182 J. A. Traherne Figure 2. A reduced map of the MHC illustrating clustering of immune system genes. Two kinds of gene clustering are apparent. First, sequence- related duplicates that have allowed diversiﬁcation of duplicates, e.g. HLA or C4 complement genes. Second, sequence unrelated genes with related immune function, e.g. PSMB8/9 — proteosome components, TAP1/2 — peptide transporters, TAPBP — peptide chaperone, and HLA — peptide presentation. immune-system genes in the MHC include enhanced coordination of gene expression and facilitated sequence exchange among sequence-related gene duplicates (paralogues). Gene families can rapidly diversify by recombination and sequence exchange, making them especially adaptable evolutionarily. A concept expanded on below proposes that clustering of polymorphic genes may help to account for marked LD within the MHC. Structural variation Recent advances in global genome-wide analysis have revealed abundant and variable segmental duplications of genomic regions among different individuals, highlighting structural and interindividual copy number variation (CNV) as an important source of genetic diversity in relation to disease (Conrad et al., 2006; Redon et al., 2006; Wong et al., 2007). Two regions of the MHC associated with disease have long been conﬁrmed to have gene CNVs. The ﬁrst is in the class II region between HLA-DRB1 and HLA-DRB9 (a non-functional gene segment) that in some haplotypes houses one additional functional DRB gene (HLA-DRB3, HLA-DRB4 or HLA-DRB5), and one, two or no additional copies of HLA-DRB pseudogenes (HLA-DRB2, HLA-DRB6, HLA-DRB7 or HLA-DRB8). The second region is the tandem duplication in the class III region termed the RCCX (RP-C4-CYP21-TNX) module, which contains a gene for complement component C4. In addition to a C4 gene, each duplicated module includes a disrupted sequence (CYP21A pseudogene) for the steroid cyto- chrome P450 21-hydroxylase (CYP21B) gene (Chung et al., 2002). A single MHC haplotype can contain one to four copies of the RCCX module (Chung et al., 2002) (Fig. 3). Sequence exchange (gene conversion) among variants of RCCX modules is a mechanism that has generated diversity and has introduced deleterious mutations with pathological consequence. For example, mutations of CYP21A transferred to CYP21B are the primary cause of congenital hyperplasia (Friaes et al., 2006; Lee et al., 2006). Sequence duplications of related CNVs are highly homologous but generally do not share identical DNA sequence. Close examination often reveals additional genetic events that result in new polymorphisms adding new functions to existing gene products. In the case of the RCCX, the breakpoint(s) of duplication are identical among duplicated modules, but secondary genetic diver- siﬁcations have led to the emergence of two forms of C4 genes (short and long, the size difference resulting from the integration of the endogenous retrovirus HERV-K into its ninth intron) and two isotypes of C4 proteins (C4A and C4B), each with multiple allotypes. Gene CNV can result in differential levels of gene expression and by this means could account for a signiﬁ- cant proportion of phenotypic variation in human health © 2008 The Author Journal compilation © 2008 Blackwell Publishing Ltd, International Journal of Immunogenetics 35, 179–192