Insights into the polymorphism in HLA-DRA and its evolutionary relationship with HLA haplotypes

Ben M. Matern*, Timo I. Olieslagers, Christina E. M. Voorter, Mathijs Groeneweg, Marcel G. J. Tilanus*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

12 Citations (Web of Science)

Abstract

HLA-DRA encodes the alpha chain of the HLA-DR protein, one of the classical HLA class II molecules. Reported polymorphism within HLA-DRA is currently limited compared with other HLA genes, as only a single polymorphism encodes an amino acid difference in the translated protein. Since this SNP (rs7192, HLA00662.1:g.4276G>T p.Val217Leu) lies within exon 4, in the region encoding the cytoplasmic tail, the resulting protein is effectively monomorphic. For this reason, in-depth studies on HLA-DRA and its function have been limited. However, analysis of sequences from the 1000 Genomes Project and preliminary data from our lab reveals unrepresented polymorphism within HLA-DRA, suggesting a more complex role within the MHC than previously assumed. This study focuses on elucidating the extent of HLA-DRA polymorphism, and extending our understanding of the gene's role in HLA-DR similar to HLA-DQ haplotypes. Ninety-eight samples were sequenced for full-length HLA-DRA, and from this analysis, we identified 20 novel SNP positions in the intronic sequences within the 5711 bp region represented in IPD-IMGT/HLA. This polymorphism gives rise to at least 22 novel HLA-DRA alleles, and the patterns of intronic and 3 ' UTR polymorphism correspond to HLA-DRA similar to HLA-DRB345 similar to HLA-DRB1 similar to HLA-DQB1 haplotypes. The current understanding of the organization of the genes within the HLA-DR region assumes a single lineage for the HLA-DRA gene, as opposed to multiple gene lineages, such as in HLA-DRB. This study suggests that the intron and 3 ' UTR polymorphism of HLA-DRA indicates different lineages, and represents the HLA-DRA similar to HLA-DRB345 similar to HLA-DRB1 similar to HLA-DQB1 haplotypes.

Original languageEnglish
Pages (from-to)117-127
Number of pages11
JournalHLA
Volume95
Issue number2
Early online date10 Nov 2019
DOIs
Publication statusPublished - Feb 2020

Keywords

  • bioinformatics
  • haplotype
  • HLA-DRA
  • MinION
  • nanopore prospector
  • polymorphism
  • MULTIPLE-SCLEROSIS
  • EXPRESSION
  • GENES

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