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, lac ks exon 1, which normally codes for the leader and the first four amin o acid residues of the mature protein. Because it also lacks the HLA p romoter, it was surprising to find that the gene is transcribed at a l ow 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 tu mor viruses was inserted into intron 1 of DRB6 >23 million years ago. The insertion was either accompanied or followed by the deletion of ex on 1 and the promoter region of DRB6. In the 3' long terminal repeat o f 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 t he new exon is a promoter enabling transcription of the DRB6 gene. Bes ides providing an example of a de novo generation of an exon, the stud y suggests a potential mechanism for generating new genes through the replacement of old exons with newly generated ones.