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Review
. 2013:14:301-23.
doi: 10.1146/annurev-genom-091212-153455. Epub 2013 Jul 15.

Major histocompatibility complex genomics and human disease

John Trowsdale  1 , Julian C Knight
Affiliations
Review

Major histocompatibility complex genomics and human disease

John Trowsdale et al. Annu Rev Genomics Hum Genet. 2013.

Abstract

Over several decades, various forms of genomic analysis of the human major histocompatibility complex (MHC) have been extremely successful in picking up many disease associations. This is to be expected, as the MHC region is one of the most gene-dense and polymorphic stretches of human DNA. It also encodes proteins critical to immunity, including several controlling antigen processing and presentation. Single-nucleotide polymorphism genotyping and human leukocyte antigen (HLA) imputation now permit the screening of large sample sets, a technique further facilitated by high-throughput sequencing. These methods promise to yield more precise contributions of MHC variants to disease. However, interpretation of MHC-disease associations in terms of the functions of variants has been problematic. Most studies confirm the paramount importance of class I and class II molecules, which are key to resistance to infection. Infection is likely driving the extreme variation of these genes across the human population, but this has been difficult to demonstrate. In contrast, many associations with autoimmune conditions have been shown to be specific to certain class I and class II alleles. Interestingly, conditions other than infections and autoimmunity are also associated with the MHC, including some cancers and neuropathies. These associations could be indirect, owing, for example, to the infectious history of a particular individual and selective pressures operating at the population level.

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Figures

Figure 1
Figure 1
Genomic landscape of the MHC. The classical MHC is shown on the short arm of chromosome 6 (base pair positions 29,640,000–33,120,000 from the Genome Reference Consortium Human Build 37, hg19), comprising the class I, II, and III regions. Transcription and chromatin states are illustrated for CD20+ normal human B cells using data from the ENCODE project (29). Constitutive expression of many MHC genes occurs in this cell type. Transcribed regions are shown by strand orientation for polyA+ RNA >200 nucleotides long from whole cells quantified by RNA-seq (red) based on short reads generated by the Illumina GAIIx platform. Separate tracks are shown for short total RNA (20–200 nucleotides long) (blue), with directional reads from the 5′ ends sequenced on an Illumina GAIIx. Chromatin accessibility is shown for the same cells based on DNase I hypersensitivity analyzed by DNase-seq (black), and is a useful guide to the location of putative regulatory regions. Data are also shown for a specific chromatin modification (H3K27ac) (green) for these cells analyzed by ChIP-seq. H3K27ac is an activating acetylation mark useful, for example, in identifying active enhancers. In terms of the recombination landscape of the MHC, data are shown for the deCODE recombination map (69) (dark brown), representing calculated rates of recombination (sex-averaged) using 10-kb windows. Vertebrate conserved elements are shown based on analysis of 46 species with prediction using PhastCons (107) (light brown). Sequence-level variation is shown for simple nucleotide polymorphisms, that is, single-nucleotide substitutions and small insertions and deletions (indels) found with at least 1% frequency in dbSNP. Variants are denoted in black except those in coding regions with synonymous variants (green), nonsynonymous variants (red), splice-site variants (red), and untranslated-region variants (blue). Remarkably high levels of polymorphism are seen, notably in classical HLA genes where variation is enriched in coding exons involved in defining the antigen-binding cleft. Structural genomic variants are also shown from the Database of Genomic Variants (54) involving segments of DNA larger than 1 kb. Copy number variants (CNVs) and indels are illustrated relative to the reference where gain in size (blue), loss in size (red), or both gain and loss in size (brown) have been reported. Structural variation is common in the MHC, including the RCCX module in the MHC class III region (comprising a number of genes, including RP-C4A/B-CYP21-TNXB), which may be duplicated or triplicated and present in different configurations, including two versions of the C4 gene (50). Other structurally complex sites include the HLA-DRB1 hypervariable region, which has five major haplogroups comprising variable numbers of functional genes and pseudogenes. All data tracks were downloaded from the UCSC Genome Browser (http://genome.ucsc.edu) (64).
Figure 2
Figure 2
The MHC, disease, and immune function. The MHC shows associations with almost all known autoimmune diseases as well as many inflammatory and infectious diseases. Major disease associations are listed by trait. Recent high-resolution SNP typing has defined specific SNP markers in some instances, but associations defined by HLA type remain robust; examples of top associations are shown. Extensive linkage disequilibrium has made fine mapping such associations challenging. In some instances, associated haplotypes span several megabases of the classical MHC. Examples of the role of MHC genes in immune function are illustrated, including the key role in antigen presentation and processing as well as inflammation, the complement cascade, and stress response (51). The tapasin-encoding gene (TAPBP), which is involved in peptide loading onto MHC class I and in the association of MHC class I with TAP, is not shown here but is just outside the class II region shown.
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