Physical map of the 3′ region of the human immunoglobulin heavy chain locus: clustering of autoantibody-related variable segments in one haplotype.

Shin, Euy Kyun; Matsuda, Fumihiko; Nagaoka, Hitoshi; Fukita, Yosho; Imai, Takashi; Yokoyama, Kazushige; Soeda, Eiichi; Honjo, Tasuku

doi:10.1002/j.1460-2075.1991.tb04930.x

Cited by 110 publications

(59 citation statements)

References 32 publications

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“…The presence of relatively large deletion/insertion polymorphisms in the IGHV region was implicated in the previous studies and together with our data could be summarized as follows: in Region I, a common deletion/ insertion polymorphism at the 3 0 -end of the IGHV includes gene IGHV7-4-1, 28 and a region containing genes IGHV1-8, IGHV3-9, and IGHV2-10 identified in a recent study from our group. 24 Redetection of this deletion (Del I) validates the high-throughput approach used in the present study.…”

Section: Discussionsupporting

confidence: 81%

Determination of gene organization in the human IGHV region on single chromosomes

Pramanik

et al. 2005

Genes Immun

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Organization of the IGHV genes (n ¼ 108) on single human chromosomes has been determined by detecting these sequences in single sperm using multiplex PCR amplification followed by microarray detection. A total of 374 single sperm samples from five Caucasian males were studied. Three deletion/insertion polymorphisms (Del I-Del III) with deletion allele frequencies ranging from 0.1 to 0.3 were identified. Del I is a previously reported polymorphism affecting three IGHV genes (IGHV1-8, IGHV3-9, and IGHV2-10). Del II affects a region 2-18 kb containing two pseudogenes IGHV(II)-28.1 and IGHV3-29, and Del III spans B21-53 kb involving genes IGHV4-39, IGHV7-40, IGHV(II)-40-1, and IGHV3-41. Deletion alleles of both Dels II and III were found in a heterozygous state, and therefore, could not be easily detected if haploid samples were not used in the study. Results of the present study indicate that deletions/insertions together with other possible chromosomal rearrangements may play an important role in forming the genetic structure of the IGHV region, and may significantly contribute to antibody diversity. Since these three polymorphisms are located within or next to the 3 0 half of the IGHV region, they may have an important role in the expressed IGHV gene repertoire during immune response.

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Section: Discussionsupporting

confidence: 81%

Determination of gene organization in the human IGHV region on single chromosomes

Pramanik

et al. 2005

Genes Immun

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“…Human germline Ig V H -gene CDRs, particularly CDR1, are highly prone to R mutations We applied the computer algorithm to the analysis of the inherent Rf and R:S mutation ratio values of the CDRs and FRs of 24 selected human germline V H genes [21][22][23][24][25][26][27][28][29][30][31][32][33][34] , including H11 (Table 1). These V H genes are among those most-frequently expressed in the early and adult B-cell repertoires and encode natural antibodies and antibodies to foreign antigens, as well as autoantibodies in autoimmune patients.…”

Section: Hhs Public Accessmentioning

confidence: 99%

The CDR1 sequences of a major proportion of human germline Ig VH genes are inherently susceptible to amino acid replacement

