title: Intrahaplotypic Variants Differentiate Complex Linkage Disequilibrium within Human MHC Haplotypes.
abstract: Distinct regions of long-range genetic fixation in the human MHC region, known as conserved extended haplotypes (CEHs), possess unique genomic characteristics and are strongly associated with numerous diseases. While CEHs appear to be homogeneous by SNP analysis, the nature of fine variations within their genomic structure is unknown. Using multiple, MHC-homozygous cell lines, we demonstrate extensive sequence conservation in two common Asian MHC haplotypes: A33-B58-DR3 and A2-B46-DR9. However, characterization of phase-resolved MHC haplotypes revealed unique intra-CEH patterns of variation and uncovered 127 single nucleotide variants (SNVs) which are missing from public databases. We further show that the strong linkage disequilibrium structure within the human MHC that typically confounds precise identification of genetic features can be resolved using intra-CEH variants, as evidenced by rs3129063 and rs448489, which affect expression of ZFP57, a gene important in methylation and epigenetic regulation. This study demonstrates an improved strategy that can be used towards genetic dissection of diseases.
authors.affiliation: Singapore Immunology Network, A*STAR, 8A Biomedical Grove, #03-06 Immunos, Singapore 138648, Singapore.|Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, MD4 Level 5, Singapore 117597, Singapore.
authors.forename: Tze Hau
authors.initials: TH
authors.lastname: Lam
authors.affiliation: Singapore Immunology Network, A*STAR, 8A Biomedical Grove, #03-06 Immunos, Singapore 138648, Singapore.|Department of Molecular Genetics and Microbiology, Duke University, Durham, NC 27710, USA.
authors.forename: Matthew Zirui
authors.initials: MZ
authors.lastname: Tay
authors.affiliation: Singapore Immunology Network, A*STAR, 8A Biomedical Grove, #03-06 Immunos, Singapore 138648, Singapore.
authors.forename: Bei
authors.initials: B
authors.lastname: Wang
authors.affiliation: Singapore Immunology Network, A*STAR, 8A Biomedical Grove, #03-06 Immunos, Singapore 138648, Singapore.
authors.forename: Ziwei
authors.initials: Z
authors.lastname: Xiao
authors.affiliation: Singapore Immunology Network, A*STAR, 8A Biomedical Grove, #03-06 Immunos, Singapore 138648, Singapore.|Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, MD4 Level 5, Singapore 117597, Singapore.
authors.forename: Ee Chee
authors.initials: EC
authors.lastname: Ren
mesh_terms: D044466:Asian People; D045744:Cell Line, Tumor; D002896:Chromosomes, Human, Pair 6; D017124:Conserved Sequence; D044127:Epigenesis, Genetic; D056426:Genetic Loci; D015894:Genome, Human; D006239:Haplotypes; D006650:Histocompatibility Testing; D006720:Homozygote; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D015810:Linkage Disequilibrium; D008285:Major Histocompatibility Complex / Q000276:immunology*; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide; D061251:Primary Cell Culture; D044465:White People