MHC architecture, evolution and disease 183 Figure 3. Simpliﬁed gene conﬁgurations in the RCCX and HLA-DRB regions on MHC reference haplotypes. The COX and QBL haplotype are monomodular for RCCX, whereas the PGF, SSTO and DBB haplotypes are bimodular. Each C4 gene may encode a C4A or a C4B protein. C4L and C4S are long and short C4 genes, respectively. 21A and 21B are CYP21A (pseudogene) and CYP21B, respectively. DRB2, DRB6, DRB7, DRB8 and DRB9 are pseudogenes. and disease (Gonzalez et al., 2005; Aitman et al., 2006; Fellermann et al., 2006). Pertinent in this regard are the strong correlations of C4 gene CNV with human systemic lupus erythematosus (SLE), from a recent study (Yang et al., 2007). A dose-dependent effect was seen; from increased SLE disease risk at low copy number, to protection against disease susceptibility at high copy number. Typical of many susceptibility genes associated with an auto- immune disease, the risk factor (low copy number of C4) is present in the general population, but the prevalence is signiﬁcantly increased in the patient population. In addition to the above structural variation, many polymorphisms resulting from presence/absence of retroviral sequences (e.g. Alu, LINE, HERV, LTR, MER and SVA) have been observed among MHC haplotypes. The retroviral insertions are often located either in the HLA-DR region or near the classical HLA class I genes. The signiﬁcance of their targeting to HLA regions is unclear, although their presence may promote molecular evolution by facilitating non-homologous recombination or gene conversion events (Stewart et al., 2004; Wurtele et al., 2005; Sen et al., 2006; Zhi, 2007). Intriguingly, a recent study highlights the possibility that a HERV- derived gene, HCP5, located at < 100 kb from HLA-B, may contribute to host control of HIV-1 attributed to allele B*57 (Fellay et al., 2007). Recombination MHC divergence patterns indicate that evolutionarily successful recombination events have been infrequent compared to the genome as a whole. Recombination ﬂuc- tuates greatly across the region, but overall MHC recom- bination is considerably lower compared with the genome average (Miretti et al., 2005; The International HapMap Consortium, 2005; de Bakker et al., 2006b). In other words, many combinations of alleles at MHC genes rarely become separated over long periods of evolution. One interpretation is to suppose that certain MHC genes are tuned to work together, as a set of alleles on a particular haplotype (interactions between DNA sites in cis). Hence, the absence of detectable recombination may reﬂect maintenance of allele combinations with favoured immunological function through selection against unfavourable recombinant haplotypes. The MHC con- tains many polymorphic genes, encoding products with related functions (e.g. PSMB8/9 — proteosome components; TAP1/2 — peptide transporters; TAPBP — peptide chaper- one; HLA — peptide presentation) or components (e.g. HLA-DQA and HLA-DQB). It therefore seems appro- priate that such genes are inherited as a coordinated set. The notion of genetic interaction (epistasis) within the MHC is expanded on below. Although preferred combinations of alleles are conceiv- ably the decisive determinant of haplotype selection, it may also have arisen through recombination suppression in regions of high divergence (Shen & Huang, 1989). The extent of reduced recombination rate acting on diverged haplotypes could be assessed by high-resolution recombi- nation analysis of sperm typing. This experiment would help resolve the question of whether haplotype divergence is predominantly the effect or the cause of the prevailing patterns of allelic association. Also warranting further investigation are sequence inversions, which can be difﬁ- cult to detect but may also inﬂuence LD patterns within the MHC and maintenance of extended haplotypes (long regions where multiple SNPs are perfectly correlated), as it is envisaged that recombination is impeded or may be lethal over an inversion interval between chromosomes with and without the inversion. Inverted and non-inverted copies of the region therefore evolve independently. Inver- sions are not uncommon in the human genome (Khaja et al., 2006) and there is evidence of inversions in this region in mouse (t complex) so inversions could account for the strong LD in the human MHC. So far, direct evidence for inversions is lacking, but new scanning methods will assist future investigation (Bansal et al., 2007; Flores et al., 2007; Korbel et al., 2007). Some recombination between deeply diverged MHC haplotypes appears to have occurred relatively recently compared to the estimated divergence times of such haplotypes. Recombination of this type was recently © 2008 The Author Journal compilation © 2008 Blackwell Publishing Ltd, International Journal of Immunogenetics 35, 179–192