Variation analysis and gene annotation of eight MHC haplotypes: the MHC Haplotype Project.
The human major histocompatibility complex (MHC) is contained within about 4 Mb on the short arm of chromosome 6 and is recognised as the most variable region in the human genome. The primary aim of the MHC Haplotype Project was to provide a comprehensively annotated reference sequence of a single, human leukocyte antigen-homozygous MHC haplotype and to use it as a basis against which variations could be assessed from seven other similarly homozygous cell lines, representative of the most common MHC haplotypes in the European population. Comparison of the haplotype sequences, including four haplotypes not previously analysed, resulted in the identification of >44,000 variations, both substitutions and indels (insertions and deletions), which have been submitted to the dbSNP database. The gene annotation uncovered haplotype-specific differences and confirmed the presence of more than 300 loci, including over 160 protein-coding genes. Combined analysis of the variation and annotation datasets revealed 122 gene loci with coding substitutions of which 97 were non-synonymous. The haplotype (A3-B7-DR15; PGF cell line) designated as the new MHC reference sequence, has been incorporated into the human genome assembly (NCBI35 and subsequent builds), and constitutes the largest single-haplotype sequence of the human genome to date. The extensive variation and annotation data derived from the analysis of seven further haplotypes have been made publicly available and provide a framework and resource for future association studies of all MHC-associated diseases and transplant medicine.
Horton
Roger
R
Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.
Gibson
Richard
R
Coggill
Penny
P
Miretti
Marcos
M
Allcock
Richard J
RJ
Almeida
Jeff
J
Forbes
Simon
S
Gilbert
James G R
JG
Halls
Karen
K
Harrow
Jennifer L
JL
Hart
Elizabeth
E
Howe
Kevin
K
Jackson
David K
DK
Palmer
Sophie
S
Roberts
Anne N
AN
Sims
Sarah
S
Stewart
C Andrew
CA
Traherne
James A
JA
Trevanion
Steve
S
Wilming
Laurens
L
Rogers
Jane
J
de Jong
Pieter J
PJ
Elliott
John F
JF
Sawcer
Stephen
S
Todd
John A
JA
Trowsdale
John
J
Beck
Stephan
S
D019295:Computational Biology / Q000379:methods / Q000639:trends; D030541:Databases, Genetic; D014644:Genetic Variation / Q000276:immunology*; D015894:Genome, Human; D006680:HLA Antigens / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D009626:Terminology as Topic
D006680:HLA Antigens