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 d escribed in the present report, comprise 3 Mb of DNA, i.e., 0.1% or on e per mill of the 3000 Mb of the human genome. Based on the work of ou r 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, f ive J(K) elements and one C-K gene; (2) specify the size of the germ-l ine repertoire of K light chains, which is one of the sources of the p ractically unlimited antibody diversity; (3) assign the known transcri ption 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 hypermu tation patterns which may contribute to the understanding of this enig matic process; (5) describe the V-K-J(K) rearrangements for half of th e V-K genes by a deletion mechanism and for the other half by a mechan ism 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 evolu tion of the K locus in terms of duplications, insertions, deletions an d gene conversions; (9) attribute the formation of the 24 V-K orphons (i.e., genes outside the locus), whose sequences were determined, to p ericentric 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 th e elucidation of the human genome.