Project Summary Infectious disease research has made it a priority to identify the genes that confer resistance to infectious disease agents. Pursuing these genes in a diversity of organisms, including humans, has revealed a fundamental obstacle: a gene may strongly predict parasite resistance in one environment but not others, or against one parasite strain but not others. This context-dependence might explain why genomic surveys have rarely been able to identify genes that consistently explain substantial variation in disease resistance in humans. To gain a general understanding of the genes that matter for parasite resistance, we must both control and account for the complexities of the natural environments in which hosts encounter their parasites. My parent award addresses this need by characterizing the genetic basis of parasite resistance across genetic and environmental contexts using diverse host and parasite genotypes sampled from nature. My lab group uses a powerful model system – the nematode Caenorhabditis elegans and its natural parasite the microscopiridia Nematocida parisii - that enables us to quickly and cheaply perform highly replicated experiments and genomic analyses to examine genetic variants across contexts. We apply high-throughput phenotyping, genome-wide association mapping, experimental evolution, and transgenic methods to 1) identify the loci that explain variation in parasite resistance in natural populations, 2) evaluate the impact of parasite genotype on the expression of genetic variation for parasite resistance, and 3) examine the sensitivity of resistance alleles to relevant environmental variation. The impact of my parent award rests fundamentally upon our ability to rapidly phenotype many genotypes, incorporating significant replication within and across contexts in conditions that minimize variation arising from non-focal factors. Therefore, we are requesting a supplement to this parent award to purchase an autosampler attachment for our large particle sorter that will increase the replication, accuracy, and repeatability of our high-throughput phenotyping efforts. This supplement will directly augment the impact of our ongoing projects on the scientific community, as well as provide long-term support to my research program and my research community.