MHC Haplotype Sequencing

The human major histocompatibility complex (MHC) is recognized as the most important genetic region in relation to common human diseases and immune function. While clinically highly informative, the complex nature of the MHC presents major challenges to genetic analysis. Based on our world-wide unique Haploid Reference Resource of 100 human fosmid libraries we have now developed a novel fosmid pool-based next generation sequencing approach to haplotype-resolve the MHC-region, and ultimately whole genomes. To this end, we have developed, established, and integrated novel molecular genetic and bioinformatic methods/algorithms. This allowed successful assembly of molecular MHC haplotypes extending over 4 Megabases, of major importance for the clinic and transplant medicine. This allowed moreover comprehensively haplotype-resolving the first German/European genome, a major achievement, which was highlighted in the Nature Methods Special „Methods of the Year 2011“ as one of the most promising approaches in genome research to watch. Altogether, we have now, with additional integration of front-end technologies, generated a total of nearly 100 MHC haplotype sequences featuring approximately 10,000 MHC variants per individual on average. We have, moreover, generated a total of nearly 20 haplotype-resolved human genomes. In doing so, we have demonstrated the power of our approach, setting a new gold standard compared to 1000 Genomes Project-released genome phasing data. We have made ample resources available to the scientific community, including a browsable phased genome reference (in a UCSC session), additional haplotype data sets, and algorithms. Our publications have been cited in the top journals, recognized in national and international meetings, and reported in the media.

Importance of MHC for Common Complex Diseases



Collaborators: *
* *
*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. *
* *
*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