184 J. A. Traherne Figure 4. A shared ancestral block between two DR3 -DQ2 MHC haplotypes. The COX and QBL haplotypes share an ~158 kb ancestral block, which contains the HLA-DRB2, HLA-DRB1, HLA-DQA1, HLA-DQB1 and MTCO3P1 loci. Within this block there are only 14 single nucleotide polymorphisms (SNPs) distinguishing the two DR3-DQ2 haplotypes, whereas there are 3808 SNPs that differ between the DR3-DQ2 haplotypes and the DR15-DQ6 haplotype (PGF). This difference can be calculated to correlate with ~3400 generations that elapsed since the two DR3-DQ2 haplotypes separated vs. greater than 20 million years that separate the DR15-DQ6 haplotype from the DR3-DQ2 haplotypes. Vertical lines represent SNPs. HLA types for each haplotype are shown. Figure 5. Frequencies of the DR3-DQ2 haplotype within 18 populations. The ﬁgure represents the ethnic diversity of DR3-DQ2 haplotype distribution (NCBI dbMHC). documented in the comparison of two complete MHC haplotype sequences that are associated with different diseases (Traherne et al., 2006b). The comparison showed distribution patterns of variation across the MHC that were similar to those of other HLA-disparate haplotypes, apart from a near identical sequence of about 158 kb within the class II region, consistent with relatively recent common ancestry (< 3400 generations) (Fig. 4). Such shared segments, as in this example, can be used to rule out sections of the haplotype from containing sequences that control disease speciﬁcity. Block swapping between haplotypes provides a footprint to trace evolution. The shared ancestral block, which encompasses the HLA-DRB1 and HLA-DQB1 loci (DR3-DQ2), is present in a number of ethnically diverse populations (Fig. 5). Similarly, other ancient, highly diverged DR-DQ blocks, such as DR15-DQ6, are also carried on diverse and widely distributed haplotypes. This suggests that numerous highly diverged, ancestral blocks are maintained in the population, and recombination enables their occasional inclusion into different haplotype backgrounds across populations, where they may be selected in response to new disease challenges. In other words, swapping of ancestral blocks is a potential mechanism, whereby certain allelic combinations with immunological advantage, in terms of HLA functions and binding speciﬁcities for example, can spread across haplotypes and populations. © 2008 The Author Journal compilation © 2008 Blackwell Publishing Ltd, International Journal of Immunogenetics 35, 179–192