Human V kappa immunoglobulin gene number: implications for the origin of antibody diversity.

To assess the relative contributions of germline versus somatically mutated genes in the human immune system, we have examined the size of the kappa light-chain variable region (V kappa) gene pool. Two cloned kappa subgroup 1 (V kappa 1) gene probes detected the same family of 15 to 20 crosshybridizing restriction fragments in human DNA, whereas flanking region probes detected fewer hybridizing fragments. Most of the hybridizing bands represent single-copy genes, as judged by a "'gene titration" experiment. Furthermore, the number of hybridization bands is a good estimate of the haploid gene number, since we observed little polymorphism of restriction sites in the V kappa locus of eight unrelated people. A cloned V kappa 3 probe hybridized to essentially the same 15--20 genes in human DNA as the V kappa 1 probes. These results strongly suggest that a discrete family of 15--20 genes constitutes a large proportion of the V genes from three of the four V kappa subgroups. The small number of V kappa genes in the human genome supports the idea that somatic mutation plays a major role in the origin of antibody diversity in man.