Evolution of the ABO supergene family
Authors: Blancher A. 
Published: May 2013

The proteins encoded by the ABO alleles are the founders of the glycosyltransferase family 6 (GT6). Among the GT6 gene family, the ABO gene is the most famous, with in humans, a polymorphism based on three types of alleles: A and B codominant and responsible for the expression of A and B antigens, alleles O silent and recessive. The A and B enzyme transfer a galactose (Gal) or an N‐acetyl‐galactosamine (GalNAc) on antigens H. Ninety years after the discovery ABO blood groups by Landsteiner, Yamamoto et al. discovered the ABO gene and described its polymorphism at the molecular level. Thereafter, an intense effort of sequencing renewed the study of the ABO gene evolution in humans, primates and other animals. The interspecies sharing of the ABO polymorphism in primates has inspired to Landsteiner and Weiner the concept of trans‐species evolution of polymorphism further developed by Jan Klein. Long term balancing selection is the best way to explain the trans‐species evolution of alleles, but the inter‐allelic recombination blurs the imprint of balancing selection. As for the ABO gene, the debate is still opened between supporters of balancing selection and those of convergent evolution. Three other proteins of GT6 family have identified functions in animal kingdom. The α 1,3‐galactosyltransferase enzyme (α 1‐3GalT) transfers a Gal on a N‐acetyl‐lactosamine producing the α‐Gal epitope found in most mammalian species except humans, all apes and Old World monkeys. The Forssman synthase (FS) produces the F antigen in many animal species (mouse, dog, chicken) by transferring a GalNAc on the globotetraosylceramide. Human, rat, pigeon and other animal species are F negative. The isogloboside 3 synthase (iGb3S) produces iGb3 by transferring a Gal on lactosylceramide. In humans, the iGb3S gene is a pseudogene. Apart the four enzymes presented above (ABO, α1‐3GalT, FS, iGb3S), three putative GT6 proteins (GT6m5, GT6m6, GT6m7) of unknown functions were described. Only GT6m7 gene persists in human as a pseudogene. In total, in humans, only the ABO gene has functional alleles, all other GT6 members are pseudogenes. The GT6 genes are also present in bird, fish and amphibian. Their long term evolution follows the ‘birth‐and‐death’ evolution model. The GT6 genes have experienced independent inactivation in various species pushed to change their glycans for limiting interactions with pathogens. As long it is not too detrimental for aptitude to the reproduction, modify the glycosylation is the best way for the host to counteract the rapid adaption of pathogens. In this context, null alleles are submitted to either a positive selection until fixation, or a balancing selection allowing long‐term persistence of polymorphism. Other mechanisms influence glycome evolution: hosts target glycans of pathogens by antibodies, the pathogens evade the host immune system by mimicking host glycans, hosts use soluble glycans as decoys which divert pathogens from adhesion to their target, thus preventing infections. All these mechanisms were evoked for explaining the evolution of ABO gene polymorphism in the light of the epistasis with H (FUT1), SE (FUT2) and LE (FUT3).