VH gene family utilization is regulated by a locus outside of the VH region.

Wu, Gillian E.; Paige, Christopher J.

doi:10.1084/jem.167.4.1499

Cited by 33 publications

(10 citation statements)

References 11 publications

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“…The concept of VH use based upon V position alone no longer adequately fits the data . Murine strain differences in the use of V families suggest that other loci outside of the IGH complex have a role in control of V gene segment expression (65,66) . However, any preferential use of specific V gene segments in murine fetal development is thought to disappear over the course of murine development .…”

Section: Discussionmentioning

confidence: 99%

A deletion map of the human immunoglobulin heavy chain variable region.

Walter

Dosch

Cox

1991

The Journal of Experimental Medicine

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SummaryAnalysis of VH gene segments deleted in the process of immunoglobulin heavy chain (IGH) variable region assembly in three series of monoclonal B cell lines has been used to determine the human VH region organization . A deletion map of the relative positions of 21 different VH gene segments has been determined . The characterization of B cell lines from three unrelated adults of two racial groups yielded the same relative VH gene segment order, suggesting that the overall order of VH genes in the normal population is constant . This VH gene segment order was consistent with what we had previously generated from physical mapping techniques . DH segments from the second DH cluster, distinct from the major D H locus 3' of the VH region, were not observed to be used in 32 different rearrangements. Approximately 77% of the VH (D)JH rearrangements involved VH gene segments within 500 kb of the JH region, indicating that human B cell lines preferentially rearrange J.-proximal VH gene segments. The switch, observed in mice, from the fetal use of J. -proximal VH gene segments to an adult VN use dependent upon VH family size may therefore not occur in humans. This detailed map of the VH gene segments is a necessary prerequisite for understanding V N usage in development and disease .T he human immunoglobulin heavy chain (IGH) gene complex is comprised of -100 heavy chain variable (VH) gene segments, at least 24 diversity (DH) elements, six functional joining aH) segments, and a constant (CH) region composed of nine genes and two pseudogenes . The IGH gene complex maps to the most distal band of chromosome 14, at 14832.33 (1, 2). The order telomere-VH JH-CH-centromere has been determined by analysis of Burkitt lymphoma cells having 8 ;14 translocations between the IGH locus and the oncogene c-myc (3) .The VH gene segments, coding for the first 95-101 amino acids of the heavy chain peptide, have been subdivided into six families (V 1 to VH 6) based upon DNA homology (4-9) . The organization of portions of the VH region has been determined from examination of cloned regions (10) and from long-range restriction mapping (4, 11) . The human Ig VH gene families are interspersed. This is in marked contrast to the murine V H organization, which has some interspersion of the members of different Vx families, but appears to be characterized predominantly by the clustering of VH families (reviewed in references 12 and 13) .The major D H region, between VH 6 (the most 3' VH gene segment) and the JH region, is composed of four 9-kb intervals (14, 15). Each 9-kb repeating unit contains six different D H gene families (16). A second DH cluster is located within the VH region (17, 18), but its functional significance, if any, is unknown . VH, DH, J., and CH gene segments are juxtaposed in the course of B cell development . IGH variable region assembly is an ordered process that begins with DH-toJH rearrangement, usually at both IGH alleles (19). The DH-to-J,, complex then may recombine with a VH gene segment . If the first IGH alle...

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Section: Discussionmentioning

confidence: 99%

A deletion map of the human immunoglobulin heavy chain variable region.

Walter

Dosch

Cox

1991

The Journal of Experimental Medicine

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“…An estimate of 18 functional VHJ558 genes requires either a very large proportion of dysfunctional genes in this family, for which size estimates range from a minimum of 60 (1) to >500 members (46), or other factors that influence VH gene utilization . The uncertainty of the actual number of functional VHJ558 genes and the demonstration of non-Igh locus influence on V gene usage (34), limits the impact of the data cited above in supporting a strict position-dependent model of V gene expression . Therefore, additional analyses will be required to ascertain the full extent of and the basis for the shift from preferential rearrangement of D-proximal V genes early in ontogeny (55,63), toward a more probabilistic pattern of V gene utilization that occurs in adult lymphoid tissues (7,63) .…”

Section: Resultsmentioning

confidence: 99%

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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“…Lastly, there may be a technical problem concerning this assay or its interpretation. Wu & Paige (1988) using an RNA colony blot method, and Jeong et al (1988), using in situ hybridization at the single cell level, found a strain-dependent difference in the expression of VH-gene segment families. Yet Schulze & Kelsoe (1987), using their filter paper cloning and in .situ hybridization technique, did not observe what they consider to be a significant difference between strains.…”

Section: E a Comment On Evolutionary Selection On The Germlinementioning

confidence: 99%