The human ABO(H) blood group phenotypes arise from the evolutionarily oldest genetic system found in primate populations. While the blood group antigen A is considered the ancestral primordial structure, under the selective pressure of life-threatening diseases blood group O(H) came to dominate as the most frequently occurring blood group worldwide. Non-O(H) phenotypes demonstrate impaired formation of adaptive and innate immunoglobulin specificities due to clonal selection and phenotype formation in plasma proteins. Compared with individuals with blood group O(H), blood group A individuals not only have a significantly higher risk of developing certain types of cancer but also exhibit high susceptibility to malaria tropica or infection by Plasmodium falciparum. The phenotype-determining blood group A glycotransferase(s), which affect the levels of anti-A/Tn cross-reactive immunoglobulins in phenotypic glycosidic accommodation, might also mediate adhesion and entry of the parasite to host cells via trans-species O-GalNAc glycosylation of abundantly expressed serine residues that arise throughout the parasite's life cycle, while excluding the possibility of antibody formation against the resulting hybrid Tn antigen. In contrast, human blood group O(H), lacking this enzyme, is indicated to confer a survival advantage regarding the overall risk of developing cancer, and individuals with this blood group rarely develop life-threatening infections involving evolutionarily selective malaria strains.

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While native blood group A‐like glycans have not been demonstrated in prokaryotic microorganisms as a source of human “natural” anti‐A isoagglutinin production, and metazoan eukaryotic N‐acetylgalactosamine O‐glycosylation of serine or threonine residues (O‐GalNAc‐Ser/Thr‐R) does not occur in bacteria, the O‐GalNAc glycan‐bearing ovarian glycolipids, discovered in C57BL/10 mice, are complementary to the syngeneic anti‐A‐reactive immunoglobulin M (IgM), which is not present in animals that have undergone ovariectomy prior to the onset of puberty. These mammalian ovarian glycolipids are complementary also to the anti‐A/Tn cross‐reactive Helix pomatia agglutinin (HPA), a molluscan defense protein, emerging from the coat proteins of fertilized eggs and reflecting the snail‐intrinsic, reversible O‐GalNAc glycosylations. The hexameric structure of this primitive invertebrate defense protein gives rise to speculation regarding an evolutionary relationship to the mammalian nonimmune, anti‐A‐reactive immunoglobulin M (IgM) molecule. Hypothetically, this molecule obtains its complementarity from the first step of protein glycosylations, initiated by GalNAc via reversible O‐linkages to peptides displaying Ser/Thr motifs, whereas the subsequent transferase depletion completes germ cell maturation and cell renewal, associated with loss of glycosidic bonds and release of O‐glycan‐depleted proteins, such as complementary IgM revealing the structure of the volatilely expressed “lost” glycan carrier through germline Ser residues. Consequently, the evolutionary/developmental first glycosylations of proteins appear metabolically related or identical to that of the mucin‐type, potentially “aberrant” monosaccharide GalNAcα1‐O‐Ser/Thr‐R, also referred to as the Tn (T “nouvelle”) antigen, and explain the anti‐Tn cross‐reactivity of human innate or “natural” anti‐A‐specific isoagglutinin and the pronounced occurrence of cross‐reactive anti‐Tn antibody in plasma from humans with histo‐blood group O. In fact, A‐allelic, phenotype‐specific GalNAc glycosylation of plasma proteins does not occur in human blood group O, affecting anti‐Tn antibody levels, which may function as a growth regulator that contributes to a potential survival advantage of this group in the overall risk of developing cancer when compared with non‐O blood groups.