PROJECT SUMMARY Many species have evolved traits that are adaptive in specific environmental contexts but would be considered pathological in humans or in closely related lineages. In Antarctic fishes alone there has been an evolved loss of red blood cells (anemia), low skeletal density (osteopenia), accumulation of triglycerides (metabolic disease), loss of the glomerulus (kidney disease) and enlargement of the heart (cardiomegaly). How do these traits evolve, and how to species overcome the deleterious trade-offs associated with these phenotypic extremes? To complement traditional forward and population genetic approaches at identifying disease modifiers, my laboratory has been developing tools and resources for analysis of natural variation across species rich datasets. These tools allow us to track the patterns of protein coding and gene regulatory evolution across a phylogeny to assess the genomic and macroevolutionary trends that precede and follow specific instances of trait evolution. Over the next five years, we will apply these resources to focus on two main research areas: 1) identification of genetic mechanisms underlying the evolution and development of disease-relevant traits and 2) discovery of the molecular mechanisms underlying tissue plasticity in organs that experience seasonal atrophy and rejuvenation. My lab will focus on a suite of convergently evolved traits that have repeatedly appeared in taxonomically divergent fish lineages, including reduced skeletal density, increased corporeal lipid content, and the dynamic seasonal atrophy of the glomerulus in the kidney. To approach these questions, we will integrate comparative omic approaches in natural systems with the experimental modeling of our findings in the zebrafish. We seek to assess the fundamental genomic basis of trait evolution and disease resilience, including the impact of protein coding and gene regulatory variants, biased patterns of variation across the genome, contributions of gene flow, and the influence of historical contingency on trait evolution. Additionally, we will integrate comparative genomic analyses with case studies tissue plasticity at single cell resolution to isolate the molecular mechanisms by which tissue structure and function adapts to changes in the environment. Together, this research program will discover the phylogenomic origins of extreme traits, identify gene by environment interactions modifying trait presentation, will explore organismal resilience to pathology.