Complete MHC haplotype sequencing for common disease gene mapping.
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.
Stewart
C Andrew
CA
Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge CB10 1SA, United Kingdom.
Horton
Roger
R
Allcock
Richard J N
RJ
Ashurst
Jennifer L
JL
Atrazhev
Alexey M
AM
Coggill
Penny
P
Dunham
Ian
I
Forbes
Simon
S
Halls
Karen
K
Howson
Joanna M M
JM
Humphray
Sean J
SJ
Hunt
Sarah
S
Mungall
Andrew J
AJ
Osoegawa
Kazutoyo
K
Palmer
Sophie
S
Roberts
Anne N
AN
Rogers
Jane
J
Sims
Sarah
S
Wang
Yu
Y
Wilming
Laurens G
LG
Elliott
John F
JF
de Jong
Pieter J
PJ
Sawcer
Stephen
S
Todd
John A
JA
Trowsdale
John
J
Beck
Stephan
S
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
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