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.

[1]  I. Dunham,et al.  DNA sequence and analysis of human chromosome 9 , 2003, Nature.

[2]  C. Y. Yu,et al.  The dichotomous size variation of human complement C4 genes is mediated by a novel family of endogenous retroviruses, which also establishes species-specific genomic patterns among Old World primates , 2004, Immunogenetics.

[3]  L. Hood,et al.  Analysis of the gene-dense major histocompatibility complex class III region and its comparison to mouse. , 2003, Genome research.

[4]  J. Ashurst,et al.  Gene annotation: prediction and testing. , 2003, Annual review of genomics and human genetics.

[5]  Michael Cullen,et al.  An integrated haplotype map of the human major histocompatibility complex. , 2003, American journal of human genetics.

[6]  J. Kulski,et al.  Dimorphic Alu element located between the TFIIH and CDSN genes within the major histocompatibility complex , 2003, Electrophoresis.

[7]  Luc J. Smink,et al.  Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease , 2003, Nature.

[8]  I. Dunham,et al.  The DNA sequence and analysis of human chromosome 6 , 2003, Nature.

[9]  R. Daza,et al.  Genetics of the immune response: identifying immune variation within the MHC and throughout the genome , 2002, Immunological reviews.

[10]  Jerzy K. Kulski,et al.  The Association Between HLA-A Alleles and Young Alu Dimorphisms Near the HLA-J, -H, and -F Genes in Workshop Cell Lines and Japanese and Australian Populations , 2002, Journal of Molecular Evolution.

[11]  C. Y. Yu,et al.  Genetic sophistication of human complement components C4A and C4B and RP-C4-CYP21-TNX (RCCX) modules in the major histocompatibility complex. , 2002, American journal of human genetics.

[12]  S Forbes,et al.  The MHC haplotype project: a resource for HLA-linked association studies. , 2002, Tissue antigens.

[13]  John A. Todd,et al.  Parameters for reliable results in genetic association studies in common disease , 2002, Nature Genetics.

[14]  Philip Lijnzaad,et al.  The Ensembl genome database project , 2002, Nucleic Acids Res..

[15]  Frank Dudbridge,et al.  Haplotype tagging for the identification of common disease genes , 2001, Nature Genetics.

[16]  A. Jeffreys,et al.  Intensely punctate meiotic recombination in the class II region of the major histocompatibility complex , 2001, Nature Genetics.

[17]  J. Mullikin,et al.  SSAHA: a fast search method for large DNA databases. , 2001, Genome research.

[18]  W S Watkins,et al.  Large-scale analysis of the Alu Ya5 and Yb8 subfamilies and their contribution to human genomic diversity. , 2001, Journal of molecular biology.

[19]  Timothy B. Stockwell,et al.  The Sequence of the Human Genome , 2001, Science.

[20]  M. Daly,et al.  A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms , 2001, Nature.

[21]  D. Haussler,et al.  A physical map of the human genome , 2001, Nature.

[22]  I. Wu,et al.  Cloning of a cDNA Encoding an Isoform of Human Protein Phosphatase Inhibitor 2 from Vascularized Breast Tumor , 2001, DNA sequence : the journal of DNA sequencing and mapping.

[23]  S. Beck,et al.  MHC-linked olfactory receptor loci exhibit polymorphism and contribute to extended HLA/OR-haplotypes. , 2000, Genome research.

[24]  C. Soderlund,et al.  Contigs built with fingerprints, markers, and FPC V4.7. , 2000, Genome research.

[25]  Eric S. Lander,et al.  An SNP map of the human genome generated by reduced representation shotgun sequencing , 2000, Nature.

[26]  James T. Elder,et al.  Localization of psoriasis-susceptibility locus PSORS1 to a 60-kb interval telomeric to HLA-C. , 2000, American journal of human genetics.

[27]  Robert I. Lechler,et al.  HLA in health and disease , 2000 .

[28]  Peter Parham,et al.  The HLA FactsBook , 1999 .

[29]  H. Inoko,et al.  Association analysis using refined microsatellite markers localizes a susceptibility locus for psoriasis vulgaris within a 111 kb segment telomeric to the HLA-C gene. , 1999, Human molecular genetics.

[30]  Gen Tamiya,et al.  Complete sequence and gene map of a human major histocompatibility complex , 1999 .

