Organization of the murine immunoglobulin VH complex in the inbred strains.

Rathbun, Gary; Capra, J D; Tucker, P W

doi:10.1002/j.1460-2075.1987.tb02597.x

Cited by 58 publications

(25 citation statements)

References 47 publications

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“…As previously reported, the VH36-65 probe, VId-130 (32), hybridizes to the VHARS-bearing Eco RI fragment (6.2 kbp) of the Igh`haplotype but does not hybridize to BALB/c (Igh°) genomic DNA. In agreement with the data of Rathbun et al (12), we have demonstrated that the VHARS gene is retained by CXAL 1.40 (Fig . 6), indicating that this gene is 5' of the rearranged VHJ606 gene on the Igh`chromosome .…”

Section: Resultssupporting

confidence: 93%

“…Bothwell et al (36) and Givol et al (37) reported similar findings for members of the VJ558 family. Previous analyses of B cell lines for V gene deletions (11,12,38,39) were consistent with a clustered organization of V gene family members. V gene analysis of Igh-recombinant mouse strains constructed by Riblet (40) also indicated a generally clustered organization of VH families (10).…”

Section: Resultssupporting

confidence: 65%

“…7 shows the relative order of these clusters along the chromosome and indicates the interspersion (VHQ52, VH7183) and dispersion (VHS107, VH36-60, VGAM3 .8) of the family clusters . gested by previous studies (11,12,25,26), the two most D-proximal VH families are completely interspersed and the two families most distal to the D region, VHJ558 and V3609, may be partially interspersed .…”

Section: Resultsmentioning

confidence: 66%

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The organization of the mouse Igh-V locus. Dispersion, interspersion, and the evolution of VH gene family clusters.

Brodeur¹,

Osman²,

Mackle³

et al. 1988

The Journal of Experimental Medicine

108

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Studies ofIg gene structure and organization during the past decade have illuminated the central mechanisms of antibody diversification: the somatic rearrangement and reassortment of multiple gene segments, junctional flexibility, and point mutation . The inherited set of Ig gene segments provides a diversified genetic basis upon which these dynamic processes operate during ontogeny. Thus, the composition of these germline genes imposes a major influence on the development of the antibody repertoire.The present study examines the germline content and organization of the mouse heavy chain variable region genes (V genes) . We set out to analyze the locus in sufficient detail and resolution to provide the basis for determining the extent of inherited Vgene diversity, the evolution ofthe germline repertoire, and any functional consequences of the physical arrangement of the V gene segments .The mouse Igh locus consists of at least 100-200 V genes (1-3). V gene families, defined by nucleotide sequence relationships, comprise distinct sets of highly related V genes that can be identified by hybridization using prototypic V gene probes . This classification of V gene families (l, 4) has provided a useful framework for the study of germline V gene content, polymorphism, and utilization (1-7). Whereas the general organization of the Igh locus is 5'-V HDJ .-C -3' (8, 9), previous studies of V gene family organization have resulted in partial, relatively low resolution maps lacking consistency between reports (10-12)."Deletion mapping" takes advantage of the fact that V, gene rearrangements result in the deletion of DNA originally separating the rearranged V gene segment and the DJ .-CH region (13). We have constructed a panel of 32 pre-B cell lines, most of which have rearranged V, genes on both chromosomes. Since these cell lines were derived from Fi mice heterozygous at the Igh locus, V, gene deletions can be identified using RFLPs. V, gene analyses of 51 independently rearranged chromosomes are consistent with a single V, gene map order of nine V, gene families. The genomic stability of these cell lines and consistent deletion profiles of all 51 rearranged loci provide a high resolution V gene map that has compelling experimental support.

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Section: Resultssupporting

confidence: 93%

Section: Resultssupporting

confidence: 65%

Section: Resultsmentioning

confidence: 66%

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The organization of the mouse Igh-V locus. Dispersion, interspersion, and the evolution of VH gene family clusters.

Brodeur¹,

Osman²,

Mackle³

et al. 1988

The Journal of Experimental Medicine

108

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“…Family size varies from 1 member (V12) to approximately 70 members (J558) (9,31,43). Although early studies showed that genes encoding members of different families were physically clustered within the Ig heavy-chain locus (9,52), subsequent studies have revealed that there is interspersion of some V H families (45,51) as shown in Fig. 1.…”

Section: Resultsmentioning

confidence: 99%

Evidence that Immunoglobulin V_H-DJ Recombination Does Not Require Germ Line Transcription of the Recombining Variable Gene Segment

