Megabase inversions in the human genome as physiological events

Abstract

The genes of the immunoglobulin kappa light chains are assembled during B-cell differentiation by somatic recombination of one of the V kappa (variable) gene segments and the J kappa-C kappa (joining-constant) gene region. This seems to occur by deletion of the DNa between V kappa and J kappa-C kappa if they are arranged in germ-line DNA in the same transcriptional polarity or by inversion of a fragment containing the V kappa gene if the polarities are opposite. We have cloned 75 V kappa genes and pseudogenes of the human kappa locus and linked them in large contigs. There seem to be no more than 85 such genes, less than 50 of these being potentially functional. Thirty-eight of the cloned genes have the same transcriptional polarity as J kappa-C kappa and are part of the so-called J kappa proximal cluster; 35 genes in a distal cluster (the result of a duplication event in evolution) have a polarity that was suggested to be opposite to the one of J kappa-C kappa. We now show that the V kappa genes of the proximal cluster rearrange by a deletion mechanism whereas the others join J kappa-C kappa by inversion of megabase-sized DNA fragments.

Tracing B cell development in human germinal centres by molecular analysis of single cells picked from histological sections.

“…Perhaps V genes differ in hypothetical, cisacting elements which target the hypermutation mechanism to the appropriate location. However, the absence of somatic hypermutation in a rearranged V,, gene could also result from a secondary V,, gene rearrangement which, if it involves inversion, could place the initial V,, joint far away from the Cx locus (Weichold et al, 1990;Huber et al, 1992). Work by Sharpe et al (1991) has shown that an enhancer element downstream of Cx is essential for full activation of the somatic hypermutation mechanism.…”

The human immunoglobulin x locus. Characterization of the duplicated A regions

“…1 and [22,35]). In RPMI6410 the A17-Jn1 rearrangement had occurred by a deletion mechanism and, consequently, in blot hybridizations with digested cell line DNA duplication-differentiating probes, as m237-1, detected an about twofold higher amount of the d copyderived fragments than of the p copy-derived fragments.…”

A defective Vkappa A2 allele in Navajos which may play a role in increased susceptibility to haemophilus influenzae type b disease.

“…As described below, it is likely that the A2 + anti-Hib antibodies are made very infrequently in A2a homozygous individuals, and the frequency may be so low that some heterozygotes may not have any appropriate A2 anti-Hib precursors when they become infected. The reason that it might be particularly hard to make the highest affinity unmutated antibody to Hib is because the V gene used in this antibody is 1.5 Mb from the J segments and it must rearrange by inversion (44,45). In addition, the light chain has an unusually long CDR and importantly, it appears to require a specific amino acid, arginine, at the V -J junction which can only be added via N region addition (7).…”