Linkage disequilibrium map of the Human MHC complex and first generation of tag SNPs

M. MIRETTI

Sao Paulo

Workshop; International Theoretical Course, Viral Hepatitis and the Human Host; 2010

Dept of Gastroeneterology, University of Sao Paulo - School of Medicine

Autoimmune, inflammatory, and infectious diseases present a major burden to human health and are frequentlyassociated with loci in the human major histocompatibility complex (MHC). Here, we report a high-resolution(1.9 kb) linkage-disequilibrium (LD) map of a 4.46-Mb fragment containing the MHC in U.S. pedigrees withnorthern and western European ancestry collected by the Centre d’Etude du Polymorphisme Humain (CEPH) andthe first generation of haplotype tag single-nucleotide polymorphisms (tagSNPs) that provide up to a fivefold increasein genotyping efficiency for all future MHC-linked disease-association studies. The data confirm previously identifiedrecombination hotspots in the class II region and allow the prediction of numerous novel hotspots in the class Iand class III regions. The region of longest LD maps outside the classic MHC to the extended class I region spanningthe MHC-linked olfactory-receptor gene cluster. The extended haplotype homozygosity analysis for recent positiveselection shows that all 14 outlying haplotype variants map to a single extended haplotype, which most commonlybears HLA-DRB1*1501. The SNP data, haplotype blocks, and tagSNPs analysis reported here have been enteredinto a multidimensional Web-based database (GLOVAR), where they can be accessed and viewed in the contextof relevant genome annotation. This LD map allowed us to give coordinates for the extremely variable LD structureunderlying the MHC.