Tempting as it may be to speculate that the spread of ancestral blocks by interhaplotype exchange may have been driven by selection, the frequency gradients between populations of the derivative haplotypes could conceivably be the outcome of neutral genetic drift and demographic history (Gherman et al., 2007). Further population studies will elucidate whether these stable ancestral sequences carry a particular selective advantage that were key to disease resistance or survival in the evolutionary history of humans. Long-range haplotypes LD varies markedly along the MHC but in general LD decay over the region falls within the typical range of genome distribution (Miretti et al., 2005; The Inter- national HapMap Consortium, 2005; de Bakker et al., 2006b). However, extensive LD is evidenced by the rela- tively high occurrence of a handful of distinct long-range haplotypes. These haplotypes have long been of interest because of their prevalence and strong associations with complex diseases, yet the mechanisms for their generation are still unclear. Several possible explanations exist for long-range LD, including low recombination rate and polymorphic inversions. Another is maintenance of functionally coordinated sets of alleles by selection. A simpler explanation would be that strong positive selection for a component of these haplotypes has expanded their frequency in recent evolutionary history, creating founder haplotypes that have had inadequate evolutionary time to degrade. Recent global studies using long-range haplotype (LRH) and extended haplotype homozygosity (EHH) tests support the hypothesis that signatures of positive selection are present in the MHC (The International HapMap Consortium, 2005, 2007; de Bakker et al., 2006b; Voight et al., 2006; Sabeti et al., 2007). Interest- ingly, MHC genes were not among the strongest signals identiﬁed in these genome-wide studies. This observation may reﬂect the nature of the MHC, where balancing selection is also active and pre-existing alleles may be recurrently selected, as well as the sensitivities of the tests; LRH tests have limited power to detect selection on stand- ing (pre-existing) variation and EHH tests have limited ability to detect low frequency selective sweeps. Two of the most frequent long-range MHC haplotypes in Northern Europeans are the HLA haplotypes HLA-A1- B8-C7-DR3-DQ2 (also termed AH 8.1) and HLA-A3-B7- C7-DR15-DQ6 (the so-called ancestral DR2 haplotype). The frequencies of these haplotypes in European Cauca- sians are in the order of 10%, which is substantially higher than expected (< 0.5%) based on the frequencies of individual alleles on the haplotypes. The high sequence similarity of long-range haplotypes suggests that their prevalence is likely due to signiﬁcant expansions in relatively recent times. Indeed, the AH 8.1 haplotype has been estimated to have diverged from a single common ancestor about 23,500 years ago (Smith et al., 2006). In other words, the constituent alleles on these haplotypes are in strong association probably because of recent MHC architecture, evolution and disease 185 expansion rather than having been derived from distinct haplotypes through multiple independent events in which selection drove or maintained the linkage of these alleles. This view suggests that there is not necessarily any functional signiﬁcance to the linkage of constituent alleles of long-range haplotypes because only one locus allele under strong positive selection in this chromosome interval could have been sufﬁcient to drive expansion of a haplotype. The occurrence of a number of other extant haplotypes that include DR3-DQ2 but have lost HLA-A1 or HLA-B8 is consistent with this theory. The estimated ages of some common long-range haplotypes typically fall within range of the human migra- tion out of Africa and expansion into Europe. This has led to theories of selective factors that acted to expand these haplotypes, which in general relate to adaptation to new environments, changes in nutrition, or resistance to infec- tion during migrations (Distante et al., 2004; Moalem et al., 2005). Although their exact anthropological origins will be difﬁcult to determine, more precise estimates for the period and the length of time such selection was operating should be possible by comparative study and phylogenetic analysis of MHC haplotypes in different populations. The identiﬁcation of the variant(s) responsible for the hypothetical selective events that led to expansions could be informative. The DRB1 gene is a prime suspect on the DR2 haplotype (Miretti et al., 2005) and it is associated with susceptibility to multiple sclerosis and protection from type 1 diabetes (Barcellos et al., 2006; Nejentsev et al., 2007). Any past survival beneﬁts of common long-range haplotypes have come at a cost since many predispose to inﬂammatory diseases prevalent in Westernized society, such as type I diabetes and multiple sclerosis. The inherently strong and long-ranging correlations (extend- ing beyond the MHC in some instances) between alleles on these haplotypes have limited the identiﬁcation of haplotype-residing variants that contribute to associated disease phenotypes. Improved resolution will likely be achievable by applying higher-throughput sequencing and higher-resolution SNP analysis to deﬁne the extent of similarity between haplotypes and reﬁne boundaries of homozygosity. In this way the evolutionary history and associations with diseases may be traceable. Haplotype tagging The International HapMap Project was set up to map human variation by characterizing LD patterns across the whole genome (Thorisson et al., 2005; Frazer et al., 2007). The project is enabling the selection of informative tag SNPs that can act as surrogate markers for most com- mon variants in human populations. This reduced set of genetic markers provides an effective, cost-efﬁcient means to conduct genome scans in large samples and to investi- gate disease associations in greater detail. The genetic complexity of the MHC necessitated a more focused project to provide a reﬁned resource for this critical region (de Bakker et al., 2006b). This study © 2008 The Author Journal compilation © 2008 Blackwell Publishing Ltd, International Journal of Immunogenetics 35, 179–192