A second uniquely human mutation affecting sialic acid biology

Siglecs are immunoglobulin superfamily member lectins that selectively reco gnize different types and linkages of sialic acids, which are major compone nts of cell surface and secreted glycoconjugates. We report here a human Si glec-like molecule (Siglec-L1) that lacks a conserved arginine residue know n to be essential for optimal sialic acid recognition by previously known S iglecs. Loss of the arginine from an ancestral molecule was caused by a sin gle nucleotide substitution that occurred after the common ancestor of huma ns with the great apes but before the origin of modern humans. The chimpanz ee Siglec-L1 ortholog remains fully functional and preferentially recognize s N-glycolylneuraminic acid, which is a common sialic acid in great apes an d other mammals. Reintroducing the ancestral arginine into the human molecu le regenerates the same properties. Thus, the single base pair mutation tha t replaced the arginine on human Siglec-L1 is likely to be evolutionarily r elated to the previously reported loss of N-glycolylneuraminic acid express ion in the human lineage. Siglec-L1 and its chimpanzee Siglec ortholog also have a different expression pattern from previously reported Siglecs becau se they are found on the lumenal edge of epithelial cell surfaces. Notably, the human genome contains several Siglec-like pseudogenes that have indepe ndent mutations that would have replaced the arginine residue required for optimal sialic acid recognition. Thus, additional changes in the biology of sialic acids may have taken place during human evolution.