Resolution of the HLA-DRB6 puzzle: a case of grafting a de novo-generated exon on an existing gene.

HLA-DRB6, one of the human major histocompatibility complex genes, lacks exon 1, which normally codes for the leader and the first four amino acid residues of the mature protein. Because it also lacks the HLA promoter, it was surprising to find that the gene is transcribed at a low level in a chimpanzee B-lymphoblastoma cell line, in which the DRB6 homolog is truncated as in humans. The study designed to resolve the paradox has revealed that a retrovirus related to the mouse mammary tumor viruses was inserted into intron 1 of DRB6 > 23 million years ago. The insertion was either accompanied or followed by the deletion of exon 1 and the promoter region of DRB6. In the 3' long terminal repeat of the retrovirus, however, an open reading frame for a new exon arose, which codes for a sequence of mostly hydrophobic amino acid residues; the sequence could function as a leader for the truncated DRB6 gene. This new exon has a functional donor splice site at its 3' end, which enables it to be spliced in register with DRB6 exon 2. Upstream from the new exon is a promoter enabling transcription of the DRB6 gene. Besides providing an example of a de novo generation of an exon, the study suggests a potential mechanism for generating new genes through the replacement of old exons with newly generated ones.