Evolutionary dynamics of the human immunoglobulin kappa locus and the germline repertoire of the V kappa genes

We have determined the entire nucleotide sequence of the human immunoglobul in kappa locus, comprising a total of 1,010,706 nucleotides. The 76 V kappa genes found by a hybridization-based approach and their classification in 7 families were confirmed. A V kappa orphon located near the locus was also sequenced. In addition, we identified 55 novel V kappa relies and truncate d pseudogenes, which establish 5 new families. Among these 132 V kappa gene s, 46 have open reading frames. According to the databases and the literatu re, 32 unique V kappa genes and 5 identical gene pairs form VJ-joints, 27 u nique genes and 4 gene pairs are transcribed, and 25 unique genes and 4 gen e pairs produce functional proteins. The V kappa gene locus contains a 360- kb inverted duplication, which harbors 118 V kappa genes. A comparison of t he duplicated V kappa genes suggests positive selection on the complementar ity-determining regions of the duplicated genes by point mutations. The ent ire duplication unit was divided into 13 blocks, each of which has its dist inct nucleotide sequence identity to its duplication counterpart (98.1-99.9 %). An inversion-mediated mechanism is suggested to generate the high-homol ogy blocks. Based on the homology blocks and the mutation rates, the invert ed duplication is assumed to have taken place similar to 5 million years ag o. An orphon V kappa gene near the kappa locus and a cluster of five V kapp a orphons on chromosome 22 have no counterparts within the kappa locus. Thi s suggests possible mechanisms of the transposition of orphon V kappa genes .