Evolutionary dynamics of the human immunoglobulin κ locus and the germline repertoire of the Vκ genes

Abstract

We have determined the entire nucleotide sequence of the human immunoglobulin κlocus, comprising a total of 1,010,706 nucleotides. The 76 Vκgenes found by a hybridization-based approach and their classification in 7 families were confirmed. A Vκorphon located near the locus was also sequenced. In addition, we identified 55 novel Vκrelics and truncated pseudogenes, which establish 5 new families. Among these 132 Vκgenes, 46 have open reading frames. According to the databases and the literature, 32 unique Vκgenes and 5 identical gene pairs form VJ-joints, 27 unique genes and 4 gene pairs are transcribed, and 25 unique genes and 4 gene pairs produce functional proteins. The Vκgene locus contains a 360-kb inverted duplication, which harbors 118 Vκgenes. A comparison of the duplicated Vκgenes suggests positive selection on the complementarity-determining regions of the duplicated genes by point mutations. The entire duplication unit was divided into 13 blocks, each of which has its distinct nucleotide sequence identity to its duplication counterpart (98.1 – 99.9 %). An inversion-mediated mechanism is suggested to generate the high-homology blocks. Based on the homology blocks and the mutation rates, the inverted duplication is assumed to have taken place ∼ 5 million years ago. An orphon Vκgene near the κlocus and a cluster of five Vκorphons on chromosome 22 have no counterparts within the κlocus. This suggests possible mechanisms of the transposition of orphon Vκgenes.