Genetic comparisons of interleukin-17 reveal a framework for complex signaling evolution

Area of Science:

• Immunology and Evolutionary Biology
• Cytokine Signaling Networks
• Genomics and Bioinformatics

Background:

• The interleukin-17 (IL-17) cytokine family plays crucial roles in immune responses, particularly at mucosal surfaces.
• Complex signaling and pathway crosstalk obscure the full biological potential of IL-17 cytokines.
• Genetic variation in IL-17 genes suggests broader roles beyond immunity.

Purpose of the Study:

• To resolve phylogenetic relationships among IL-17 ligands and receptors using integrated evolutionary analyses.
• To uncover hidden signaling interactions within and beyond the IL-17 family.
• To understand the evolutionary basis for the diversification and functional expansion of IL-17 biology.

Main Methods:

• Comparative genomics to analyze evolutionary relationships.
• Evolutionary Rate Covariation (ERC) analysis to identify co-evolving genes and infer interactions.
• Analysis of natural selection signatures to detect functional adaptations.

Main Results:

• Identified putative ligand-receptor interactions for IL-17D, IL-17RC, and IL-17REL (potentially IL-17B).
• Discovered co-evolutionary signals linking IL-17 family genes with neurodevelopmental and growth factor genes.
• Found signatures of positive selection in the IL-17E/IL-17RB pathway, suggesting functional importance of specific domains.

Conclusions:

• IL-17 biology is shaped by lineage-specific selective pressures, influencing both immune and non-immune functions.
• An evolutionary framework is essential for understanding the diversification and expanded roles of cytokine families like IL-17.
• The study proposes a model for cytokine family evolution, highlighting immune and neuromodulatory connections.