Variation analysis and gene annotation of eight MHC haplotypes: The MHC Haplotype Project

Abstract

The human major histocompatibility complex (MHC) is contained within about 4 Mb on the short arm of chromosome 6 and is recognised as the most variable region in the human genome. The primary aim of the MHC Haplotype Project was to provide a comprehensively annotated reference sequence of a single, human leukocyte antigen-homozygous MHC haplotype and to use it 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. Comparison of the haplotype sequences, including four haplotypes not previously analysed, resulted in the identification of >44,000 variations, both substitutions and indels (insertions and deletions), which have been submit- Immunogenetics (2008) ted to the dbSNP database. 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 datasets revealed 122 gene loci with coding substitutions of which 97 were non-synonymous. The haplotype (A3-B7-DR15; PGF cell line) designated as the new MHC reference sequence, has been incorporated into the human genome assembly (NCBI35 and subsequent builds), and constitutes the largest single-haplotype sequence of the human genome to date. The extensive variation and annotation data derived from the analysis of seven further haplotypes have been made publicly available and provide a framework and resource for future association studies of all MHC-associated diseases and transplant medicine.

Fine-tuned characterization of RCCX copy number variants and their relationship with extended MHC haplotypes

“…Otherwise, we have found that telomeric C4 genes of multimodular structures usually code for a C4A isotype protein, which is in agreement with previous assumptions deducted from sparse sequencing data 2 and results of the MHC Haplotype Project. 20 Here we also give evidence of the assumption that C4A genes are almost always long and that there is an approximately equal chance that a C4B gene belongs to the short or the long variant. 21 Former RCCX-related studies sometimes also detected dosage ratios of TNX and CYP21 active genes and pseudogenes.…”

Multiple sclerosis genetics

“…Many of the HLA alleles were first identified serologically and gave rise to a complex and often inconsistent nomenclature. Recent extensive efforts were made at mapping the serologic types to DNA sequences and the genetic architecture of the MHC is now much better understood (Allcock et al, 2002;Stewart et al, 2004;Miretti et al, 2005;de Bakker et al, 2006;Horton et al, 2008). As a consequence, the genetic basis of the serotypes has been defined and a consistent nomenclature has finally come into focus that will help advance further study of the MHC (http:/ /hla.alleles.org/).…”

Regulation of major histocompatibility complex class II gene expression, genetic variation and disease

“…155 Similarly, several other class II loci including HLA-DRB1 and HLA-DQA1 are known to show haplotypic variation at splice sites, which may affect expression at a post-transcriptional level. 156 A growing number of reports highlight the role of DNA sequence variation in modulating alternative splicing, which can contribute to disease susceptibility. 157 The MHC class II region has already provided one of the clearest examples of a SNP modulating alternative splicing resulting in common disease through the work of Valentonyte et al (2005) 158 on genetic determinants of sarcoidosis, a chronic granulomatous condition.…”