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The HLA-B locus is the most polymorphic of the class I genes encoded within the human major histocompatibility complex. This polymorphism is mainly located in exons 2 and 3, which code for the molecule's alpha1 and alpha2 domains and includes the antigenic peptide binding site. However, information about adjacent non-coding regions (introns 1 and 2) has not been extensively reported but could be very important in establishing an understanding of the evolutionary mechanisms involved in the polymorphism generation of HLA-B and the Mhc loci. In the present work, introns 1 and 2 of 14 HLA-B alleles are studied and their significance is discussed; 10 have been sequenced in our own laboratory and the other 4 have been previously reported by others. Different serological families share the complete intron 1 sequence; at this region, 12 out of 14 HLA-B alleles could be included in four groups with the same intron 1 sequence: a) B*0702, B*4201, B*4801; b) B*27052, B*4002, B*4011; c) B*40012, B*4101, including B*4501, B*5001 (these latter two alleles have specific characteristics in both introns 1 and 2, which may reflect a common evolutionary pathway); and d) B*44031, B*44032. The other alleles, B*1402, and B*1801, do not have identical intron 1 sequences compared to any of the described groups, but share many similarities with them. The B*1801 evolutionary pathway seems to be very specific since it branches separately from other alleles both in intron 1 and intron 2 dendrograms. On the other hand, HLA-B allelic group distribution and similarities according to intron 1 sequences were not confirmed when using intron 2, especially in the cases of B*4002, B*4101 and B*4801. This would suggest that both point mutations fixed by genetic drift and gene conversion events are involved in HLA-B diversification. The latter events could be supported by the strong homology between intron 1 and, to a lesser extent, intron 2, and also the CG content within them. Finally, the precise knowledge of these non-coding regions could be important for developing DNA base typing strategies for the HLA-B alleles.

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Ten new primate Mhc‐DMB complete cDNA sequences have been obtained in chimpanzee (n=four), gorilla (n=three) and orangutan (n=three); this gene has not been previously studied in these species. Exon‐ic allelism has been recorded all along the molecule domains and also in the leader peptide, but not in the transmembrane segment. An analysis of the residues critical in the conformation of the Mhc‐DR peptide‐binding site was done in order to look for a Mhc‐DR homologue site; synonymous substitutions are favoured in this homologous HLA‐DM region. This is another finding that supports the possibility that DM could not be typically presenting molecules. The immunoreceptor inhibition motif Tyr 230‐Thr/Ser 231‐Pro 232‐Leu 233 (ITIM) is invariantly present in apes for at least 15 million years, and may have a double function: 1) To direct DMB‐DMA molecules from the endoplasmic reticulum or cell surface towards the endosom‐al/lysosomal class II compartment and 2) to send an inhibitory signal to the cell in order to stop synthesis of unnecessary HLA‐DR molecules, once all available antigenic peprides are loaded. Other molecules, like NK‐cell receptors and Fc receptors, bear this type of tyrosine‐based inhibitory motifs in order to switch off specific cell functions. DMB molecules (as previously shown in C4d molecules) do not present species‐specific motifs in common chimpanzee, suggesting that this species is very close to gorilla or man; also, DMB, like C4d molecules, do not show a trans‐species evolution pattern, suggesting the existence of extensive homogenization of DMB genes within each species or a recent generation of alleles. Finally, a clade grouping human and gorilla DMB cDNA sequences is obtained using a dendrogram (as for C4d trees); this is in contrast to others' results that obtain a human/ chimpanzee clade using different DNA sequences.