Co-evolutionary Genetics of Host-Parasite Interactions

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PROJECT SUMMARY/ABSTRACT Long-lived and directly transmitted parasitic animals are among the most potent agents of natural selection known from human populations. Yet, there is a fundamental gap in our knowledge of the co-evolutionary mechanisms producing these patterns. This is, in part, because host-parasite interactions are notoriously difficult to study. Until remedied, progress toward understanding an elusive process that has profoundly shaped our biology is impeded. New model host-parasite systems are therefore critical for advancing the field. The long- term goal of our research is to develop and leverage new model host-parasite models for mechanistic studies of co-evolution. Over the past nearly four years of ESI MIRA support, we have made considerable progress toward dissecting the genomic basis of the evolution of parasitism and host specialization, and in determining the extent to which co-evolutionary interactions maintain genome-wide variation in host and parasite populations. The rationale is that parasitism evolved repeatedly in the lineage that includes the genetic model animal Drosophila melanogaster. Conveniently, these parasitic flies complete development in the genetic model plant Arabidopsis thaliana, facilitating in-depth mechanistic study. In addition to addressing our core objectives, the MIRA’s transformative flexibility allowed pursuit of risky new leads, resulting in a number of fundamental discoveries of broad interest to biologists. This included characterization of the first odorant receptors specific to volatile mustard oil toxins (isothiocyanates or ITCs) known in animals, the first use of CRISPR-Cas9 gene editing technology to fully retrace an adaptive walk in an animal (the mutations sufficient for resistance to cardiac glycoside toxins in monarch butterflies) using an in vivo knock-in approach, and identification of the first genes from animals known to encode cytolethal distending toxin (CDT) subunit B proteins, which is our model for the evolution of toxins used by human immune cells. These discoveries now form the basis of our proposed transition to EI MIRA support over the next five years. Our specific goal in the next phase of research is to identify the evolution and mechanistic bases of interactions between hosts and parasites that are mediated by three toxin classes: ITCs, cardiac glycosides, and CDTs. Three projects already underway that will address this goal are: (1) the evolution and mechanistic basis of toxin detection by parasites (ITCs), (2) the evolution and mechanistic basis of toxin resistance by parasites (ITCs and cardiac glycosides), and (3) the evolution and mechanistic basis of toxin co-option by the immune system (CTDs). This research is expected to inform our understanding of how toxins of