The nature of diversity of HLA‐DRB1 exon 3

Abstract

Exon 3 of DRB1 is known to be polymorphic, but thought to be conserved within allelic groups. This implies that exon 3 polymorphisms would not need to be considered in evolutionary studies or clinical settings when assessing immunogenicity of allelic mismatches in stem cell transplantation. To further assess this, we determined the sequences of DRB1 exon 3 by hemizygote amplification and direct sequencing on 55 selected DNA samples containing 42 DRB1 alleles for which no exon 3 sequence data were previously available. The data confirmed the high degree of overall sequence conservation. The DRB4- and DRB5-associated alleles were completely conserved within their DRB1 groups. However, it could be shown that exon 3 is more diverse than previously expected. Multiple allelic differences within each group of DRB3-associated DRB1 alleles were found, without identifying unique group-related sequence motifs differentiating between these groups. For DRB1*1402 and DRB1*1406, it could be shown that they originated from DRB1*0302. In several samples previously typed as DRB1*1401, a novel DRB1 allele was identified: DRB1*1454. Thus, from a clinical viewpoint, the availability of exon 3 sequence information may be useful for optimizing typing as well as matching strategies. Additionally, it will allow for more detailed evolutionary studies, further elucidating the origin of alleles and the mechanisms driving sequence diversification.

High-resolution human leukocyte antigen (HLA) haplotypes and linkage disequilibrium of HLA-B and -C and HLA-DRB1 and -DQB1 alleles in a Taiwanese population

“…DRB1*1454 was originally identified as DRB1*1401, but repeated SSP typing with up-to-date typing kits (Lot 010, DRB1*14 SSP Unitray, Invitrogen, UK) indicated that all of the DRB1*1401 were DRB1*1454 [8]. This typing change differs from that reported by Albis-Camps et al [9] and Horn et al [10], who indicated that not all DRB1*1401 were DRB1*1454 in Caucasians. Uncommon alleles found in the DRB1 locus included DRB1*1312, DRB1*1314, DRB1*1350, DRB1*1407, and DRB1*1418.…”

Additional sequence analysis outside exon 2 clarifies DRB1*12 and DRB1*14 allelic frequencies in Koreans

“…In contrast, it seems unlikely that DRB1*140101 versus DRB1*1454 mismatched transplantation has been performed in the study population because of the rarity of the DRB1*140101 allele. Although DRB1*1454 links exclusively to DQB1*0503 in Caucasians [11], it appears that this allele is associated with two different DQB1 alleles with similar frequencies in Koreans: DQB1*0502 (54.6%) and DQB1*0503 (45.4%; Table 1). A recent study categorized this DQB1 mismatch pair as nonpermissive in HSCT [22].…”

“…DRB1*1454, a recently characterized allele, differs from DRB1*140101 only at codon 112 in exon 3, where the nucleotide sequence has changed from TAC to CAC, resulting in an amino acid substitution from tyrosine to histidine [11]. Because histidine is a conserved amino acid at codon 112 and more than 60% of Caucasian individuals initially assigned as DRB1*140101 were actually DRB1*1454 in the previous study, it has been suspected that DRB1*1454, rather than DRB1*140101, is the more frequent allele.…”

Group-Specific Amplification of cDNA From DRB1 Genes. Complete Coding Sequences of Partially Defined Alleles and Identification of the New Alleles DRB1*040602, DRB1*111102, DRB1*080103, and DRB1*0113

“…Although this new polymorphismwhich generates a new allele officially named as DRB1*040602-possibly has no functional relevance, additional analysis must be carried out to determine its distribution in the population. Additional polymorphism at exon 3 in common alleles has been also reported by Horn et al [16] for DRB1*1401. A high number of samples previously reported as DRB1*1401 indicated a new polymorphism at amino acid position 112, giving rise to the new DRB1*1454 allele.…”