Conflicts with diarrheal pathogens trigger rapid evolution of an intestinal signaling axis

Clayton M. Carey; Sarah E. Apple; Zoe A. Hilbert; Michael S. Kay; Nels C. Elde

In order to regulate intestinal water levels GC-C must interact with endogenous guanylin and uroguanylin peptides 8 . To determine how rapid divergence of GC-C might influence the evolution of its cognate ligands, we next examined diversity in uroguanylin, the more potent of the two peptides 22 . Sequence comparisons revealed that secreted uroguanylin peptides are generally highly conserved across mammals with little variation occurring outside the most N-and C-terminal residues ( Figure S4 ). In bats, however, uroguanylin sequences are highly variable, with frequent mutations occurring in core residues of the peptide ( Figure 4A ). Given the variability in sequence and toxin interactions we observed in bat GC-C, we hypothesized that sequence variation in bat uroguanylin might reflect compensatory mutations required to maintain affinity for its rapidly evolving receptor.