title: Complete MHC haplotype sequencing for common disease gene mapping.
abstract: The future systematic mapping of variants that confer susceptibility to common diseases requires the construction of a fully informative polymorphism map. Ideally, every base pair of the genome would be sequenced in many individuals. Here, we report 4.75 Mb of contiguous sequence for each of two common haplotypes of the major histocompatibility complex (MHC), to which susceptibility to >100 diseases has been mapped. The autoimmune disease-associated-haplotypes HLA-A3-B7-Cw7-DR15 and HLA-A1-B8-Cw7-DR3 were sequenced in their entirety through a bacterial artificial chromosome (BAC) cloning strategy using the consanguineous cell lines PGF and COX, respectively. The two sequences were annotated to encompass all described splice variants of expressed genes. We defined the complete variation content of the two haplotypes, revealing >18,000 variations between them. Average SNP densities ranged from less than one SNP per kilobase to >60. Acquisition of complete and accurate sequence data over polymorphic regions such as the MHC from large-insert cloned DNA provides a definitive resource for the construction of informative genetic maps, and avoids the limitation of chromosome regions that are refractory to PCR amplification.
authors.affiliation: Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom.
authors.forename: C Andrew
authors.initials: CA
authors.lastname: Stewart
authors.forename: Roger
authors.initials: R
authors.lastname: Horton
authors.forename: Richard J N
authors.initials: RJ
authors.lastname: Allcock
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Ashurst
authors.forename: Alexey M
authors.initials: AM
authors.lastname: Atrazhev
authors.forename: Penny
authors.initials: P
authors.lastname: Coggill
authors.forename: Ian
authors.initials: I
authors.lastname: Dunham
authors.forename: Simon
authors.initials: S
authors.lastname: Forbes
authors.forename: Karen
authors.initials: K
authors.lastname: Halls
authors.forename: Joanna M M
authors.initials: JM
authors.lastname: Howson
authors.forename: Sean J
authors.initials: SJ
authors.lastname: Humphray
authors.forename: Sarah
authors.initials: S
authors.lastname: Hunt
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Mungall
authors.forename: Kazutoyo
authors.initials: K
authors.lastname: Osoegawa
authors.forename: Sophie
authors.initials: S
authors.lastname: Palmer
authors.forename: Anne N
authors.initials: AN
authors.lastname: Roberts
authors.forename: Jane
authors.initials: J
authors.lastname: Rogers
authors.forename: Sarah
authors.initials: S
authors.lastname: Sims
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Laurens G
authors.initials: LG
authors.lastname: Wilming
authors.forename: John F
authors.initials: JF
authors.lastname: Elliott
authors.forename: Pieter J
authors.initials: PJ
authors.lastname: de Jong
authors.forename: Stephen
authors.initials: S
authors.lastname: Sawcer
authors.forename: John A
authors.initials: JA
authors.lastname: Todd
authors.forename: John
authors.initials: J
authors.lastname: Trowsdale
authors.forename: Stephan
authors.initials: S
authors.lastname: Beck
mesh_terms: D001327:Autoimmune Diseases / Q000235:genetics*; D002460:Cell Line; D002874:Chromosome Mapping / Q000379:methods* / Q000706:statistics & numerical data; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics; D003241:Consanguinity; D005796:Genes / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation; D015894:Genome, Human; D015788:HLA-A1 Antigen / Q000235:genetics; D015791:HLA-A3 Antigen / Q000235:genetics; D015795:HLA-B8 Antigen / Q000235:genetics; D015236:HLA-C Antigens / Q000235:genetics; D015803:HLA-DR3 Antigen / Q000235:genetics; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008285:Major Histocompatibility Complex / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics; D044465:White People / Q000235:genetics
chemical_list: D015788:HLA-A1 Antigen; D015791:HLA-A3 Antigen; D015795:HLA-B8 Antigen; D015236:HLA-C Antigens; C040178:HLA-C*70 antigen; D015803:HLA-DR3 Antigen