Figure 6.

Proposed evolutionary history of human Siglec‐XII. A, The last common human‐chimpanzee ancestor and modern chimpanzees had a functional CMAH enzyme and an abundance of Neu5Gc‐terminated cell‐surface glycans. Chimpanzee Siglec‐12 recognizes Neu5Gc through an arginine‐dependent binding pocket in its terminal V‐set domain. B, After divergence from chimpanzees CMAH was completely inactivated in human ancestor, leaving Siglec‐12 with no endogenous ligand. C, Another unknown evolutionary event fixed a mutation in the critical arginine rendering human “Siglec‐XII” incapable of binding any sialic acids, however, the full‐length protein continues to recruit Shp2 and alter gene expression. D, Modern humans are experiencing purifying selection acting to increase the frequency of common null‐state alleles across population