Long-range multilocus haplotype phasing of the MHC

Proc Natl Acad Sci U S A. 2006 May 2;103(18):6964-9. doi: 10.1073/pnas.0602286103. Epub 2006 Apr 21.

Abstract

Haplotypes are a powerful tool for identifying the genetic basis of common complex diseases. Disease-association mapping requires molecular methods for haplotyping biallelic SNP variation and highly complex polymorphisms. We developed a method for phasing HLA-A, HLA-B, and HLA-DRB1 alleles on chromosome 6 in unrelated individuals. This method uses the highly polymorphic HLA-B locus to discriminate the two HLA haplotypes in heterozygous individuals and its ideal location 1.4 Mbp telomeric to HLA-DRB1 and 1.2 Mbp centromeric to HLA-A to capture 2-Mbp-long genomic DNA. Genomic DNA representing a single HLA-B-captured haplotype is genotyped for HLA-A and HLA-DRB1 alleles and linkage to HLA-B is established. Proof of principle was established in a large blinded study of phase-known samples. Availability of an efficient method for MHC haplotype phase determination will facilitate the mapping of causative MHC-resident genes in many human diseases and has the potential to be broadened to other polymorphic gene complexes.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Genes, MHC Class I
  • Genes, MHC Class II
  • Genetic Predisposition to Disease
  • Genetic Variation*
  • HLA Antigens / genetics*
  • Haplotypes*
  • Humans
  • Major Histocompatibility Complex / genetics*
  • Oligonucleotide Array Sequence Analysis

Substances

  • HLA Antigens