[31]  Jerzy K. Kulski,et al.  Extensive nucleotide variability within a 370 kb sequence from the central region of the major histocompatibility complex. , 1999, Gene.

[32]  A. Little,et al.  Characterization of the major susceptibility region for psoriasis at chromosome 6p21.3. , 1999, The Journal of investigative dermatology.

[33]  N. Shen,et al.  Patterns of single-nucleotide polymorphisms in candidate genes for blood-pressure homeostasis , 1999, Nature Genetics.

[34]  V. Stanton,et al.  Screening Large‐Insert Libraries by Hybridization , 1999 .

[35]  Jerzy K. Kulski,et al.  The P5 multicopy gene family in the MHC is related in sequence to human endogenous retroviruses HERV-L and HERV-16 , 1999, Immunogenetics.

[36]  F. Christiansen,et al.  The genetic basis for the association of the 8.1 ancestral haplotype (A1, B8, DR3) with multiple immunopathological diseases , 1999, Immunological reviews.

[37]  Elena S. Babaylova,et al.  Complete sequence and gene map of a human major histocompatibility complex , 1999, Nature.

[38]  E. Lander,et al.  Characterization of single-nucleotide polymorphisms in coding regions of human genes , 1999, Nature Genetics.

[39]  G. Benson,et al.  Tandem repeats finder: a program to analyze DNA sequences. , 1999, Nucleic acids research.

[40]  S Beck,et al.  Large-scale sequence comparisons reveal unusually high levels of variation in the HLA-DQB1 locus in the class II region of the human MHC. , 1998, Journal of molecular biology.

[41]  C. Nusbaum,et al.  Large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genome. , 1998, Science.

[42]  J E Sulston,et al.  Short-insert libraries as a method of problem solving in genome sequencing. , 1998, Genome research.

[43]  P Green,et al.  Base-calling of automated sequencer traces using phred. II. Error probabilities. , 1998, Genome research.

[44]  P. Green,et al.  Base-calling of automated sequencer traces using phred. I. Accuracy assessment. , 1998, Genome research.

[45]  C. Heiner,et al.  New dye-labeled terminators for improved DNA sequencing patterns. , 1997, Nucleic acids research.

[46]  R. Durbin,et al.  A dot-matrix program with dynamic threshold control suited for genomic DNA and protein sequence analysis. , 1995, Gene.

[47]  J. Bonfield,et al.  A new DNA sequence assembly program. , 1995, Nucleic acids research.

[48]  N. Dracopoli,et al.  Current protocols in human genetics , 1994 .

[49]  C. Y. Yu,et al.  Structure and genetics of the partially duplicated gene RP located immediately upstream of the complement C4A and the C4B genes in the HLA class III region. Molecular cloning, exon-intron structure, composite retroposon, and breakpoint of gene duplication. , 1994, The Journal of biological chemistry.

[50]  Jean Thierry-Mieg,et al.  The ACEDB genome database , 1994 .

[51]  Wen-Hsiung Li,et al.  Low nucleotide diversity in man. , 1991, Genetics.

[52]  I. Dunham,et al.  An analysis of variation in the long-range genomic organization of the human major histocompatibility complex class II region by pulsed-field gel electrophoresis. , 1989, Genomics.

[53]  Richard Durbin,et al.  Image analysis of restriction enzyme fingerprint autoradiograms , 1989, Comput. Appl. Biosci..

[54]  M. Nei,et al.  Nucleotide substitution at major histocompatibility complex class II loci: evidence for overdominant selection. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[55]  B. Dupont,et al.  Immunobiology of HLA , 1989, Springer New York.

[56]  M. Nei,et al.  Pattern of nucleotide substitution at major histocompatibility complex class I loci reveals overdominant selection , 1988, Nature.

[57]  A. Bankier,et al.  Random cloning and sequencing by the M13/dideoxynucleotide chain termination method. , 1987, Methods in enzymology.

[58]  D. Mccormick.  Sequence the Human Genome , 1986, Bio/Technology.

[59]  M S Waterman,et al.  Identification of common molecular subsequences. , 1981, Journal of molecular biology.

[60]  F. Sanger,et al.  DNA sequencing with chain-terminating inhibitors. , 1977, Proceedings of the National Academy of Sciences of the United States of America.

[61]  J. M. Smith,et al.  The hitch-hiking effect of a favourable gene. , 1974, Genetical research.