HLA A1-B8-DR3-DQ2 haplotype (Also: AH8.1, COX, Super B8, ancestral MHC 8.1 or 8.1 ancestral haplotype) is a multigene haplotype that covers a majority of the human major histocompatibility complex on chromosome 6 (not to be confused with the HLA-DQ heterodimer DQ8.1). A multigene haplotype is set of inherited alleles covering several genes, or gene-alleles; common multigene haplotypes are generally the result of descent by common ancestry (share a recent common ancestor for that segment of the chromosome). Chromosomal recombination fragments multigene haplotypes as the distance to that ancestor increases in number of generations. The haplotype can be written in an extended form covering the major histocompatibility loci as follows:
HLA A*0101 : Cw*0701 : B*0801 : DRB1*0301 : DQA1*0501 : DQB1*0201 or shorthand A1::DQ2 There are many other gene-alleles within the haplotype, including more than 250 coding loci that produce transcripts. At 4.7 million nucleotides in length, A1::DQ2 is the second longest haplotype identified within the human genome. A1::DQ2 creates a conundrum for the evolutionary study of recombination. The length of the haplotype is remarkable because of the rapid rate of evolution at the HLA locus should degrade such long haplotypes. A1::DQ2's origin is difficult to trace, suggestions of a common ancestor in Iberia or Africa have been put forward. Although its place of origin is not certain there is agreement that bearers of the European AH8.1 bear a haplotype related by a common descent. A1::DQ2 is the most frequent haplotype of its length found in US Caucasians, ~15% carry this common haplotype. Studies indicate that A1::DQ2 prominence is likely due to positive selection in the pre-Neolithic period and isolation in countries where wheat was not a prominent cereal. Outside of DR3-DQ2 with known associations to autoimmune disease, other factors within A1::DQ2 are believed to also contribute to autoimmune disease. Also a dozen inflammatory diseases of the immune system can attribute some risk to the haplotype. Some disease like coeliac disease primarily associate with certain genes. While other diseases, like type 1 diabetes may have several, highly different, genes that attribute risk. Still other diseases, like myasthenia gravis have undetermined linkage to the haplotype.
Recombination dynamics Each person has unique chromosomes, unless they are identical twins. These unique chromosomes are produced by recombination of each unique chromosome passed by each grandparent to each parent. These chromosome chimerize within the reproductive cells of each parent which are then passed to the developing person during fertilization. The recombination that creates these blended chromosomes occurs almost randomly along the length, 1 Morgan per generation. Within 100 generations in humans (about 2100 years in ancient times) one expects a few hundred of these 'blending' events to have occurred across a single chromosome, the average size is 1 centiMorgan (or 1 cM). The average length of these 'haplotypes' are about 1 million nucleotides. Multigene haplotypes following standard dynamics only exist in robust populations for a short time, the average distance between genes of about 200,000 nts, which means that over 250 generations (~5000 years) one expects 1/2 of adjacent genes to have new gene-alleles, unless the genes are small and very close together. This dynamic can change if the population expands rapidly from a few individuals that lived in isolation as long as other haplotypes are maintained. A1::DQ2 does not follow the expected dynamics. Other haplotypes exist in the region of Europe where this haplotype formed and expanded, some of these haplotypes also are ancestral and also are quite large. At 4.7 million nucleotides in length and ~300 genes the locus had resisted the effects of recombination, either as a consequence of recombination-obstruction within the DNA, as a consequence of repeated selection for the entire haplotype, or both.
Structure A1::DQ2 is 4,731,878 nucleotides in length. The haplotype begins before the TRIM27 locus approximately 28.8 million nucleotides from the telomere of chromosome 6's shorter arm. AH8.1 extends past the SYNGAP1 about 33.5 million nucleotides from the telomer. Marked deterioration occurs however after the DQB1 gene at 32.8 million nucleotides. A1::DQ2 is not the longest haplotype, but the longest, HLA A3-Cw7-B7-DR15-DQ6 (A3::DQ6), had already undergone significant recombination and is nearly equal in frequency to HLA A2-Cw7::DQ6 bearing version. In the US Caucasians, 57% of haplotypes with a core component, Cw7-B8, extend from HLA-A1 locus to DQ2 locus. This compares with 25% of Cw7-B7 that extend to A3::DQ6 Of 25 potential genetic recombinants of A1::DQ2, none exceed 10% of the Cw*0702-B*0801 frequency. Two recombinants A24-Cw7~DQ2, A1::B8-DR1-DQ5 are notable. Thus, A1::DQ2 haplotype is both long and shows greater deficiency of recombination (called linkage disequilibrium).
Evolution The evolution of A1::DQ2 appears to be key to its structure. The haplotype, at 4.7 million nucleotide, exists in a population with other haplotypes which, when combined, exceed A1::DQ2 in frequency. Genetics of recombination in humans suggests that common haplotypes of this length that Cw7-B8 component should be in other haplotypes, Ax-Cw7::DQ2, A1-B8-DRx-DQx, or A1-B8-DR3-DQx (where Ax is not A1, DRx is not DR3, or DQx is not DQ2). For a haplotype of this length the process is fast, 50% loss of the complete haplotype within 500 years. And yet the haplotype is found largely intact in people who settled out of Europe hundreds of years ago.
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