MHC Haplotype Sequencing

The human major histocompatibility complex (MHC) is recognized as the most important genetic region in relation to common human diseases including inflammatory, infectious and autoimmune diseases as well as transplant medicine. Major National and International Genome Research Networks including the largest whole-genome association studies to date have now demonstrated associations between the MHC and numerous disease phenotypes of interest such as inflammatory bowel disease (IBD), psoriasis, sarcoidosis, atopic eczema, susceptibility to sepsis, asthma, diabetes type 1, and many more. The question now arises, how to move from the regions of association to the underlying causal variants for functional analysis and translation into diagnostics and therapeutics. The complex nature of the MHC poses major challenges: structural variation in the form of copy-number variations, insertions, deletions and inversions coupled with unprecedented levels of single nucleotide polymorphisms and differing degrees of recombination and linkage disequilibrium, severely hampering the hunt for disease genes. Genomic sequencing is by far the most efficient and possibly the only means to unravel this extraordinary genetic complexity.

Our major goal is therefore to sequence complete MHC haplotypes at greater depth, utilizing key resources and technologies:

1) A worldwide unique ‘Haploid Reference Resource’, fosmid libraries from 100 individuals of a representative German population cohort (200 haploid genomes), with Affymetrix 1000K genotype data available for all and HLA-typing confirming presence of a broad spectrum of MHC risk haplotypes for many common MHC-related diseases;

2) An efficient next-generation sequencing platform established within our group. We will combine several approaches to be able to assemble contiguous molecular MHC haplotype sequences spanning the MHC region. These involve the identification of MHC haplotype informative fosmids by application of MHC SNP mapping panels to the librabries, the selective enrichment of particular MHC clones for next-generation sequencing, and the sequence analysis of entire pools containing thousands of fosmid clones. The data will be documented in a database and released to the scientific community.

This project will add substantial knowledge and value to existing resources, provide new data, empower clinicians to move from associated to causal variants for many common diseases and prepare the ground for haploid sequencing.


Importance of MHC for Common Complex Diseases



Collaborators: *
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*S. Schreiber, Uni Kiel; M.Nöthen, Uni Bonn; M.Riemenschneider/L.Bertram, TU München/ MPI-MG; J. Hebebrand, Uni Duisburg-Essen; R. Balling, HZI Braunschweig; T. Chakraborty, Uni Giessen; C. Zouboulis, Städtisches Klinikum Dessau; M. Wjst, Helmholtz Zentrum München; H.E. Wichmann, Helmholtz Zentrum München. *
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*Abbreviations: *
*AA Alopecia Areata *
*ABD Adamantiades-Behcet's Disease *
*AD Alzheimer**´**s Disease *
*AS Ankylosing Spondylitis *
*CeD Celiac Disease *
*CD Crohn**´**s Disease *
*HBV Hepatitis caused by HBV *
*MS Multiple Sclerosis *
*PSC Primary Sclerosing Cholangitis *
*Psor Psoriasis *
*RA Rheumatoid Arthritis *
*Sarc Sarcoidosis *
*SLE Systemic Lupus Erythematosus *
*T1D Type 1 Diabetes *
*UC Ulcerative colitis