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The defective major histocompatibility complex (MHC) DRB6 gene is transcribed into mRNA in human [peripheral blood lymphocytes, transfected and Epstein-Barr virus (EBV)] and chimpanzee EBV cell lines. MHC-DRB6 presents several anomalies, which include stop codons in exon 2, lack of the usual polyadenilation signal of other MHC-DRB genes, and a promoter region and exon 1 taken from a locally inserted retrovirus. The complete cDNA sequences from human DRB6*0201 and three common chimpanzee alleles (Patr-DRB6*0108, Patr-DRB6*0109, Patr-DRB6*0111) have been obtained; two exon 1-exon 2 cDNA sequences from bonobos (Papa-DRB6*0101 and Papa-DRB6*0102) are also shown. In contrast to chimpanzee DRB6 transcripts, the human ones: (1) present an exon 1-exon 2 splicing site that includes the transcription of the first 141 nucleotides of intron 1, rendering a longer exon 1, and (2) show a duplication of exon 6, which would render a longer cytoplasmic tail in a putative DRB6 protein. These two characteristics are found in all the human sequences obtained, regardless of the cellular type tested, and they are not present in any of the chimpanzee alleles reported; consequently, they are human-specific. All the alleles reported here bear stop codons in the three possible reading frames; however, a certain level of expression of DRB6 has been observed by cytofluorometry. This could be due to the presence of a selenocysteine insertion sequence (SECIS) stem-loop structure located at the 3 untranslated region of the DRB6 mRNA, which directs selenocysteine incorporation at UGA codons. DRB6 transcription and translation would be the first gene model of a readingthrough stop codon mechanism in primate MHC. It is also feasible that the DRB6 gene might generate a population of short polypeptides, bound to plasmatic membranes, having non-antigen-presenting functions or which are presented by other MHC molecules as HLA-E presents HLA-G and -B leader sequence-derived peptides.

HLA-DRB6 is one of the human major histocompatibility complex (MHC) genes present in DR1, DR2, and DR10 haplotypes (approximately 26% of individuals). It shows several anomalies in human and non-human primates, including exon 2 stop codons (non-randomly grouped between codons 74 and 94) and a promoter region, and an exon 1 coming from an inserted retrovirus. It has been shown that not only chimpanzee but also human Mhc-DRB6 lack the usual 3' untranslated (UT) polyadenylation signal, and in the present work it was found that the human DRB6 gene coming from an HLA-DR2 haplotype is effectively transcribed after transfection in mouse L cells, and that HLA-DRB6 molecules may be expressed on the cell surface. DRB6 transcription level is remarkably lower in human than in chimpanzee. Moreover, their exons 1 (both taken from the 3'LTR region of a mammary tumor retrovirus) are also different; this shows that these viral insertions may be an important mechanism for different evolutionary changes in orthologous genes of different species. The pathways by which DRB6 molecules may be expressed on the membrane are unclear but other examples of truncated protein expression have also been described, even within the human major histocompatibility complex (i. e., in HLA-G). Finally, the presence of mature HLA-DRB6 mRNA molecules supports the notion that splicing may take place even in the absence of a canonical 3'UT polyadenylation signal.

The HLA-DRB6 gene (also called DRB sigma/V1) has been found only in about 26% of human HLA haplotypes, i.e.; DR1, DRw10, and DR2-bearing ones (Corell et al. 1991). In contrast, exon-2 DRB6 sequences have been obtained from all tested primates: nine chimpanzees (Pan troglodytes), three gorillas (Gorilla gorilla) and three orangutans (Pongo pygmaeus); other apes which had already been sequenced (one gorilla and one chimpanzee) also had the DRB6 gene. Thus, all apes tested from three different species, some of them evolutionary separated by at least 14-16 million years, bear the DRB6 gene. In addition, more than one gene copy per haplotype has been found in one chimpanzee; this, together with the apparent loss of this gene in some of the human DR haplotypes, may indicate that the DR genome has undergone evolutionary changes more recently and more actively than class I or III genes. In addition, ten different and presumably allelic DRB6 exon-2 sequences have been obtained, and some of them coming from different species are more similar to each other than the one from the same species; this finding goes in favor of the trans-species theory of major histocompatibility complex polymorphism generation. Also, data are presented supporting that DRB6 may be one of the eldest genes of the DRB family, thus one of the first to diverge from the ancestral DRB gene.