RESUMEN
We have determined the entire nucleotide sequence of the human immunoglobulin kappa locus, comprising a total of 1,010,706 nucleotides. The 76 Vkappa genes found by a hybridization-based approach and their classification in 7 families were confirmed. A Vkappa orphon located near the locus was also sequenced. In addition, we identified 55 novel Vkappa relics and truncated pseudogenes, which establish 5 new families. Among these 132 Vkappa genes, 46 have open reading frames. According to the databases and the literature, 32 unique Vkappa genes 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 Vkappa gene locus contains a 360-kb inverted duplication, which harbors 118 Vkappa genes. A comparison of the duplicated Vkappa genes 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 approximately 5 million years ago. An orphon Vkappa gene near the kappa locus and a cluster of five Vkappa orphons on chromosome 22 have no counterparts within the kappa locus. This suggests possible mechanisms of the transposition of orphon Vkappa genes.
Asunto(s)
Evolución Molecular , Duplicación de Gen , Genes de Inmunoglobulinas/genética , Mutación de Línea Germinal/genética , Región Variable de Inmunoglobulina/genética , Cadenas kappa de Inmunoglobulina/genética , Composición de Base , Cromosomas Humanos Par 22/genética , Bases de Datos como Asunto , Genes Duplicados/genética , Humanos , Cinética , Mutagénesis/genética , Sistemas de Lectura Abierta/genética , Filogenia , Mapeo Físico de Cromosoma , Seudogenes/genética , Secuencias Repetitivas de Ácidos Nucleicos/genética , Alineación de Secuencia , Homología de Secuencia de Ácido Nucleico , Terminología como AsuntoRESUMEN
A total of 1,025,415 bases of nucleotide sequence, including the entire human immunoglobulin lambda gene locus has been determined. This is the largest contiguous human DNA sequence ever published. The sequence data revealed the organization of 36 potentially active V lambda gene segments, 33 pseudogene segments, and seven J lambda-C lambda gene segments. Among these 69 functional or nonfunctional V lambda gene segments, 32 were newly discovered. These V lambda gene segments are located within five gene-rich clusters and are divided into five clans based on sequence identity. Five potentially active nonimmunoglobulin genes were also detected within the lambda gene locus, and two other genes were observed in the upstream region. Sequence organization suggests that large DNA duplications diversified the germ-line repertoire of the V lambda gene segments.