title: Pervasive haplotypic variation in the spliceo-transcriptome of the human major histocompatibility complex.
abstract: The human major histocompatibility complex (MHC) on chromosome 6p21 is a paradigm for genomics, showing remarkable polymorphism and striking association with immune and non-immune diseases. The complex genomic landscape of the MHC, notably strong linkage disequilibrium, has made resolving causal variants very challenging. A promising approach is to investigate gene expression levels considered as tractable intermediate phenotypes in mapping complex diseases. However, how transcription varies across the MHC, notably relative to specific haplotypes, remains unknown. Here, using an original hybrid tiling and splice junction microarray that includes alternate allele probes, we draw the first high-resolution strand-specific transcription map for three common MHC haplotypes (HLA-A1-B8-Cw7-DR3, HLA-A3-B7-Cw7-DR15, and HLA-A26-B18-Cw5-DR3-DQ2) strongly associated with autoimmune diseases including type 1 diabetes, systemic lupus erythematosus, and multiple sclerosis. We find that haplotype-specific differences in gene expression are common across the MHC, affecting 96 genes (46.4%), most significantly the zing finger protein gene ZFP57. Differentially expressed probes are correlated with polymorphisms between haplotypes, consistent with cis effects that we directly demonstrate for ZFP57 in a cohort of healthy volunteers (P = 1.2 × 10(-14)). We establish that alternative splicing is significantly more frequent in the MHC than genome-wide (72.5% vs. 62.1% of genes, P ≤ 1 × 10(-4)) and shows marked haplotypic differences. We also unmask novel and abundant intergenic transcription involving 31% of transcribed blocks identified. Our study reveals that the renowned MHC polymorphism also manifests as transcript diversity, and our novel haplotype-based approach marks a new step toward identification of regulatory variants involved in the control of MHC-associated phenotypes and diseases.
authors.affiliation: Wellcome Trust Centre for Human Genetics, Oxford University, Oxford, UK. claire.vandiedonck@inserm.fr
authors.forename: Claire
authors.initials: C
authors.lastname: Vandiedonck
authors.forename: Martin S
authors.initials: MS
authors.lastname: Taylor
authors.forename: Helen E
authors.initials: HE
authors.lastname: Lockstone
authors.forename: Katharine
authors.initials: K
authors.lastname: Plant
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Taylor
authors.forename: Caroline
authors.initials: C
authors.lastname: Durrant
authors.forename: John
authors.initials: J
authors.lastname: Broxholme
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Fairfax
authors.forename: Julian C
authors.initials: JC
authors.lastname: Knight
mesh_terms: D000483:Alleles; D017398:Alternative Splicing; D002478:Cells, Cultured; D002874:Chromosome Mapping; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D015234:HLA-A Antigens / Q000235:genetics / Q000378:metabolism; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008180:Lupus Erythematosus, Systemic / Q000235:genetics; D008285:Major Histocompatibility Complex; D009103:Multiple Sclerosis / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D040641:Quantitative Trait Loci; D017422:Sequence Analysis, DNA; D014158:Transcription, Genetic
chemical_list: D015234:HLA-A Antigens