Pervasive haplotypic variation in the spliceo-transcriptome of the human major histocompatibility complex
- Claire Vandiedonck1,2,3,5,
- Martin S. Taylor1,4,
- Helen E. Lockstone1,
- Katharine Plant1,
- Jennifer M. Taylor1,
- Caroline Durrant1,
- John Broxholme1,
- Benjamin P. Fairfax1 and
- Julian C. Knight1,5
- 1Wellcome Trust Centre for Human Genetics, Oxford University, Oxford OX3 7BN, United Kingdom;
- 2INSERM, UMRS-958, 75010 Paris, France;
- 3Université Paris 7 Denis-Diderot, 75013 Paris, France;
- 4MRC Human Genetics Unit, Edinburgh EH4 2XU, United Kingdom
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.
Footnotes
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↵5 Corresponding authors.
E-mail claire.vandiedonck{at}inserm.fr.
E-mail julian{at}well.ox.ac.uk.
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[Supplemental material is available for this article. The microarray data from this study have been submitted to the NCBI Gene Expression Omnibus (GEO; http://www.ncbi.nlm.nih.gov/geo) under accession no. GSE22455.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.116681.110.
- Received October 31, 2010.
- Accepted April 15, 2011.
- Copyright © 2011 by Cold Spring Harbor Laboratory Press
Freely available online through the Genome Research Open Access option.
