MHC architecture, evolution and disease 189 Figure 7. A summary of potential factors involved in an MHC association with a complex disease. CNV, copy number variation; HLA, human leucocyte antigen; KIR, killer immunoglobulin receptor; SNP, single-nucleotide polymorphism. balancing selection and whose products functionally interact. Epistasis may lie behind some aspects of the MHC, such as ancient highly diverged haplotypes that seem to be evolving independently except for ‘block shufﬂing’. It could also be responsible for difﬁculties in locating single gene contributions to disease in which multiple-linked interacting genes are at work. Methods of analysis that allow for, or exploit, the phenomenon of epistasis are being developed and successfully applied. Allowing for epistatic interactions may permit identiﬁca- tion of genetic effects that might otherwise have remained undetected. The index of variation built from the MHC Haplotype Project and related projects have dramatically improved our ability to deﬁne the sequence variants within the MHC involved in human disease. Higher-resolution analysis of gene CNV and structural variation associated with MHC genetic diversities in human populations promises to provide further insights into complex diseases and quantitative genetic traits. Technological develop- ments will play a key role in future MHC studies. In the very near future, next-generation sequencing platforms are likely to identify new miRNAs and provide quantitative tag-based gene expression data relevant to disease phenotypes. Large-scale re-sequencing could potentially replace tag-based WGA studies, even though the WGA approach has become commonplace only relatively recently. However, high-throughput re-sequencing projects will bring new analytical challenges, especially in the detection of functionally important but rare variants among the background diversity. Recent epigenetic studies provide a ﬁrst impression of how the MHC is packaged and functionally organized to regulate gene activities. Clearly, we have much more to learn in mapping the MHC. It is already recognized that chromatin domains that envelop individual gene regula- tory regions, whole genes and groups of genes modulate cellular activities. Perhaps a complete view of the MHC disease involvement will require maps of chromatin topography that characterizes the cell types involved in disease. The net impact will be a substantially enhanced annotation of the MHC, which will in turn dramatically increase our ability to interpret sequence-level variations. The projects described here are the start of another long and fertile period of MHC research. Essentially, a truly integrated epigenetic–genetic approach to common disease is sought, including development of molecular technologies to identify and screen gene regulators and elucidate how and when transcription factors and chromatin remodelling proteins interact with the genetic code. Such study promises to unveil some of the mysteries that have long shrouded the MHC, and provide future directions for diagnostics and therapeutic interventions of many prevalent and debilitating diseases. Acknowledgements I would like to thank John Trowsdale, Roger Horton and Stephan Beck for critical reading of this manuscript. JAT is supported by the MRC. References Aitman, T.J., Dong, R., Vyse, T.J., Norsworthy, P.J., Johnson, M.D., Smith, J. et al. (2006) Copy number polymorphism in Fcgr3 predisposes to glomerulonephritis in rats and humans. Nature, 439, 851. Apanius, V., Penn, D., Slev, P.R., Ruff, L.R. & Potts, W.K. (1997) The nature of selection on the major histocompatibility complex. Critical Reviews in Immunology, 17, 179. Baena, A., Mootnick, A.R., Falvo, J.V., Tsytskova, A.V., Ligeiro, F., Diop, O.M. et al. (2007) Primate TNF promoters reveal markers of phylogeny and evolution of innate immunity. PLoS ONE, 2, e621. de Bakker, P.I., Burtt, N.P., Graham, R.R., Guiducci, C., Yelensky, R., Drake, J.A. et al. (2006a) Transferability of tag SNPs in genetic association studies in multiple populations. Nature Genetics, 38, 1298. de Bakker, P.I., McVean, G., Sabeti, P.C., Miretti, M.M., Green, T., Marchini, J. et al. (2006b) A high-resolution HLA and SNP © 2008 The Author Journal compilation © 2008 Blackwell Publishing Ltd, International Journal of Immunogenetics 35, 179–192