MHC architecture, evolution and disease 181 Figure 1. Annotation of MHC reference haplotypes in VEGA. Representation of the PGF, COX and QBL haplotypes and variation in the Vega Genome Browser ‘MultiContigView’. MultiContigView allows simultaneous display and navigation of genome annotation between the human MHC regions in the different reference haplotypes. Manually curated gene structures within the HLA-DR region are shown (see Fig. 3 and accompanying text). loci (Horton et al., 2008). Some MHC loci possess over 20 splice variants, e.g. BAT1/3 and LST1 (VEGA). At least eight MHC loci are known to exhibit haplotypic variation at their splice sites, which may affect expression at the post-transcriptional level (Kralovicova et al., 2004; Traherne et al., 2006a; Horton et al., 2008). A signiﬁcant proportion of sequence variation outside splice sites is also likely to affect splicing efﬁciency (Hull et al., 2007). A growing number of reports are identifying disease- susceptibility alleles, across the genome, that are associated with speciﬁc splicing patterns (Wang & Cooper, 2007). Alterations in splicing can be directly causative, modify severity or be linked with disease susceptibility. Full characterization of the MHC transcriptome and splicing code is therefore likely to provide new insights, and useful diagnostic and prognostic tools for MHC-linked diseases. Gene clustering The MHC is one of the most gene-dense regions of the genome. One explanation for this is that the region favours high levels of expression (Horton et al., 2004). It contains a disproportionately high number of immune- system genes (Fig. 2). Possible advantages of clustering of © 2008 The Author Journal compilation © 2008 Blackwell Publishing Ltd, International Journal of Immunogenetics 35, 179–192