Evolution of gastrointestinal plasticity in the eyeless Mexican cavefish Misty R. Riddle (1), Fleur Damen (1), John N. Hutchinson (2), Sergey Naumenko (2), Clifford J. Tabin (1) 1. Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02115 2. Department of Biostatistics, The Harvard Chan School of Public Health, Boston, MA 02115 Animal diets vary widely in composition and seasonal availability. How evolution has modified the response of the gastrointestinal tract to nutritional stimuli to balance energy assimilation and expenditure is not well understood. The Mexican tetra, Astyanax mexicanus, is a species of small fish that consist of river-dwelling and eyeless cave-dwelling morphotypes that have adapted to dramatically different diets; surface fish consume plants and insects year-round while cavefish eat mostly bat guano and debris washed into caves during seasonal floods. Both morphotypes are easy to maintain in the laboratory and have a sequenced and annotated genome. Methods for investigating and manipulating gene function are also available for this species. We found that gastrointestinal plasticity has evolved in cavefish potentially as an adaptation to the fluctuating nutrient content in the cave. Under fed conditions, cavefish display more folds and greater proliferation in the intestinal epithelium compared to surface fish. When starved, gut proliferation decreases in the cavefish and increases in surface fish. These results suggest that cavefish may expand the absorptive surface area of the gut only when nutrients are available. Comparison of the surface fish and cavefish gut transcriptome revealed the most significantly differentially expressed genes are associated with gut development, pancreas development, lipid metabolism, and retinoic acid signaling. Analysis of allelic imbalance in surface/cave hybrids revealed that a combination of cis- and trans-regulatory changes underly evolution of gene expression in the cavefish gut. Utilizing cavefish as “natural mutants” will lead to a better understanding of how external and internal cues are integrated to regulate intestinal plasticity.