅓ of genes with a defined genotype in all but a handful of subjects 20 .…”

Section: Discussionmentioning

confidence: 99%

“…When heterozygosity was explored at 50 IGHV gene loci in 98 individuals, only 5 genes were heterozygous in more than 50% of individuals, while 19 genes were heterozygous in more than 20% of individuals 20 . Homozygosity was a conspicuous feature of individual genotypes, with heterozygosity being seen at fewer than ⅓ of genes with a defined genotype in all but a handful of subjects 20 . A further measure of human diversity comes from reported allele usage in geographically distant communities.…”

Section: Discussionmentioning

confidence: 99%

“…There was a sharp decline in the reporting of new sequences once the complete human IGH locus was published in 1998 14 , but the advent of high-throughput sequencing of human antibody genes reawakened interest in the documentation of allelic variants 15,16 . A surprising level of antibody gene variation, including structural variation of the IGH locus, has since been shown within the human population 17,18,19,20 , and such variation can have important consequences for the development of a suitable protective antibody repertoire 21,22 .…”

Section: Introductionmentioning

confidence: 99%

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A comparison of immunoglobulin IGHV, IGHD and IGHJ genes in wild-derived and classical inbred mouse strains

Watson

Kos

Gibson

et al. 2019

Preprint

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To better understand the subspecies origin of antibody genes in classical inbred mouse strains, the IGH gene loci of four wild-derived mouse strains were explored by analysis of VDJ gene rearrangements. A total of 341 unique IGHV gene sequences were inferred in the wild-derived strains, including 247 sequences that have not previously been reported. The genes of the Non-Obese Diabetic (NOD) strain were also documented, and all but one of the 84 inferred NOD IGHV genes have previously been observed in C57BL/6 mice. This is surprising because the Swiss mouse-derived NOD strain and the C57BL/6 strain have no known shared ancestry. The relationships between the genes of the wild-derived inbred strains and of the C57BL/6, NOD and BALB/c classical inbred strain were then explored. The IGH loci of the C57BL/6 and the MSM/MsJ strains share many sequences, but analysis showed that few sequences are shared with wild-derived strains representing the three major subspecies of the house mouse. There were also few IGHV sequences that were shared by the BALB/c strain and any of the four wild-derived strains. The origins of IGHV genes in the C57BL/6, MSM/MsJ and BALB/c strains therefore remain unclear. These unexpected similarities and differences highlight our lack of understanding of the antibody gene loci of the laboratory mouse, with implications for the interpretation of strain-specific differences in models of antibody-mediated diseases, and of Adaptive Immune Receptor Repertoire sequencing (AIRR-seq) data. These results also suggest that a position-based immunoglobulin gene nomenclature may be unworkable in the mouse.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A comparison of immunoglobulin IGHV, IGHD and IGHJ genes in wild-derived and classical inbred mouse strains

Watson

Kos

Gibson

et al. 2019

Preprint

Self Cite

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show abstract

“…One measure of diversity is provided by consideration of heterozygous loci in individuals who have been genotyped by the analysis of VDJ rearrangements. When heterozygosity was explored at 50 IGHV gene loci in 98 individuals, only five genes were heterozygous in more than 50% of individuals, and only 19 genes were heterozygous in more than 20% of individuals . However, it is notable that more extreme examples of IGHV heterozygosity have been reported in some populations; for example, a study of genomic DNA in 28 South Africans characterized >50 IGHV alleles in all but two individuals .…”

Section: Discussionmentioning

confidence: 99%

A comparison of immunoglobulin IGHV, IGHD and IGHJ genes in wild‐derived and classical inbred mouse strains

et al. 2019

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The genomes of classical inbred mouse strains include genes derived from all three major subspecies of the house mouse, Mus musculus. We recently posited that genetic diversity in the immunoglobulin heavy chain (IGH) gene loci of C57BL/6 and BALB/c mice reflects differences in subspecies origin. To investigate this hypothesis, we conducted high‐throughput sequencing of IGH gene rearrangements to document IGH variable (IGHV), joining (IGHJ) and diversity (IGHD) genes in four inbred wild‐derived mouse strains (CAST/EiJ, LEWES/EiJ, MSM/MsJ and PWD/PhJ) and a single disease model strain (NOD/ShiLtJ), collectively representing genetic backgrounds of several major mouse subspecies. A total of 341 germline IGHV sequences were inferred in the wild‐derived strains, including 247 not curated in the international ImMunoGeneTics information system. By contrast, 83/84 inferred NOD IGHV genes had previously been observed in C57BL/6 mice. Variability among the strains examined was observed for only a single IGHJ gene, involving a description of a novel allele. By contrast, unexpected variation was found in the IGHD gene loci, with four previously unreported IGHD gene sequences being documented. Very few IGHV sequences of C57BL/6 and BALB/c mice were shared with strains representing major subspecies, suggesting that their IGH loci may be complex mosaics of genes of disparate origins. This suggests a similar level of diversity is likely present in the IGH loci of other classical inbred strains. This must now be documented if we are to properly understand interstrain variation in models of antibody‐mediated disease.

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“…This is consistent with our understanding of both length and D R A F T Table 1. Structurally profiling the baseline repertoire snapshots (30). A full table containing the values for all 41 baseline datasets is available in the Supporting Information (SI Table 2).…”

Section: Structurally Profiling the Baseline Immune Repertoirementioning

confidence: 99%

Evidence of Antibody Repertoire Functional Convergence through Public Baseline and Shared Response Structures

Raybould¹,

Marks²,

Kovaltsuk³

et al. 2020

Preprint

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The antibody repertoires of different individuals ought to exhibit significant functional commonality, given that most pathogens trigger a successful immune response in most people. Sequence-based approaches have so far offered little evidence for this phenomenon. For example, a recent study estimated the number of shared ('public') antibody clonotypes in circulating baseline repertoires to be around 0.02% across ten unrelated individuals. However, to engage the same epitope, antibodies only require a similar binding site structure and the presence of key paratope interactions, which can occur even when their sequences are dissimilar. Here, we investigate functional convergence in human antibody repertoires by comparing the antibody structures they contain. We first structurally profile baseline antibody diversity (using snapshots from 41 unrelated individuals), predicting all modellable distinct structures within each repertoire. This analysis uncovers a high degree of structural commonality. For instance, around 3% of distinct structures are common to the ten most diverse individual samples ('Public Baseline' structures). Our approach is the first computational method to provide support for the long-assumed levels of baseline repertoire functional commonality. We then apply the same structural profiling approach to repertoire snapshots from three individuals before and after flu vaccination, detecting a convergent structural drift indicative of recognising similar epitopes ('Public Response' structures). Antibody Model Libraries (AMLs) derived from Public Baseline and Public Response structures represent a powerful geometric basis set of low-immunogenicity candidates exploitable for general or target-focused therapeutic antibody screening. antibody repertoire | structural profiling | public structures | antibody model libraries | antibody screening Correspondence: deane@stats.ox.ac.uk

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Mosaic deletion patterns of the human antibody heavy chain gene locus shown by Bayesian haplotyping

Cited by 93 publications

References 41 publications

A comparison of immunoglobulin IGHV, IGHD and IGHJ genes in wild-derived and classical inbred mouse strains

A comparison of immunoglobulin IGHV, IGHD and IGHJ genes in wild-derived and classical inbred mouse strains

A comparison of immunoglobulin IGHV, IGHD and IGHJ genes in wild‐derived and classical inbred mouse strains

Evidence of Antibody Repertoire Functional Convergence through Public Baseline and Shared Response Structures

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