The Surprisingly Dynamic Evolution of Self Recognition: Sugar-Protein Interactions Mediate Inflammation and Cognitive Decline

BY: Stevan A Springer, Flavio Schwarz, Tasha Altheide, Nissi Varki, Pascal and Ajit Varki

Human cells are unusual because they lack Neu5Gc, a sialic acid monosaccharide found at the tips of cell surface sugars in most mammals. Sialic acids are markers of self: they typically reduce inflammation when bound by immunoregulatory proteins called Siglecs. This talk will trace the dynamic patterns of evolution that surround this self-signal. We will propose a model of sexual conflict that can explain the rapid loss of Neu5Gc. We describe the consequences of this loss for pathogen interaction and the evolution of Siglecs with altered patterns of immune regulation: including paired activating and inhibiting Siglecs. We describe comparative phylogenetic data that implicate the Siglec family in longevity. One Siglec in particular, CD33, has variants that maintain cognitive function in the elderly, which may have evolved by kin selection. We will close with new findings from other primate genomes: including human-unique evolution of the Siglec gene family, and parallel losses of Neu5Gc in other mammals