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Chromosome 6 MHC Haplotype Project

The human major histocompatibility complex (MHC) contains many immune related genes including highly polymorphic examples encoding MHC class I and class II molecules that present antigens to T lymphocytes. Genetic determinants for many autoimmune diseases and some infectious diseases have been linked to the MHC, but the precise determinants have proven difficult to identify.

This project determined the genomic sequences of 8 different HLA haplotypes from the major histocompatibility complex region contained within about 4.7 Mb on the short arm of chromosome 6. It provided a comprehensively annotated reference sequence (NCBI35 and subsequent builds) of a single, human leukocyte antigen-homozygous MHC haplotype (A3-B7-DR15; PGF cell line), which constitutes the largest single-haplotype sequence of the human genome to date. This was used as a basis against which variations could be assessed from seven other similarly homozygous cell lines, representative of the most common MHC haplotypes in the European population, and differing in their complement component C4, and MHC class II HLA-DRB, gene content. Comparison of these haplotype sequences resulted in the identification and submission to the dbSNP database of >44,000 variations, both substitutions and indels (insertions and deletions). The gene annotation uncovered haplotype-specific differences and confirmed the presence of more than 300 loci, including over 160 protein-coding genes. Combined analysis of the variation and annotation data revealed 122 gene loci with coding substitutions of which 97 were non-synonymous. These data provide a framework and resource for future association studies of all MHC-associated diseases and transplant medicine.

The 8 haplotypes for the chromosome 6 MHC region in Vega are as follows:

Relevant Publications

The MHC haplotype project: a resource for HLA-linked association studies, Allcock et al., Tissue Antigens, 59(6):520-1 (2002).

Megabase MHC haplotype sequencing for common disease gene mapping, Stewart et al., Genome Research, 14:1176-1187 (2004).

Genetic analysis of completely sequenced disease-associated MHC haplotypes identifies shuffling of segments in recent human history. Traherne et al., PLoS Genet. 2;e9. (2006).

Variation Analysis and Gene Annotation of Eight MHC Haplotypes: The MHC Haplotype Project, Horton et al., Immunogenetics 60; 1-18. (2008).