Chromosomal organization of the human VH4 gene family. Location of individual gene segments.

To investigate the organization and evolution of VH gene segments, we characterized the elements belonging to the VH4 gene family from the germline of a single subject. One hundred sixty VH4-carrying lambda-phage clones were isolated from a genomic library. A combination of hybridization and sequence analysis yielded 13 distinct VH4 clones. Six of these elements had one or more nucleotide substitutions that distinguished them from previously identified VH4 genes, whereas seven elements were identical to previously described VH4 genes. In four of the six new sequences, nucleotide substitutions resulted in amino acid replacements. One pseudogene was identified. On the basis of sequence-specific hybridization using oligonucleotide probes corresponding to these sequences, each of the elements could be assigned to a specific band in a BglII digest. Since the VH4-carrying BglII bands have been mapped in genomic DNA, it was also possible to assign chromosomal locations to the specific VH4 elements. The results indicate that the majority of VH4 elements are located in a region of approximately 500 kb, extending from approximately 500 to 1000 kb 5' of the JH locus. The distribution of shared structural motifs among the VH4 elements indicates that the VH4 gene family has evolved through repeated duplication and gene conversion events.