title: Sequences of 95 humanMHChaplotypes reveal extreme coding variation in genes other than highly polymorphicHLA class IandII.
abstract: The most polymorphic part of the human genome, theMHC,encodes over 160 proteins of diverse function. Half of them, including theHLA class IandIIgenes, are directly involved in immune responses. Consequently, theMHCregion strongly associates with numerous diseases and clinical therapies. Notoriously, theMHCregion has been intractable to high-throughput analysis at complete sequence resolution, and current reference haplotypes are inadequate for large-scale studies. To address these challenges, we developed a method that specifically captures and sequences the 4.8-MbpMHCregion from genomic DNA. For 95MHChomozygous cell lines we assembled, de novo, a set of high-fidelity contigs and a sequence scaffold, representing a mean 98% of the target region. Included are six alternativeMHCreference sequences of the human genome that we completed and refined. Characterization of the sequence and structural diversity of theMHCregion shows the approach accurately determines the sequences of the highly polymorphicHLA class IandHLA class IIgenes and the complex structural diversity of complement factorC4A/C4BIt has also uncovered extensive and unexpected diversity in otherMHCgenes; an example isMUC22, which encodes a lung mucin and exhibits more coding sequence alleles than anyHLA class IorIIgene studied here. More than 60% of the coding sequence alleles analyzed were previously uncharacterized. We have created a substantial database of robust referenceMHChaplotype sequences that will enable future population scale studies of this complicated and clinically important region of the human genome.
authors.affiliation: Departments of Structural Biology and Microbiology & Immunology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Norman
authors.affiliation: Illumina Incorporated, San Diego, California 92122, USA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Norberg
authors.affiliation: Departments of Structural Biology and Microbiology & Immunology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Lisbeth A
authors.initials: LA
authors.lastname: Guethlein
authors.affiliation: Departments of Structural Biology and Microbiology & Immunology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Neda
authors.initials: N
authors.lastname: Nemat-Gorgani
authors.affiliation: Illumina Incorporated, San Diego, California 92122, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Royce
authors.affiliation: Departments of Structural Biology and Microbiology & Immunology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Emily E
authors.initials: EE
authors.lastname: Wroblewski
authors.affiliation: Illumina Incorporated, San Diego, California 92122, USA.
authors.forename: Tamsen
authors.initials: T
authors.lastname: Dunn
authors.affiliation: Illumina Incorporated, San Diego, California 92122, USA.
authors.forename: Tobias
authors.initials: T
authors.lastname: Mann
authors.affiliation: Departments of Structural Biology and Microbiology & Immunology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Alicata
authors.affiliation: Department of Neurology, University of California San Francisco School of Medicine, San Francisco, California 94158, USA.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Hollenbach
authors.affiliation: Illumina Incorporated, San Diego, California 92122, USA.
authors.forename: Weihua
authors.initials: W
authors.lastname: Chang
authors.affiliation: Illumina Incorporated, San Diego, California 92122, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Shults Won
authors.affiliation: Illumina Incorporated, San Diego, California 92122, USA.
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Gunderson
authors.affiliation: Departments of Structural Biology and Microbiology & Immunology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Laurent
authors.initials: L
authors.lastname: Abi-Rached
authors.affiliation: Illumina Incorporated, San Diego, California 92122, USA.
authors.forename: Mostafa
authors.initials: M
authors.lastname: Ronaghi
authors.affiliation: Departments of Structural Biology and Microbiology & Immunology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Parham
mesh_terms: D000818:Animals; D002460:Cell Line; D003181:Complement C4 / Q000235:genetics*; D020451:Contig Mapping / Q000379:methods / Q000592:standards; D005805:Genes, MHC Class I; D005802:Genes, MHC Class II; D015894:Genome, Human; D023281:Genomics / Q000379:methods / Q000592:standards; D006239:Haplotypes; D006801:Humans; D009077:Mucins / Q000235:genetics*; D016366:Open Reading Frames; D002679:Pan troglodytes / Q000235:genetics; D011110:Polymorphism, Genetic; D012015:Reference Standards
chemical_list: D003181:Complement C4; D009077:Mucins