Angelin-Duclos

Calame

1998

Molecular and Cellular Biology

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V(D)J recombination is a specialized DNA rearrangement which is unique to immunoglobulin (Ig) and T-cell receptor (TCR) genes. The process involves recognition and doublestranded cleavage by recombinase-activating gene 1 and 2 (RAG1 and RAG2) proteins (47, 56), which recognize highly conserved recombination signal sequences (RSSs) flanking Ig and TCR variable (V), diversity (D), and joining (J) gene segments. Following RAG-dependent DNA cleavage, ubiquitously expressed components of the normal double-strand break repair machinery carry out end processing and religation, so that specific V, D, and J gene segments are fused and the DNA between them is deleted and ultimately lost from the cell. V(D)J recombination is essential for functional expression of Ig and TCR genes and is critical for generating antigen recognition diversity in the immune system (4,41,57,70,72).Since cutting, deletion, and rejoining of DNA could potentially be detrimental to genomic integrity, it is not surprising that V(D)J recombination is highly regulated. This process is controlled in several ways (60). First, V(D)J recombination is lymphoid cell specific, occurring only in B and T lymphocytes. Second, it is lineage specific, since Ig gene segments are fully rearranged only in B cells and TCR gene segments are rearranged only in T cells. Third, it is developmental stage specific, occurring only at specific stages of lymphocyte development. Fourth, it is an ordered process in which specific gene segments rearrange at particular developmental stages. For example, in B cells the Ig heavy-chain locus always undergoes rearrangement before the and light-chain loci. Furthermore, D-to-J H recombination usually precedes V H -D recombination. Finally, successful V(D)J recombination causes feedback regulation that halts further rearrangement of a rearranging locus, so that only one Ig or TCR allele is functionally rearranged in each cell. This aspect of regulation is critical for the phenomenon of allelic exclusion of Ig and TCR genes, which ensures that each lymphocyte expresses TCR or Ig with a single antigen recognition specificity. Given the importance of V(D)J recombination for immune function and the potential hazards of its inappropriate occurrence, the need to understand the mechanisms of its exquisite regulation is obvious.The lymphoid and developmental stage-specific expression of the RAG1 and RAG2 genes accounts for some regulatory aspects of V(D)J recombination. However, since all Ig and TCR genes have identical RSSs, which are recognized and rearranged by common recombinase enzymes, regulated RAG gene expression cannot account for lineage specificity, ordered rearrangement, or negative feedback (2,48,76). A model involving regulated chromatin accessibility has been suggested to account for these aspects of V(D)J recombination regulation (12,60,64,75). The accessibility hypothesis posits that V, D, and J gene segments must acquire an altered chromatin structure which makes them accessible to the recombination enzymatic machinery before ...

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“…Differences in the replication times observed between different strains of mice could be due to differences in the relative sizes or order of the VK families or could be due to the degree of interspersion among the different mouse strains. Interspersion has been observed in the human VH (1,39) and VK loci (44) and to a much lesser extent the VH locus in the mouse (2,8,9,37,58,59). In the human kappa locus, a large region of the locus was duplicated (38,54).…”

Section: Discussionmentioning

confidence: 99%

The mouse immunoglobulin kappa light-chain genes are located in early- and late-replicating regions of chromosome 6.

Hatton¹,

Schildkraut²

1990

Mol. Cell. Biol.

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The murine immunoglobulin kappa (K) light-chain multigene family includes the constant region (CK), joining-region genes, and approximately 30 kappa-variable (VK) region families. The entire region occupies an estimated 1,000 to 3,000 kilobases, and some VK families have been linked by recombinant inbred mapping. The CK gene and 14 VK families replicated differently among cell lines of lymphoid and nonlymphoid origin. In nonlymphoid cells, the CK gene replicated earlier than the VK families. A transition from replication during the second third of S phase for the CK gene to later replication during S for VK families was observed. The VK family (VK21) that maps closest to the CK gene, replicated during the first half of the S phase; most of the other VK families replicated during the second half of S, and some replicated during the last quarter of the S phase. In lymphoid cells, the K locus replicated earlier in the pre-B than in the B-cell lines. In one pre-B-cell line, 22D6, the K genes examined replicated at the beginning of the S phase. In the B-cell lines, the EcoRI segment containing the transcribed gene replicated near the beginning of the S phase. Other VKc families replicated within the first two-thirds of S phase. Some linked VK families replicated at similar times. In the B-cell lines, a transition from replication at the beginning of S for the transcribed CK and VK genes and surrounding DNA sequences to later replication for the other VK families was observed. However, in contrast to the non-lymphoid cell lines, the replication of this locus occurred predominantly during the first half of S. The K locus contains both early-and late-replicating genes, and early replication is usually associated with transcriptional activity. The results are discussed with respect to the organization of transcriptionally active chromatin domains. 300 (7, 12, 18, 22, 40, 52, 55, 57). Based on results from the VK21 locus, which determined that the VK genes are separated by about 10 kb (29), the entire K locus could occupy 1,000 to 3,000 kb. A suggested gene order from crossover analysis of congenic and recombinant inbred strains of mice has been produced (5,16,17,22,25,40,61,68). The order of the kappa variable-region genes relative to the centromere and telomere was inferred from these studies (17). The gene order was determined to be centromere; hypodactyly; (IgK-V11, IgK-V24, and IgK-V9-26); (IgK-V9 and IgK-V1); IgK-V12,13; (IgK-V4, IgK-V8, IgK-V1O, IgK-V19); (IgK-V28 and Rn7s-6); IgK-V23; (IgK-V21, IgK-J, and IgK-C); (Ly2, Ly3); waved-1; and telomere (17) Contiguous

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Organization of the murine immunoglobulin VH complex in the inbred strains.

Cited by 58 publications

References 47 publications

The organization of the mouse Igh-V locus. Dispersion, interspersion, and the evolution of VH gene family clusters.

The organization of the mouse Igh-V locus. Dispersion, interspersion, and the evolution of VH gene family clusters.

Evidence that Immunoglobulin V_H-DJ Recombination Does Not Require Germ Line Transcription of the Recombining Variable Gene Segment

The mouse immunoglobulin kappa light-chain genes are located in early- and late-replicating regions of chromosome 6.

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Organization of the murine immunoglobulin VH complex in the inbred strains.

Cited by 58 publications

References 47 publications

The organization of the mouse Igh-V locus. Dispersion, interspersion, and the evolution of VH gene family clusters.

The organization of the mouse Igh-V locus. Dispersion, interspersion, and the evolution of VH gene family clusters.

Evidence that Immunoglobulin VH-DJ Recombination Does Not Require Germ Line Transcription of the Recombining Variable Gene Segment

The mouse immunoglobulin kappa light-chain genes are located in early- and late-replicating regions of chromosome 6.

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Evidence that Immunoglobulin V_H-DJ Recombination Does Not Require Germ Line Transcription of the Recombining Variable Gene Segment