Megabase inversions in the human genome as physiological events

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Abstract
THE genes of the immunoglobulin κ light chains are assembled during B-cell differentiation by somatic recombination of one of the Vκ (variable) gene segments and the Jκ–Cκ (joining–constant) gene region. This seems to occur by deletion of the DNA between Vκ and Jκ–Cκ if they are arranged in germ-line DNA in the same transcriptional polarity or by inversion of a fragment containing the Vκ gene if the polarities are opposite (Fig. la; see refs 1–3 for reviews; refs 4–8). We have cloned 75 Vκ genes and pseudogenes of the human K locus and linked them in large contigs (refs 3, 9 for reviews). There seem to be no more than 85 such genes, less than 50 of these being potentially functional10. Thirty-eight of the cloned genes have the same transcriptional polarity as Jκ–Cκ and are part of the so-called Jκproximal 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 Jκ–Cκ (refs 9, 11). We now show that the Vκ genes of the proximal cluster rearrange by a deletion mechanism whereas the others join Jκ–Cκ by inversion of megabase-sized DNA fragments.