Review Article doi: 10.1111/j.1744-313X.2008.00765.x BHlackwel PuublishingmLtdan MHC architecture and evolution: implications for disease association studies J. A. Traherne Summary Major histocompatibility complex (MHC) variation is a key determinant of susceptibility and resistance to a large number of infectious, autoimmune and other diseases. Identiﬁcation of the MHC variants conferring susceptibility to disease is problematic, due to high levels of variation and linkage disequilibrium. Recent cataloguing and analysis of variation over the complete MHC has facilitated localization of susceptibility loci for autoimmune diseases, and provided insight into the MHC’s evolution. This review considers how the unusual genetic characteristics of the MHC impact on strategies to identify variants causing, or contributing to, disease phenotypes. It also considers the MHC in relation to novel mechanisms inﬂuencing gene function and regulation, such as epistasis, epigenetics and microRNAs. These developments, along with recent technological advances, shed light on genetic association in complex disease. Introduction The classical major histocompatibility complex (MHC) spans ~4 Mb and comprises over 160 protein-coding genes. Compared with other similar-sized sections of the human genome, the MHC holds the most, and some of the longest recognized associations with disease. The MHC inﬂuences numerous chronic inﬂammatory and autoimmune conditions, including type I diabetes, multiple sclerosis and Crohn’s disease. MHC variants also confer susceptibility to many infectious diseases, such as malaria and HIV. However, for most diseases the precise genetic components and mechanisms involved remain undeﬁned. The genetic basis of phenotypic traits within the MHC has been analysed in terms of several principle Cambridge Institute for Medical Research, Addenbrookes Hospital, Wellcome Trust/MRC Building, Cambridge, UK Received 22 January 2008; accepted 5 March 2008 Correspondence: James A. Traherne, Cambridge Institute for Medical Research, Addenbrookes Hospital, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 0XY, UK. E-mail: jat51@cam.ac.uk Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation. axes, including epistasis, penetrance, phenotypic plasticity, pleiotropy and polygeny. These underscore the complexity in resolving genetic effects within the MHC and relate largely to its unique evolutionary history. The MHC, which possibly originated as a rudimentary protochordate histocompatibility locus (De Tomaso et al., 2005), has evolved over many millions of years to become a master coordinator of speciﬁcity in both adaptive and innate immune systems. This responsibility may explain some distinctive features of the MHC, such as high gene density and diversity, and low recombination. Yet it is these features together with the complex aetiology of multifactorial MHC-linked diseases and frequent non- Mendelian inheritance that hamper precise identiﬁcation of variants contributing to disease phenotypes. In addition to being one of the most gene-dense regions of our genome, the MHC is one of the most variable. This diversity is a major contributor to individual differences in immune responsiveness. In relation to complex diseases, the MHC’s importance was recently conﬁrmed and emphasized by whole-genome association (WGA) studies (WTCCC, 2007). The strongest associations were found with the autoimmune diseases type 1 diabetes and rheumatoid arthritis. Another WGA study demonstrated that the three major determi- nates for host control of HIV-1 are also contained within the MHC, serving as testimony to its further role in conferring resistance to infectious diseases (Fellay et al., 2007). Many genetic risk variants in the MHC are common, suggesting that they bestow a past, or possibly enduring, evolutionary advantage. Consequently, a high proportion of individuals carry genetic risk factors for complex disease, however, the majority are healthy because of low penetrance and/or the combination of genetic and environmental risk factors required are incomplete. Substantial evidence supports pathogen-driven balancing selection as a major force driving and maintaining human leucocyte antigen (HLA) diversity. This hypothesis is supported by a recent study which showed that populations from areas with high pathogen diversity have increased HLA diversity relative to their average genomic diversity (Prugnolle et al., 2005). Furthermore, other mechanisms may also be involved, such as MHC-dependent mate selection and preferential abortion (Apanius et al., © 2008 The Author Journal compilation © 2008 Blackwell Publishing Ltd, International Journal of Immunogenetics 35, 179–192 179