Glycobiology Advance Access originally published online on December 23, 2003
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Glycobiology vol 14 no 4 pp. 339-346, 2004
Glycobiology vol. 14 no. 4 © Oxford University Press 2004; all rights reserved.
A uniquely human consequence of domain-specific functional adaptation in a sialic acid–binding receptor
3 Glycobiology Research and Training Center, Departments of Medicine and Cellular & Molecular Medicine, University of California, San Diego, La Jolla, CA 92093-0687
Received on November 15, 2003; revised on November 19, 2003; accepted on November 24, 2003
Most mammalian cell surfaces display two major sialic acids (Sias), N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid (Neu5Gc). Humans lack Neu5Gc due to a mutation in CMP-Neu5Ac hydroxylase, which occurred after evolutionary divergence from great apes. We describe an apparent consequence of human Neu5Gc loss: domain-specific functional adaptation of Siglec-9, a member of the family of sialic acid–binding receptors of innate immune cells designated the CD33-related Siglecs (CD33rSiglecs). Binding studies on recombinant human Siglec-9 show recognition of both Neu5Ac and Neu5Gc. In striking contrast, chimpanzee and gorilla Siglec-9 strongly prefer binding Neu5Gc. Simultaneous probing of multiple endogenous CD33rSiglecs on circulating blood cells of human, chimp, or gorilla suggests that the binding differences observed for Siglec-9 are representative of multiple CD33rSiglecs. We conclude that Neu5Ac-binding ability of at least some human CD33rSiglecs is a derived state selected for following loss of Neu5Gc in the hominid lineage. These data also indicate that endogenous Sias (rather than surface Sias of bacterial pathogens) are the functional ligands of CD33rSiglecs and suggest that the endogenous Sia landscape is the major factor directing evolution of CD33rSiglec binding specificity. Exon-1-encoded Sia-recognizing domains of human and ape Siglec-9 share only 
93–95% amino acid identity. In contrast, the immediately adjacent intron and exon 2 have the 98–100% identity typically observed among these species. Together, our findings suggest ongoing adaptive evolution specific to the Sia-binding domain, possibly of an episodic nature. Such domain-specific divergences should also be considered in upcoming comparisons of human and chimpanzee genomes.
2 Current address: Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, MO
Sequences reported here are deposited in GenBank, under accession numbers AY532661, AY532662 and AY532663.
1 To whom correspondence should be addressed; e-mail: avarki{at}ucsd.edu
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