Ancestry runs deeper than blood: The evolutionary history of ABO points to cryptic variation of functional importance

The ABO histo-blood group, first discovered over a century ago, is found not only in humans but also in many other primate species, with the same genetic variants maintained for at least 20 million years. Polymorphisms in ABO have been associated with susceptibility to a large number of human diseases, from gastric cancers to immune or artery diseases, but the adaptive phenotypes to which the polymorphism contributes remain unclear. We suggest that variation in ABO has been maintained by frequency-dependent or fluctuating selection pressures, potentially arising from co-evolution with gut pathogens. We further hypothesize that the histo-blood group labels A, B, AB, and O do not offer a full description of variants maintained by natural selection, implying that there are unrecognized, functionally important, antigens beyond the ABO group in humans and other primates.