Novel Substitution Polymorphisms of Human Immunoglobulin VH Genes in Mexicans

Romo‐González, Tania; Morales‐Montor, Jorge; Rodríguez-Dorantes, Mauricio; Vargas-Madrazo, Enrique

doi:10.1016/j.humimm.2005.03.002

Cited by 6 publications

(4 citation statements)

References 74 publications

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“…Reported immunoglobulin heavy‐chain gene sequences are overwhelmingly the product of early studies, principally between 1987 and 1995, 17 while over the last 10 years, only two supposedly functional alleles have been reported 18 , 19 . Early workers had little understanding of the organization of the immunoglobulin locus, other than knowing that it contained multiple highly similar genes.…”

Section: Discussionmentioning

confidence: 99%

Many human immunoglobulin heavy‐chain IGHV gene polymorphisms have been reported in error

et al. 2007

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The identification of the genes that make up rearranged immunoglobulin genes is critical to many studies. For example, the enumeration of mutations in immunoglobulin genes is important for the prognosis of chronic lymphocytic leukemia, and this requires the accurate identification of the germline genes from which a particular sequence is derived. The immunoglobulin heavy-chain variable (IGHV) gene repertoire is generally considered to be highly polymorphic. In this report, we describe a bioinformatic analysis of germline and rearranged immunoglobulin gene sequences which casts doubt on the existence of a substantial proportion of reported germline polymorphisms. We report a five-level classification system for IGHV genes, which indicates the likelihood that the genes have been reported accurately. The classification scheme also reflects the likelihood that germline genes could be incorrectly identified in mutated VDJ rearrangements, because of similarities to other alleles. Of the 226 IGHV alleles that have previously been reported, our analysis suggests that 104 of these alleles almost certainly include sequence errors, and should be removed from the available repertoire. The analysis also highlights the presence of common mismatches, with respect to the germline, in many rearranged heavy-chain sequences, suggesting the existence of twelve previously unreported alleles. Sequencing of IGHV genes from six individuals in this study confirmed the existence of three of these alleles, which we designate IGHV3-49*04, IGHV3-49*05 and IGHV4-39*07. We therefore present a revised repertoire of expressed IGHV genes, which should substantially improve the accuracy of immunoglobulin gene analysis.

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Section: Discussionmentioning

confidence: 99%

Many human immunoglobulin heavy‐chain IGHV gene polymorphisms have been reported in error

et al. 2007

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“…Interest in these germline genes has increased in recent years, resulting in 40 new allelic variants being reported since 2005 (13–17). Many additional IGHV allelic variants have also been identified in recent high-throughput sequencing studies, through analysis of cDNA-derived VDJ gene rearrangements (18, 19), but these have not been accepted as part of the official IGHV dataset.…”

Section: Germline Genes and Lymphocyte Diversitymentioning

confidence: 99%

The Shape of the Lymphocyte Receptor Repertoire: Lessons from the B Cell Receptor

Jackson¹,

Kidd²,

Wang³

et al. 2013

Front. Immunol.

104

112

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Both the B cell receptor (BCR) and the T cell receptor (TCR) repertoires are generated through essentially identical processes of V(D)J recombination, exonuclease trimming of germline genes, and the random addition of non-template encoded nucleotides. The naïve TCR repertoire is constrained by thymic selection, and TCR repertoire studies have therefore focused strongly on the diversity of MHC-binding complementarity determining region (CDR) CDR3. The process of somatic point mutations has given B cell studies a major focus on variable (IGHV, IGLV, and IGKV) genes. This in turn has influenced how both the naïve and memory BCR repertoires have been studied. Diversity (D) genes are also more easily identified in BCR VDJ rearrangements than in TCR VDJ rearrangements, and this has allowed the processes and elements that contribute to the incredible diversity of the immunoglobulin heavy chain CDR3 to be analyzed in detail. This diversity can be contrasted with that of the light chain where a small number of polypeptide sequences dominate the repertoire. Biases in the use of different germline genes, in gene processing, and in the addition of non-template encoded nucleotides appear to be intrinsic to the recombination process, imparting “shape” to the repertoire of rearranged genes as a result of differences spanning many orders of magnitude in the probabilities that different BCRs will be generated. This may function to increase the precursor frequency of naïve B cells with important specificities, and the likely emergence of such B cell lineages upon antigen exposure is discussed with reference to public and private T cell clonotypes.

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“…17 A second study screening four IGHV genes in a sample of 20 Mexican individuals also identified two novel alleles. 18 However, perhaps surprisingly, examples of such underreporting are not unique to less studied populations, as an extensive investigation of expressed antibody repertoires from 12 Caucasians has also recently led to the identification of 14 novel IGHV gene polymorphisms. 6 Alleles described from germline sequences have been compiled from decades of surveys of IGHV allelic diversity, and are found in the IMGT database (the only official reference of the WHO/IUIS nomenclature committee).…”

Section: Introductionmentioning

confidence: 99%

The immunoglobulin heavy chain locus: genetic variation, missing data, and implications for human disease

2012

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The immunoglobulin (IG) loci consist of repeated and highly homologous sets of genes of different types, variable (V), diversity (D) and junction (J), that rearrange in developing B cells to produce an individual's highly variable repertoire of expressed antibodies, designed to bind to a vast array of pathogens. This repeated structure makes these loci susceptible to a high frequency of insertion and deletion events through evolutionary time, and also makes them difficult to characterize at the genomic level or assay with high-throughput techniques. Given the central role of antibodies in the adaptive immune system, it is not surprising that early candidate gene approaches showed that germline polymorphisms in these regions correlated with susceptibility to both infectious and autoimmune diseases. However, more recent studies, particularly those using high-throughput genome-wide arrays, have failed to implicate these loci in disease. In this review of the IG heavy chain variable gene cluster (IGHV), we examine how poorly we understand the distribution of haplotype variation in this genomic region, and we argue that this lack of information may mask candidate loci in the IGHV gene cluster as causative factors for infectious and autoimmune diseases.

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Novel Substitution Polymorphisms of Human Immunoglobulin VH Genes in Mexicans

Cited by 6 publications

References 74 publications

Many human immunoglobulin heavy‐chain IGHV gene polymorphisms have been reported in error

Many human immunoglobulin heavy‐chain IGHV gene polymorphisms have been reported in error

The Shape of the Lymphocyte Receptor Repertoire: Lessons from the B Cell Receptor

The immunoglobulin heavy chain locus: genetic variation, missing data, and implications for human disease

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