"A fundamental question in biology is how multicellular organisms distinguish self and non-self. The requirement to specifically recognize only foreign cells and molecules constrains the diversification of the immune system, resulting in conflicts between effective detection of enemies, adaptive changes in the cellular machinery and mating with divergent genotypes from the same species. In plants, there is generally a trade-off between immunity and growth, and immune system activation is often associated with impaired development. There are many examples of autoimmunity in hybrids, caused by a gene product from one parent erroneously interpreting a gene product from the other parent as foreign. This is not surprising, given the extraordinary diversity of many immune genes. On the other hand, hybrid vigor, or heterosis, is commonly observed in F1 progeny from two inbred parents, and this is widely exploited in breeding. Thus, it is also of practical importance to understand how outcrossing affects the plant immune system. We hypothesize that overt hybrid autoimmunity represents only the tip of the iceberg, and that there are many more subtle non-additive genetic interactions that affect both the plant immune system and growth. We therefore propose a comprehensive research program to dissect epistatic interactions with effects on plant growth and health. Specifically, we will conduct genomics-enabled, systematic forward genetic studies with natural genotypes of the model plant Arabidopsis thaliana and its outcrossing sister species A. lyrata. This will be complemented by experiments that will link diversity of microbial communities with that of the immune system in natural plant populations. The systematic understanding of forces that shape the distribution of immune gene alleles in the wild will have important implications for engineering disease resistance in crops, by helping to chose the best ensembles of resistance genes."