THE IMMUNOGLOBULIN-KAPPA LOCUS - OR - WHAT HAS BEEN LEARNED FROM LOOKING CLOSELY AT ONE-TENTH OF A PERCENT OF THE HUMAN GENOME

The immunoglobulin K locus and its immediate surroundings, which are described in the present report, comprise 3 Mb of DNA, i.e., 0.1% or one per mill of the 3000 Mb of the human genome. Based on the work of our group during the past 12 years, we can now (1) depict in much detail the structure of the K locus with its 76 V-K genes and pseudogenes, five J(K) elements and one C-K gene; (2) specify the size of the germ-line repertoire of K light chains, which is one of the sources of the practically unlimited antibody diversity; (3) assign the known transcription products (studied as cDNAs) and K proteins to certain germ-line V-K genes and attribute the differences in sequences to hypermutation and, to a lesser extent, to allelic variation; (4) analyze the hypermutation patterns which may contribute to the understanding of this enigmatic process; (5) describe the V-K-J(K) rearrangements for half of the V-K genes by a deletion mechanism and for the other half by a mechanism involving inversions of Mb-sized (i.e., 0.5 mm long) DNA fragments; (6) define various regulatory and other conserved sequence elements; (7) get clues as to the variation of the structure of the K locus in different individuals and populations, including a haplotype with only half the number of V-K genes; (8) interpret many aspects of the evolution of the K locus in terms of duplications, insertions, deletions and gene conversions; (9) attribute the formation of the 24 V-K orphons (i.e., genes outside the locus), whose sequences were determined, to pericentric inversions and other transposition processes; (10) answer a series of questions of biomedical interest; and (11) contribute 12.5 Mb of restriction maps, 1.8 Mb of clones and 250 kb of sequences to the elucidation of the human genome.