single parent. distribution and evolutionary history main article: blood type distribution by country the distribution of the blood groups a, b, o and ab varies across the world according to the population. there are also variations in blood type distribution within human subpopulations. in the uk, the distribution of blood type frequencies through the population still shows some correlation to the distribution of placenames and to the successive invasions and migrations including celts, norsemen, danes, anglo-saxons, and normans who contributed the morphemes to the placenames and the genes to the population. the native celts tended to have more type o blood, while the other populations tended to have more type a. the two common o alleles, o01 and o02, share their first 261 nucleotides with the group a allele a01. however, unlike the group a allele, a guanosine base is subsequently deleted. a premature stop codon results from this frame-shift mutation. this variant is found worldwide, and likely predates human migration from africa. the o01 allele is considered to predate the o02 allele. some evolutionary biologists theorize that there are four main lineages of the abo gene and that mutations creating type o have occurred at least three times in humans. from oldest to youngest, these lineages comprise the following alleles: a101/a201/o09, b101, o02 and o01. the continued presence of the o alleles is hypothesized to be the result of balancing selection. both theories contradict the previously held theory that type o blood evolved first. origin theories it is possible that food and environmental antigens (bacterial, viral, or plant antigens) have epitopes similar enough to a and b glycoprotein antigens. the antibodies created against these environmental antigens in the first years of life can cross-react with abo-incompatible red blood cells that it comes in contact with during blood transfusion later in life. anti-a antibodies are hypothesized to originate from immune response towards influenza virus, whose epitopes are similar enough to the α-d-n-galactosamine on the a glycoprotein to be able to elicit a cross-reaction. anti-b antibodies are hypothesized to originate from antibodies produced against gram-negative bacteria, such as e. coli, cross-reacting with the α-d-galactose on the b glycoprotein. however, it is more likely that the force driving evolution of allele diversity is simply negative frequency-dependent selection; cells with rare variants of membrane antigens are more easily distinguished by the immune system from pathogens carrying antigens from other hosts. thus, individuals possessing rare types are better equipped to detect pathogens. the high within-population diversity observed in human populations would, then, be a consequence of natural selection on individuals. clinical relevance the carbohydrate molecules on the surfaces of red blood cells have roles in cell membrane integrity, cell adhesion, membrane transportation of molecules, and acting as receptors for extracellular ligands, and enzymes. abo antigens are found having similar roles on epithelial cells as well as red blood cells. bleeding and thrombosis (von willebrand factor) the abo antigen is also expressed on the von willebrand factor (vwf) glycoprotein, which participates in hemostasis (control of bleeding). in fact, having type o blood predisposes to bleeding, as 30% of the total genetic variation observed in plasma vwf is explained by the effect of the abo blood group, and individuals with group o blood normally have significantly lower plasma levels of vwf (and factor viii) than do non-o individuals. in addition, vwf is degraded more rapidly due to the higher prevalence of blood group o with the cys1584 variant of vwf (an amino acid polymorphism in vwf): the gene for adamts13 (vwf-cleaving protease) maps to human chromosome 9 band q34.2, the same locus as abo blood type. higher levels of vwf are more common amongst people who have had ischemic stroke (from blood clotting) for the first time. the results of this study found that the occurrence was not affected by adamts13 polymorphism, and the only significant genetic factor was the person's blood group. abo hemolytic disease of the newborn main article: hemolytic disease of the newborn (abo) abo blood group incompatibilities between the mother and child do not usually cause hemolytic disease of the newborn (hdn) because antibodies to the abo blood groups are usually of the igm type, which do not cross the placenta. however, in an o-type mother, igg abo antibodies are produced and the baby can potentially develop abo hemolytic disease of the newborn. clinical applications in human cells, the abo alleles and their encoded glycosyltransferases have been described in several oncologic conditions. using anti-gta/gtb monoclonal antibodies, it was demonstrated that a loss of these enzymes was correlated to malignant bladder and oral epithelia. furthermore, the expression of abo blood group antigens in normal human tissues is dependent the type of differentiation of the epithelium. in most human carcinomas, including oral carcinoma, a significant event as part of the underlying mechanism is decreased expression of the a and b antigens. several studies have observed that a relative down-regulation of gta and gtb occurs in oral carcinomas in association with tumor development. more recently, a genome wide association study (gwas) has identified variants in the abo locus associated with susceptibility to pancreatic cancer. in addition, another large gwas study has associated abo-histo blood groups as well as fut2 secretor status with the presence in the intestinal microbiome of specific bacterial species. in this case the association was with bacteroides and faecalibacterium spp. bacteroides of the same otu (operational taxonomic unit) have been shown to be associated with inflammatory bowel disease, thus the study suggests an important role for the abo histo-blood group antigens as candidates for direct modulation of the human microbiome in health and disease. clinical marker a multi-locus genetic risk score study based on a combination of 27 loci, including the abo gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. the study was based on a community cohort study (the malmo diet and cancer study) and four additional randomized controlled trials of primary prevention cohorts (jupiter and ascot) and secondary prevention cohorts (care and prove it-timi 22). alteration of abo antigens for transfusion in april 2007, an international team of researchers announced in the journal nature biotechnology an inexpensive and efficient way to convert types a, b, and ab blood into type o. this is done by using glycosidase enzymes from specific bacteria to strip the blood group antigens from red blood cells. the removal of a and b antigens still does not address the problem of the rh blood group antigen on the blood cells of rh positive individuals, and so blood from rh negative donors must be used. the sort of blood is named "enzyme converted to o" (eco) blood. patient trials will be conducted before the method can be relied on in live situations. one such phase ii trial was done on b-to-o blood in 2002. another approach to the blood antigen problem is the manufacture of artificial blood, which could act as a substitute in emergencies. pseudoscience main article: blood type personality theory during the 1930s, connecting blood groups to personality types became popular in japan and other areas of the world. studies of this association have yet to confirm its existence definitively. other popular but unsupported ideas include the use of a blood type diet, claims that group a causes severe hangovers, group o is associated with perfect teeth, and those with blood group a2 have the highest iqs. scientific evidence in support of these concepts is limited at best.