Stress Response Pathways and the Origins of Novelty: How Snakes Regenerate Organs and Regulate Venom

Abstract

Snakes have captured evolutionary biologists’ attention for decades as extreme examples of adaptive evolution models for studying how novel and extreme traits evolve in nature, but research has long overlooked or been unable to determine the molecular and genomic bases of these traits, and their underlying mechanisms. Here, I dissect the molecular mechanisms and associated signaling pathways underlying two such extreme traits – extreme intestinal regenerative capacity and the evolution of venom regulation – using functional genomics approaches to understand the conserved and non-canonical gene regulatory cascades that drives them. I first combined physiological data with RNA sequencing, proteomics, and phosphoproteomics to establish a model for the interaction of pathways that modulate regeneration in the boa constrictor intestine that identified the unexpected roles of stress response pathways. I then generated both tissue-level and single-nucleus RNA sequencing from Burmese python small intestine during regeneration to investigate early-stage and among-cell signaling that underlies regeneration, which highlights the central role of tissue heterogeneity and stress response pathways. Finally, I performed analyses of ATACseq, RNAseq, and single nucleus RNAseq data from prairie rattlesnake venom glands to understand the functional roles of stress response and other pathways that have been evolutionarily co-opted to regulate venom, and venom expression heterogeneity. Together, this work contributes new understanding of the importance of stress responses to the origins of novel and extreme traits in vertebrates.