Collaborative Research: Understanding the molecular diversification of self recognition through ray-finned fish innate immune receptor families

The ability of an organism to recognize invading pathogens, infected cells, or cancerous cells and kill them without causing excessive damage to itself is essential for survival. From fish to frogs to humans, all of the ~60,000 vertebrate species on earth use sophisticated immune cells to 'inspect' every other cell in their body to determine if it is friend or foe. These immune cells possess a large number of protein receptors on their surface that work to maintain the peace. Many of these receptors are designed to recognize specific types of pathogens, forming a front line of defense. However, pathogens typically reproduce quickly, allowing them to evolve or change faster than most vertebrates and thereby develop ways to escape detection. In response, vertebrates have evolved a complex immune system that includes large groups of receptors that evolve faster than most other proteins and are specialized for anticipated as well as unanticipated pathogens. Fish represent half of all vertebrates and, as a group, are a great model for studying the genetic basis of these defenses. This project will use new and existing genomic data from numerous fish species to determine the origins of these receptors and study how these receptors have evolved to achieve the diversity observed today. Using fish as a model, this work will reveal fundamental aspects of immunity in all vertebrates. Data collected from this project will be incorporated into multiple new exhibits at the North Carolina Museum of Natural Sciences.

Ray-finned fish (Actinopterygii) constitute over half of the extant vertebrates on earth, making them a powerful system for understanding the genetic and functional evolution of immune genes. Fish not only share certain immune gene families with mammals, but also encode a number of highly diverse 'fish-specific' immune gene families. Understanding the factors that underlie the diversification of gene families involved in immunity is critical for explaining the origins and sub-/neo-functionalization of new genes and for understanding the molecular basis of pathogen recognition and resistance. In order to provide an in-depth understanding of the origins of vertebrate immune gene families and their diversification dynamics, this project will integrate a phylogenetic comparative framework with new and existing transcriptome and genomic sequence data from multiple ray-finned fish lineages to determine how genomic architecture impacts the rate and mechanism of gene family evolution. This project will also evaluate the interdependence between genetically encoded markers of self and their candidate receptors. In total, this project will illuminate the evolution of recognition mechanisms that delineate self from non-self in all ray-finned fish, and reveal novel insight into both conserved and divergent means of accomplishing this critical immune function. Finally, this project will enable the creation of media content and interactive exhibits at the North Carolina Museum of Natural Sciences including a virtual reality and augmented reality video-game that teaches visitors fundamental aspects of how immune systems function.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.