Co-evolutionary Genetics of Host-Parasite Interactions

ABSTRACTThere is a fundamental gap in our understanding of how host-parasite interactions maintain genetic variationwithin species, including humans. Interactions between humans and long-lived eukaryotic parasites may be themost important agents of natural selection across the human genome and may be responsible for themaintenance of genome-wide functional variation within humans (balancing selection). However, linking theagents of balancing selection with their genomic targets remains a major challenge. Continued existence of thisgap is an important problem because until it is filled there is a limited understanding of the mechanismsresponsible for potential maintenance of genetic variation within species. The long-term goal of the investigator'slaboratory is to understand the genetic basis of host-parasite adaptations. The objective over the next five yearsis to identify agents and targets of selection arising from host-parasite interactions. The central hypothesis is thathost-parasite interactions maintain genetic variation within species. The rationale is that transitions to parasitismon the genetic model plant Arabidopsis thaliana has occurred within the genetic model Drosophila lineage,allowing in-depth study. Guided by strong preliminary data, this hypothesis will be tested by pursuing these twooverarching research questions: 1). Identify molecular genetic changes that underpin the transition to parasitismin a fly, 2) Determine if host-parasite interactions lead to the maintenance of genome-wide variation in flies andplants. Under the first question, the genomic architecture underlying the evolutionary transition to parasitism willbe identified in the Drosophilidae. Next-generation sequencing and comparative genomics studies will identifygenes necessary for the evolution parasitism from free living fruit flies. Preliminary studies show that thisapproach holds great promise for finding ?parasite-genes? and that the approach is feasible in the applicants'hands. Under the second question, populations of parasitic flies will be evolved with single or mixed hostgenotypes that vary in resistance traits. An evolve-and-resequence approach will test if genome-wide variationis maintained by balancing selection in flies. In the plants, a genome-wide association (GWAS) study approachwill be used to identify loci associated with resistance to flies. The applicants have shown that these approacheswill identify targets of balancing selection. Under both aims, functional studies using in vitro and in vivoapproaches will be used to link evolutionary patterns with functional phenotypes. The proposed research issignificant because it will be the first study in a continuum of research expected to lead to an integrativeunderstanding of the role that host-parasite interactions play in shaping patterns of genome evolution. There ispromise that general principles will be discovered relating to the role host-parasite interactions play in themaintenance of genetic variation. The research proposed is innovative because it represents a departure fromcurrent approaches to studies on the evolution of host-parasite interactions, which are restricted to microbes ornon-model systems.