A combined DPA1∼DPB1 amino acid epitope is the primary unit of selection on the HLA-DP heterodimer

Jill A Hollenbach,Bronwen Shaw,Abeer Madbouly,Martin Maiers,Tom Williams,Loren Gragert,Elizabeth Trachtenberg,Cynthia Vierra-Green,Susan Flesch,Stephen Spellman,Katharina Fleischhauer,Marcelo Fernandez-Vina,Neng Yu,Ann Begovich,Harriet Noreen

doi:10.1007/s00251-012-0615-3

Abstract

Here, we present results for DPA1 and DPB1 four-digit allele-level typing in a large (n = 5,944) sample of unrelated European American stem cell donors previously characterized for other class I and class II loci. Examination of genetic data for both chains of the DP heterodimer in the largest cohort to date, at the amino acid epitope, allele, genotype, and haplotype level, allows new insights into the functional units of selection and association for the DP heterodimer. The data in this study suggest that for the DPA1-DPB1 heterodimer, the unit of selection is the combined amino acid epitope contributed by both the DPA1 and DPB1 genes, rather than the allele, and that patterns of LD are driven primarily by dimer stability and conformation of the P1 pocket. This may help explain the differential pattern of allele frequency distribution observed for this locus relative to the other class II loci. These findings further support the notion that allele-level associations in disease and transplantation may not be the most important unit of analysis, and that they should be considered instead in the molecular context.Electronic supplementary materialThe online version of this article (doi:10.1007/s00251-012-0615-3) contains supplementary material, which is available to authorized users.

Highlights

The human leukocyte antigen (HLA) complex on chromosome 6 is the most polymorphic region of the human genome, and while doubly polymorphic heterodimeric molecules are relatively rare in human biology, this is a defining feature of the HLA class II gene products
More diversity is observed for DPB1 (Table 2), where 33 distinct DPB1 alleles are seen in this cohort, but a single allele predominates and a handful of other alleles are present at moderate frequencies
The high levels of linkage disequilibrium between DPA1 and DPB1 suggest the possibility of nonpermissive combinations for the heterodimer, similar to that suggested for the DQ molecule

Summary

Introduction

The human leukocyte antigen (HLA) complex on chromosome 6 is the most polymorphic region of the human genome, and while doubly polymorphic heterodimeric molecules are relatively rare in human biology, this is a defining feature of the HLA class II gene products. In the DQ system, alpha chain diversity, coupled with relatively even allele frequency distributions for both DQA1 and DQB1 in most human populations (Fernandez-Vina et al 1991; Solberg et al 2008; Begovich et al 1992; Slatkin 2000), potentially increases polymorphism at the heterodimer level. In contrast to the balanced polymorphism observed for DQA1 and DQB1, only a few alleles predominate in most human populations for both DPA1 and DPB1 (Gendzekhadze et al 2004; Steiner et al 2000) (Begovich et al 2001; Pérez-Miranda et al 2004; Solberg et al 2008), resulting in significantly less potential heterodimeric diversity within a given population. While much is known about alpha–beta haplotypic associations in the HLA-DQ system, because DPA1 genotyping is infrequently performed, there have been only limited studies with relatively small sample sizes describing DPA1∼DPB1 haplotypes (Begovich et al 2001; Gendzekhadze et al 2004)

Methods

Results

Conclusion