Chromosomal recombination fragments multigene haplotypes as the distance to that ancestor increases in number of generations.
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.
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).
This dynamic can change if the population expands rapidly from a few individuals that lived in isolation as long as other haplotypes are maintained.
[1] The haplotype begins before the TRIM27 locus approximately 28.8 million nucleotides from the telomere of chromosome 6's shorter arm.
Thus, A1::DQ2 haplotype is both long and shows greater deficiency of recombination (called linkage disequilibrium).
And yet the haplotype is found largely intact in people who settled out of Europe hundreds of years ago.
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.
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.
One hypothesis supported by frequencies in Iberia and North Africa suggest that A1::DQ2 formed from A1::B8-DR7-DQ2 with DR3 bearing source.
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.
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.
The region between and including B8 and DR3 bears a number of genes of interest in the study of human disease.
Starting from B8, immediately followed by the MICA and MICB which stand for MHC I-like chain A and B.
This aided in the proper identification of transplant matches prior to the era of PCR-gene testing.
Prior to refined typing for HLA-DQ and DR, the association with HLA-A1 and B8 was identified for coeliac disease in 1973 and dermatitis herpetiformis in 1976 .
[3] For example, MICA and MICB are mhc class 1 genes found expressed in the epithelium of the gut.
A more recent paper shows that Inositol triphosphate receptor 3 gene which is ~ 1 million base pairs centromeric from DQ2.5 may also be associated with Type 1 diabetes.
Type 1 diabetes has a risk associated with coxsackie 4B virus, there is a potential for involvement of class I loci, particularly those expressed in the GI tract.
To segregate disease groups have attempted to further define population to earliest onset (presumbably most susceptibility) and females.
[27] Primary biliary cirrhosis which often follows chronic active hepatitis is linked to "DRw3", DR3, gene.
[29] This could indicate an association with subclinical enteropathy, or alternatively the result of chronic viral infection which is known to also elevate anti-tranglutaminase antibody.
[32] The entire haplotype, A1-Cw7-B8-TNFB*1-C4A(Null)-DR3-DQ2, is increased in patients and the genetic susceptibility to SLE cannot be distinguished.
[40] Research published in October 2015 by the National Institute of Environmental Health Sciences compared 1,710 cases of either adult- or juvenile-onset myositis, with 4,724 control subjects.