New high resolution typing strategy for HLA-A locus alleles based on dye terminator sequencing of haplotypic group-specific PCR-amplicons of exon 2 and exon 3

Tissue Antigens. 1999 Jan;53(1):81-96. doi: 10.1034/j.1399-0039.1999.530109.x.

Abstract

In this study, a new sequencing-based typing strategy for the HLA-A locus is presented which involves group-specific separate amplification of exon 2 and 3 of HLA-A alleles in a first step. Conserved HLA-A locus-specific primers of intron 1 or 3 were combined in 10 primer-mixes with group-specific primers hybridizing to the 5'- or 3'-end of exon 3 or 2 for pre-typing of the HLA-A alleles in 14 allelic groups. Maximally four overlapping short amplicons are produced under identical polymerase chain reaction (PCR) conditions with individual separate amplification of exon 2 and exon 3 of the haplotypic alleles in most heterozygous combinations. Time- and money-saving one-directional Big Dye Terminator cycle sequencing is shown to provide reliable high resolution typing of the HLA-A alleles, even in a few cases of two amplicons in one primer reaction mixture. In comparison, to other sequencing-based typing (SBT) techniques the applied typing strategy minimizes the risk of unequal amplification or of drop-outs of one of the haplotypic alleles and allows unequivocal definition of the cis/ trans linkage of polymorphic positions of the complete exon 2 and exon 3 in most heterozygous cells. This also includes detection of new alleles differing in the polymorphic template generating primer annealing sites as well as in unusual combinations of known exon 2 and 3 sequences. With 10 primer sets working under identical conditions for pre-grouping and separate amplification of the haplotypic alleles our SBT procedure also could be implemented in clinical settings of large-scale stem cell donor histocompatibility testing for fast molecular HLA-A matching.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Base Sequence
  • Cell Line
  • DNA Primers
  • Deoxyribonucleotides
  • Exons / genetics*
  • Fluorescent Dyes
  • Genes, MHC Class I*
  • HLA-A Antigens / genetics*
  • Haplotypes / genetics
  • Histocompatibility Testing / methods*
  • Humans
  • Infant, Newborn
  • Molecular Sequence Data
  • Polymerase Chain Reaction*
  • Reference Standards
  • Sequence Analysis, DNA / instrumentation
  • Sequence Analysis, DNA / methods*

Substances

  • DNA Primers
  • Deoxyribonucleotides
  • Fluorescent Dyes
  • HLA-A Antigens