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 locus approximately 28.8 million nucleotides from the telomere of chromosome 6's shorter arm. AH8.1 extends past the 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.
Resistance to recombination A1::DQ2 is found in Iceland, Pomors of Northern Russia, the Serbians of Northern Slavic descent, Basque, and areas of Mexico where Basque settled in larger numbers. The haplotypes great abundance in the most isolated geographic region of Western Europe, Ireland, in Scandinavians and Swiss suggests that low abundance in France and Latinized Iberia are the result of displacements that took place after the Neolithic onset. This implies a founding presence in Europe that exceeds 8000 years. The SNP analysis of the haplotype suggests a potential founding effect of 20,000 years within Europe, though conflicts in interpreting this information are now apparent. The last possible point of a constriction forcing climate was the Younger Dryas before 11,500 calendar years ago, and so the haplotype has taken on various forms of the name, Ancestral European Haplotype, lately called Ancestral Haplotype A1-B8 (AH8.1). It is one of 4 that appear common to western Europeans and other Asians. Assuming that the haplotype frequency was 50% at the Younger Dryas and declined by 50% every 500 years the haplotypes should only be present below 0.1% in any European population. Therefore, it exceeds the expected frequency for a founding haplotype by almost 100 fold.
Diet in Evolution Beyond frequent interpretations of this nature, little more is known as to why the haplotype has not undergone equilibration. The haplotype appears to be recombination resistant, it appears to also have been under positive selection relative to other haplotypes in Europe, although currently disease instances suggest cereal-based negative selection is acting. One possible explanation comes from the study of remains of the pre-Neolithic period. Given food selects the haplotype now, might food have also positively selected the haplotype in the past. During the early period of European settlement, what remains of coastal settlements suggests a high marine-based food calorie intake, and, in particular, shellfish. Marine carbon component of Western European diet has declined from the Mesolithic to present, however the haplotype has not undergone equilibration, therefore diet alone cannot explain its resistance to recombination.
Formation Of the haplotypes mentions above, A24-Cw*0702::DQ2 or A1::B8-DR1-DQ5, none appear to be ancestral to A1::DQ2. An A1::DQ2 appears in India, however its major antigen genes superficially resemble European A1-B8 and it appears to be a homoplastic recombinant from a common DR3-DQ2 ancestor, about 70,000 years ago. Components of the haplotype are found in Europe (Basque have two major haplotypes of DR3-DQ2) and A1-B8 of Indian origin is of very low frequency. In Morocco B8::DQ2, in the Western Sahara A1-B8 haplotype if found and also DQ2.5 is found in high frequency, but not as a single haplotype. In Kenya two slightly variant HLA-A and B alleles for an A1-B8 haplotype. One possibility is that peoples from central Asia or the Middle East migrated into Iberia as peoples from Africa crossed into Iberia from the south prior to the Neolithic, recombination occurred resulting in the haplotype, and bearers favorably expanded into Europe prior to the Holocene. Another possibility is that if formed in West Africa, but because it was less selective in African holocene relative to European holocene climate/culture, the haplotype underwent equilibration in N. Africa. One hypothesis supported by frequencies in Iberia and North Africa suggest that A1::DQ2 formed from A1::B8-DR7-DQ2 with DR3 bearing source. One possible source is the HLA Cw*1701 : B*4201 : DRB1*0302 (The most common haplotype in African Americans is an extended haplotype) However possible, it would require the introduction of a modified *0505 allele. In addition, the Indian/European branch of DQ2.5 is much older, thus it appears at least 2 major recombinant steps were required to form the haplotype, and after its formation evolution markedly slowed down.
Variants There is a variant of A1←→B8 found in India. This variant carries the different Cw*07 (Cw*0702 is a very ancient allele that differs from Cw*0701 of A1::DQ2). It bears C4A a different DRB3 allele as well as numbers of other differences. This variant likely evolved from A24 or A26-Cw*0702-B*0801-DR3-DQ2 that independently arrived and evolved in India.
Components Large haplotypes can be thought of as steps between adjacent loci. For example, A1-Cw*0701, Cw*0701-B8, B8 to DR3, and DR3-DQ2 are each steps. Each step is a haplotype in its own right, however, the closer two loci are together, the longer it takes recombination to alter the step. Both Cw-B and DR-DQ are close together, A-Cw and B-DR are far apart. As a result, components of a haplotype evolve at different paces.
A1-Cw7-B8 Early studies of families across Europe recognized what most HLA associations had already shown, that there is an inherited (genetic) linkage between A1 and B1, this was extended to Cw7 locus.
And while the level of A-B linkage in general was nowhere near Cw-B linkage, the linkage between A1-Cw7-B8 was reasonably strong.
B8-DR3 The region between and including B8 and DR3 bears a number of genes of interest in the study of human disease. Most important of which is the TNF (tumor necrosis factors) with 3 loci in the region. Starting from B8, immediately followed by the MICA and MICB which stand for MHC I-like chain A and B. These two functional class I molecules are expressed on intestinal interocytes and may have interest in autoimmune disease, they are variable, but the MICA mutants so-far found do not seem to correlate with autoimmune diseases of the GI tract.
HLA DR3-DQ2 DR3-DQ2 is either a known or highly suspect factor in most autoimmune diseases that link to the A1::DQ2 haplotype.
Importance to Medicine
In organ transplantion