Proposed evolutionary scenario linking human-specific changes in Sia-related genes. It is impossible to conclusively prove evolutionary events and selection factors affecting Sia biology before the origin of modern humans. The speculative scenario presented here is based on available information and takes the parsimonious view that the events are related to one another. The first event may have been loss of Neu5Gc expression via CMAH inactivation and fixation (steps 1 and 2). A possible selection mechanism was a Neu5Gc-binding pathogen such as an NHH malaria, combined with genetic drift caused by ancestral demography. Because such organisms prefer binding α2–3-linked Sias, the increased human expression of α2–6-linked Sias may have been related. Human pathogen regimes would also have changed because of loss of Neu5Gc and excess of Neu5Ac. Some outcomes may have been positive (i.e., temporary escape from preexisting pathogens), and others may have been negative (e.g., increase susceptibility to Neu5Ac-binding pathogens and inability to modulate Neu5Gc/Neu5Ac ratios). Meanwhile, the loss of Neu5Gc should have resulted in loss of CD33rSiglec ligands needed for “self-recognition” (step 3). The likely hyperimmune state following Siglec ligand loss would have been followed by positive selection to allow multiple Siglecs (e.g., Siglec-9 and -7) to recognize Neu5Ac (step 4). Following this readjustment to the new “self,” a new risk would emerge. Although microbes appear incapable of synthesizing Neu5Gc, they have repeatedly reinvented Neu5Ac in multiple ways. Such pathogens would now be able to “hijack” inhibitory Siglecs such as Siglec-7 and -9, dampening the innate immune response of hominins (step 4). Indeed, several such organisms tend to be human-specific commensals. Notably, this proposed phase of pathogen exploitation of adjusted Siglecs is also the period of human evolution when newborns were becoming increasingly immature and more susceptible to these types of pathogens, especially those involved in brain invasion. Macrophage Siglec-1 might have then been up-regulated to enhance phagocytosis of Neu5Ac-expressing pathogens (step 5). Consequences of this proposed episode of pathogen exploitation of adjusted Siglecs could have been mutations of the Arg residue required for Sia recognition (Siglec-12, step 6) and the gene conversion event in Siglec-11 associated with recruitment to brain microglia (step 7). Eventually, immune cells would have down-regulated inhibitory Siglecs to escape the Neu5Ac-expressing pathogens while also up-regulating activatory Siglecs to respond to them (step 8). Perhaps this process explains why the critical Arg residue of the activatory Siglec-14 may have been restored in humans. This attempted reestablishment of a balanced response may have resulted in excessive activatory Siglecs (step 9), perhaps explaining the tendency of activatory Siglecs to be pseudogenized in modern humans (step 10). Of course, pathogens always evolve faster, and Neu5Ac-expressing pathogens are likely continuing to evolve to “hijack” our inhibitory Siglecs (step 11). Thus we likely have ongoing adjustments, with balancing selection for pseudogenes of the remaining activatory Siglecs and continued down-regulation of inhibitory Siglecs (step 12). It is also possible that these complex episodes of selection resulted in a changed profile of Siglec expression and function, not only in the innate immune system but also in other organs such as the placenta and the brain. Note that the human-specific changes in SIGLEC6 (placental trophoblast expression) and SIGLEC13 (deletion) are not incorporated into this model.