Novel HLA-B35 subtypes: putative gene conversion events with donor sequences from alleles common in native Americans (HLA-B*4002 or B*4801).

In a study of 523 normal subjects of differing ethnic groups, including 189 South American Indians, we have described novel hybridization pattern corresponding to 22 potentially new HLA-B locus alleles. Three of these alleles were subtypes of B35. The locally, assigned alleles, B-3504v, B-3505v, and B-3508v have been sequenced and were officially designated as B3512, B3517, and B3518, respectively. In addition, we determined the nucleotide sequence of another new variant, locally designated B-3509.2. B3517, was found in 3 individuals (2 Hispanic, 1 Caucasian), it differs from B3505 by 3 nucleotide substitutions that lead to changes in residues 94, 95, and 103. B3517 differs from B3501 in residues 97 and 103. B3518 was found in 7 South American Indian individuals (6 of 124 Toba Indians, 1 of 18 Pilaga Indians). It differs from B3509 by 2 silent nucleotide substitutions and by one nonsynonymous substitution in codon 156 (Arg-->Leu). B3512 differs from B3504 by 3 nucleotides, one of them leading to a substitution in residue 103 (Val-->Leu). B3509 was observed in 3 individuals from the Wichi tribe. The nucleotide sequence of one of these was determined and was found to differ from B35091 by two synonymous nucleotide substitutions. The distinguishing amino acid substitutions in residues 95, 97, and 156 contribute to the structure of specificity pockets F, C, and E, and D and E respectively, therefore, it is possible that some of the new alleles may have different peptide binding profiles. It has been shown that differences at residue 156 may elicit different allorecognition and mediate graft-versus-host disease and rejection in bone marrow transplantation. The mechanisms for the generation of these novel alleles may involve gene conversion events in which short exon-3 segments from the common Native American alleles B4002 or B4801 were inserted in HLA-B35 backbone structures. The novel allele B3518 is closely related to B35092 and to B3508. Two alternative hypotheses for its generation can be suggested, the most plausible one would involve B35092, the putative progenitor of B3518, since both alleles are prevalent in the same Indian tribes.