A Novel Framework for Characterizing Genomic Haplotype Diversity in the Human Immunoglobulin Heavy Chain Locus

Rodriguez, Oscar L.; Gibson, William S; Parks, Tom; Emery, Matthew; Powell, James; Strahl, Maya; Deikus, Gintaras; Auckland, Kathryn; Eichler, Evan E.; Marasco, Wayne A.; Sebra, Robert; Sharp, Andrew J.; Smith, Melissa; Bashir, Ali Kashif; Watson, Corey T.

doi:10.3389/fimmu.2020.02136

Cited by 76 publications

(97 citation statements)

References 80 publications

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“…Within this 45 kb CNV, we also noticed a 2.66 kb cluster of tandem repeats with a 59-mer motif (Figs 5A and S12) that was not correctly assembled in either GRCh37 or GRCh38 (see GenBank: AC245369.4). Similar repeat clusters have also been reported for CHM1 (from which the GRCh38 sequence for IGH region was derived) and NA19240 samples, though the copy numbers of the 59-mer motif varied [15].…”

Section: A Tandem Repeat Within a 45kb Cnv Involving Ighv1-69 And Ighv2-70supporting

confidence: 78%

“…The greatest progress in this direction has been made for inference of HLA alleles [42][43][44][45] and to a lesser extent KIR alleles [46] based on large databases of known gene sequences. More recent approaches have used targeted long-read sequencing to characterize immunoglobulin variation [15]. However, much functional genetic variation affecting core immune system genes is still to be discovered and made accessible to larger studies.…”

Section: Plos Computational Biologymentioning

confidence: 99%

“…Although some structural errors do remain-and might be resolvable with future work based on the breadth of data we have generated here-our results suggest we have produced an essentially correct representation of the regions reported here, with some caveats that we have noted. Our assembly thus adds to growing numbers of reference-quality assemblies that can be utilized in these regions [15,23,47,48] and to the catalogue of known alleles at these loci. The sequencing data and finished assemblies generated in this study have also been deposited at the European Genome-Phenome Archive (Data Availability) for future use.…”

Section: Plos Computational Biologymentioning

confidence: 99%

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Using de novo assembly to identify structural variation of eight complex immune system gene regions

et al. 2021

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Driven by the necessity to survive environmental pathogens, the human immune system has evolved exceptional diversity and plasticity, to which several factors contribute including inheritable structural polymorphism of the underlying genes. Characterizing this variation is challenging due to the complexity of these loci, which contain extensive regions of paralogy, segmental duplication and high copy-number repeats, but recent progress in long-read sequencing and optical mapping techniques suggests this problem may now be tractable. Here we assess this by using long-read sequencing platforms from PacBio and Oxford Nanopore, supplemented with short-read sequencing and Bionano optical mapping, to sequence DNA extracted from CD14+ monocytes and peripheral blood mononuclear cells from a single European individual identified as HV31. We use this data to build a de novo assembly of eight genomic regions encoding four key components of the immune system, namely the human leukocyte antigen, immunoglobulins, T cell receptors, and killer-cell immunoglobulin-like receptors. Validation of our assembly using k-mer based and alignment approaches suggests that it has high accuracy, with estimated base-level error rates below 1 in 10 kb, although we identify a small number of remaining structural errors. We use the assembly to identify heterozygous and homozygous structural variation in comparison to GRCh38. Despite analyzing only a single individual, we find multiple large structural variants affecting core genes at all three immunoglobulin regions and at two of the three T cell receptor regions. Several of these variants are not accurately callable using current algorithms, implying that further methodological improvements are needed. Our results demonstrate that assessing haplotype variation in these regions is possible given sufficiently accurate long-read and associated data. Continued reductions in the cost of these technologies will enable application of these methods to larger samples and provide a broader catalogue of germline structural variation at these loci, an important step toward making these regions accessible to large-scale genetic association studies.

