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presented on “clustered saccharide patches” (Varki, 1994) on cell surfaces, involving glycans of different types (Cohen et al., 2009). Thus, even specific epitopes in glycan arrays may not be representative of the “sialome” at the cell surface. These considerations apply not only to Siglecs but also to anti-Neu5Gc antibody epitopes. Another unexplored issue is whether loss of CMP-Neu5Gc in the Golgi has other consequences for competing biosynthetic pathways (e.g., we found an increase in Sia O-acetylation in the Cmah-null Neu5Gc-deficient mouse) (Hedlund et al., 2007). Finally, relative differences in biophysical properties between Neu5Gc and Neu5Ac could have consequences. Overall, the Sia biology changes in humans could alter more cell phenomena than we can currently imagine. One approach to exploring this issue is to feed different types of human cells with Neu5Gc (or Neu5Ac as a control) and then study interactions of anti-Neu5Gc antibodies or Siglecs, looking for differential binding by these proteins that cannot be explained by cell-surface glycan sequences.

Additional Phenotypes of Cmah-null Mice

The genomic lesion in our Cmah-null mice is almost identical to that of humans (Hedlund et al., 2007). The mice are viable and capable of reproduction, a situation that is not surprising, because the same is true of humans. Further studies of fertility are under way to look for any subtler differences. We have already reported that these mice show delayed wound healing and age-dependent hearing loss, similar to humans (Hedlund et al., 2007). We have preliminary evidence of metabolic differences that also deserve further study. Detailed neurobiological and cognitive studies are required to see if any known differences between human and NHH brains might be manifest. Of course, mice shared a common ancestor with primates more than 60 Mya, and the impact of this biochemical change in a rodent brain may not necessarily reflect what occurred in a hominid ancestor ~2–3 Mya. In this regard, it is fascinating that, even in animals with intact CMAH genes, the levels of brain Neu5Gc expression always seem very low (Gottschalk, 1960).

CONCLUSIONS AND PERSPECTIVES

The fact that so many genes related to Sia biology show human-specific differences from NHHs supports the notion that this system was a “hotspot” for evolutionary changes in the human lineage. Discussed here are some specific ways in which these changes would have impacted the immune system and human pathogen regimes. Although this discussion focuses on current human diseases, it also suggests a role for infectious diseases during human evolution. Of course, Sias and Siglecs are involved



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