Microbial communities drive important biogeochemical cycles, from the ocean to the soil to the human gut. High rates of cell turnover provide these ecosystems with an enormous potential for rapid evolutionary change: billions of new mutations are produced within each of our gut microbiota every day. We and others have recently shown that these genetic changes can sweep through resident populations of gut bacteria on timescales ranging from a few months to a few days. This rapid pace of evolution is hypothesized to have important practical consequences, from the spread of antibiotic resistance mutations to the success of fecal microbiome transplants and other personalized therapies. Despite the potential importance of these effects, we currently know very little about the evolutionary forces that operate within complex communities like the gut microbiota, or how they influence (or are influenced by) the composition of the surrounding community. A central challenge is that we lack a population genetic framework for predicting how mutations spread in communities with large numbers of ecologically interacting strains. This limits our ability to predict how microbiota will evolve in response to environmental perturbations such as drugs or diet, or to interpret functional changes that we observe in these communities over time. My lab aims to address this gap in our understanding by combining biophysical and population genetic modeling with the development of computational tools for measuring in situ evolution in both natural and synthetic gut communities. Our long-term goal is to decipher the population genetic “rules” that govern the short-term evolution of the gut microbiota, and to use these insights to guide future experimental and therapeutic efforts. In the next five years, we will pursue this goal through a multi-pronged strategy: First, we will develop new time-series methods for analyzing the trajectories of linked mutations in longitudinally sampled human gut metagenomes. These methods will allow us to address key open questions about the strength and duration of natural selection on sweeping genetic variants, and whether they are correlated with broader shifts in taxonomic or functional composition. Second, we will develop new methods for leveraging widely deployed transposon insertion libraries to measure the rates and fitness effects of spontaneous beneficial mutations in vivo in ex-germ-free mice, and we will quantify for the first time how this landscape varies across species, diets, and community contexts. Finally, to interpret these new data and to craft driving hypotheses, we will develop a mechanistic modeling framework for predicting how ecological diversity influences short-term evolutionary dynamics in highly diverse communities that compete for common metabolites. Together, this work will provide unprecedented insight into the short-term evolution of our gut microbiota, and will constitute a crucial step toward the development of...