1994

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The variable (V) genes of antigen-selected antibodies are known to exhibit a higher frequency of amino acid replacement mutations in the sequences encoding the antigen-contacting complementarity-determining regions (CDRs) than in those encoding the 'structural' framework regions (FRs). Here, Bernard Chang and Paolo Casali analyse the impact of regional differences in the codon composition of human germline Ig V H and V L genes on regional differences in the frequency of replacement mutations in the gene products (i.e. the antigen-binding sites of antibody molecules). This analysis reveals that CDR and FR sequences can differ significantly in their inherent susceptibility to amino acid replacement given any single nucleotide change. Thus, the CDR sequences of all the Ig V H genes analysed comprise a higher frequency of codons susceptible to replacement mutations than would be expected for a random sequence. Conversely, the FR sequences comprise codons less susceptible to replacement mutations than expected. Random accumulation of nucleotide changes throughout the coding sequence of an Ig V-gene segment containing CDRs inherently more prone to replacement mutations than the respective FRs would inevitably yield a higher rate of amino acid replacements in the CDRs than in the FRs. This would provide a fertile structural substrate of hypervariability for antigen selection while still maintaining the structural integrity of the FRs.The production of antibodies with progressively higher affinity for antigen is an important feature of B-cell clonotypes recruited by repeated antigenic challenge, and is referred to as affinity maturation 1 . The molecular basis of this process was first unveiled by the analysis of the binding affinity and primary structure of monoclonal antibodies (mAbs) generated at successive stages of murine immune responses to different conjugated haptens and antigens [2][3][4][5][6][7][8][9][10] . The first exposure to antigen results in recruitment of B-cell clonotypes that bind antigen by virtue of the combinatorial and junctional specificity of their unmutated surface receptors (Ig V segments). Subsequent exposures to antigen lead to accumulation of somatic point mutations in the antibody V segments and antigen selection of the highaffinity mutated B-cell clonotypes. Sequential rounds of mutation and selection eventually result in restriction of the response to those B cells with the best 'fit' for antigen 11,12 . Somatic point mutations in Ig V-gene segmentsIn the absence of negative or positive selective pressure on the gene product, a random mutational process would entail an even distribution of nucleotide changes yielding amino HHS Public Access Author ManuscriptAuthor Manuscript Author ManuscriptAuthor Manuscript acid replacements (R mutations) and nucleotide changes not yielding amino acid replacements (S, or silent, mutations) throughout the coding sequence. However, antigenselected antibodies have been shown to include a higher frequency of R mutations in the Ig V-gene complemen...

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“…Biased expression of IgH J-proximal V genes has been demonstrated in neonatal mice (41), although the mouse model is controversial (42,43). Interestingly, not all human V H segments preferentially expressed during early stages of ontogeny map in the proximity of the J H segments (44). A defect specific to the rearrangement of the J H -distal V H gene segments has been described in mice that lack the ␣-chain of the IL-7R (45).…”

Section: Third Wave: a Clan Of Three Homologous Subfamilies Dominatesmentioning

confidence: 99%

Vδ Repertoire During Thymic Ontogeny Suggests Three Novel Waves of γδ TCR Expression

Weber-Arden

Wilbert

Kabelitz

et al. 2000

The Journal of Immunology

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Taking advantage of a PCR technique that allows amplification of all variable region genes with equal efficiency, we defined three novel waves of TCR δ-chain transcription during thymic ontogeny. The canonical DV101-D2-J2 rearrangement was confined to a narrow window from days 14 to 18 of gestation, indicating that the postulated two consecutive γδ precursor waves bearing this canonical DV101 rearrangement will coincide on day 16. Neonatal δ-chain transcripts used a second wave of diverse Vα gene segments that are exclusively located in the δ locus-proximal gene cluster of intermingled single members of different Vα subfamilies. In the adult, only expression of a clan of three homologous subfamilies, ADV7, DV104, and ADV17, persists. The members of the ADV7 subfamily are also scattered across the α locus, but their usage does not show the position-dependent bias of the other Vα-to-δ rearrangements.

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Physical map of the 3′ region of the human immunoglobulin heavy chain locus: clustering of autoantibody-related variable segments in one haplotype.

Cited by 110 publications

References 32 publications

Determination of gene organization in the human IGHV region on single chromosomes

Determination of gene organization in the human IGHV region on single chromosomes

The CDR1 sequences of a major proportion of human germline Ig VH genes are inherently susceptible to amino acid replacement

Vδ Repertoire During Thymic Ontogeny Suggests Three Novel Waves of γδ TCR Expression

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