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Section: A Tandem Repeat Within a 45kb Cnv Involving Ighv1-69 And Ighv2-70supporting

confidence: 78%

Section: Plos Computational Biologymentioning

confidence: 99%

Section: Plos Computational Biologymentioning

confidence: 99%

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Using de novo assembly to identify structural variation of eight complex immune system gene regions

et al. 2021

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“…Nevertheless, more complex patterns might be hidden in the regulatory regions of the BCR encoding loci ( 26 ). In the future, these regions may be sequenced directly using tailored long-read sequencing approaches ( 51 ).…”

Section: Discussionmentioning

confidence: 99%

Machine Learning Analysis of Naïve B-Cell Receptor Repertoires Stratifies Celiac Disease Patients and Controls

et al. 2021

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Celiac disease (CeD) is a common autoimmune disorder caused by an abnormal immune response to dietary gluten proteins. The disease has high heritability. HLA is the major susceptibility factor, and the HLA effect is mediated via presentation of deamidated gluten peptides by disease-associated HLA-DQ variants to CD4+ T cells. In addition to gluten-specific CD4+ T cells the patients have antibodies to transglutaminase 2 (autoantigen) and deamidated gluten peptides. These disease-specific antibodies recognize defined epitopes and they display common usage of specific heavy and light chains across patients. Interactions between T cells and B cells are likely central in the pathogenesis, but how the repertoires of naïve T and B cells relate to the pathogenic effector cells is unexplored. To this end, we applied machine learning classification models to naïve B cell receptor (BCR) repertoires from CeD patients and healthy controls. Strikingly, we obtained a promising classification performance with an F1 score of 85%. Clusters of heavy and light chain sequences were inferred and used as features for the model, and signatures associated with the disease were then characterized. These signatures included amino acid (AA) 3-mers with distinct bio-physiochemical characteristics and enriched V and J genes. We found that CeD-associated clusters can be identified and that common motifs can be characterized from naïve BCR repertoires. The results may indicate a genetic influence by BCR encoding genes in CeD. Analysis of naïve BCRs as presented here may become an important part of assessing the risk of individuals to develop CeD. Our model demonstrates the potential of using BCR repertoires and in particular, naïve BCR repertoires, as disease susceptibility markers.

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“…Despite the fact that the Ig loci of natural outbred organisms are known to be extremely diverse, much of our understanding of the mechanisms dictating V(D)J recombination have come from studies of inbred models. However, even in inbred models, it has been demonstrated that Ig genetic diversity is more extensive than initially appreciated, in many cases mirroring (or even exceeding) what has been observed in human populations and other more outbred organisms (19)(20)(21)(22)(23)(24)(25)(26)(27)(28). In mouse, for example, a comparison of germline V H sequences between C57BL/6 and BALB/c revealed surprisingly little overlap in the germline repertoires of these two strains.…”

Section: The V H Gene Usage Conundrummentioning

confidence: 98%

Igh Locus Polymorphism May Dictate Topological Chromatin Conformation and V Gene Usage in the Ig Repertoire

2021

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Vast repertoires of unique antigen receptors are created in developing B and T lymphocytes. The antigen receptor loci contain many variable (V), diversity (D) and joining (J) gene segments that are arrayed across very large genomic expanses and are joined to form variable-region exons of expressed immunoglobulins and T cell receptors. This process creates the potential for an organism to respond to large numbers of different pathogens. Here, we consider the possibility that genetic polymorphisms with alterations in a vast array of regulatory elements in the immunoglobulin heavy chain (IgH) locus lead to changes in locus topology and impact immune-repertoire formation.

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A Novel Framework for Characterizing Genomic Haplotype Diversity in the Human Immunoglobulin Heavy Chain Locus

Cited by 76 publications

References 80 publications

Using de novo assembly to identify structural variation of eight complex immune system gene regions

Using de novo assembly to identify structural variation of eight complex immune system gene regions

Machine Learning Analysis of Naïve B-Cell Receptor Repertoires Stratifies Celiac Disease Patients and Controls

Igh Locus Polymorphism May Dictate Topological Chromatin Conformation and V Gene Usage in the Ig Repertoire

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