Glycan Diversity and Anti-Glycan Antibodies as Barriers to Gene Flow Mammalian cells are covered with a dense layer of sugar chains (glycans). Patterns of glycan diversity exist between cell types, between individuals, and between species. The evolutionary mechanisms underlying such patterns remain unknown but protective functions of glycan diversity have been proposed, given that non-self glycans are targets of innate and adaptive immunity. Mammalian glycans commonly terminate in sugars called sialic acids (Sias). The two most common Sias are N-Acetylneuraminic acid (Neu5Ac) and N- Glycolylneuraminic acid (Neu5Gc). Humans have lost the ability to produce Neu5Gc from its precursor Neu5Ac due to a gene inactivation. Humans together with all other old world monkeys (OWM) and apes have lost the ability to make another common glycan, the 1-Gal epitope, due to another mutation. The molecular cell surface "landscape" of each human cell thus differs from those of most other mammals by lacking millions of 1-Gal molecules and tens of millions of Neu5Gc molecules. Humans also make antibodies to both of these "xenoglycans" but how we get immunized remains unknown. This project will test the effect of these two xenoglycans on different forms of gene flow, viral infection and reproduction. Humans are unique among African primates for lacking endemic infection and ancient coevolution with two different enveloped retroviruses, immune deficiency viruses (SIV/HIV) and foamy viruses (SFV) until very recently. Glycans on enveloped viruses or sperm and fetal tissues can be targeted by the immune system. We propose that natural selection by glycan-binding pathogens may underlie initial glycan diversification, but that sexual selection in the form reproductive incompatibility may lead to fixation of glycan repertoires between species. In the process, these glycan differences provide partial protection from cross-species transmission of enveloped viruses. We will utilize gene knockout mice and mouse cell lines to test the effect of glycan mismatch and anti-glycan antibodies on both, viral and reproductive gene flow. We will also test the effect of anti-glycan antibodies from human sera for their neutralizing effects on viruses produced in Old and New World monkey cell lines which naturally differ in their xenoglycan profiles. This project promises important insights into the mechanism of poorly understood glycan evolution, reproductive compatibility and determinants of cross-species viral infections.

Public Health Relevance

Glycan Diversity and Anti-Glycan Antibodies as Barriers to Gene Flow Human cells differ from those of most other mammals by the absence of millions of molecules from each cell surface against which most humans make circulating antibodies. The underlying genetic change responsible for this is known, but nothing is known of the evolutionary mechanisms, which favored this change in our species. We propose to test the consequences of this difference for reproduction and cross-species viral infections, such as in emerging diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM095882-04
Application #
8653968
Study Section
Intercellular Interactions (ICI)
Program Officer
Marino, Pamela
Project Start
2011-07-15
Project End
2016-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
4
Fiscal Year
2014
Total Cost
$291,090
Indirect Cost
$103,290
Name
University of California San Diego
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Springer, Stevan A; Diaz, Sandra L; Gagneux, Pascal (2014) Parallel evolution of a self-signal: humans and new world monkeys independently lost the cell surface sugar Neu5Gc. Immunogenetics 66:671-4
Springer, Stevan A; Gagneux, Pascal (2013) Glycan evolution in response to collaboration, conflict, and constraint. J Biol Chem 288:6904-11
Varki, Ajit; Gagneux, Pascal (2012) Multifarious roles of sialic acids in immunity. Ann N Y Acad Sci 1253:16-36