SignificanceAll animals have associated microbial communities called microbiomes that influence the physiology and fitness of their host. It is unclear to what extent individual microbial species versus interactions between them influence the host. Here, we mapped all possible interactions between individual species of bacteria against Drosophila melanogaster fruit fly fitness traits. Our approach revealed that the same bacterial interactions that shape microbiome abundances also shape host fitness traits. The fitness traits of lifespan and fecundity showed a life history tradeoff, where equal total fitness can be gotten by either high fecundity over a short life or low fecundity over a long life. The microbiome interactions are as important as the individual species in shaping these fundamental aspects of fly physiology.

Darwinian fitness is a central concept in evolutionary biology. In practice, however, it is hardly possible to measure fitness for all genotypes in a natural population. Here, we present quantitative tools to make inferences about epistatic gene interactions when the fitness landscape is only incompletely determined due to imprecise measurements or missing observations. We demonstrate that genetic interactions can often be inferred from fitness rank orders, where all genotypes are ordered according to fitness, and even from partial fitness orders. We provide a complete characterization of rank orders that imply higher order epistasis. Our theory applies to all common types of gene interactions and facilitates comprehensive investigations of diverse genetic interactions. We analyzed various genetic systems comprising HIV-1, the malaria-causing parasite Plasmodium vivax, the fungus Aspergillus niger, and the TEM-family of β-lactamase associated with antibiotic resistance. For all systems, our approach revealed higher order interactions among mutations.