E. coli is perhaps the most studied microorganism, with nearly 100,000 publicly available genome sequences. Analysis of these genomes shows excellent diversity within this species structured into very different sequence types. Most sequence types have global distributions but different associations with habitats and hosts. Comparisons seeking to understand the movement of antibiotic resistance in the local One Health context of clinical, animal, and environmental distributions show strong evidence for clonal (whole genome) human-to-human transmission but very little evidence for sharing E. coli clones between human, animal, and ecological habitats. These One Health studies do, however, uncover sporadic sharing of identical antibiotic and virulence genes and very rarely identical plasmids. This suggests that the mobility of both genes and MGEs (mostly plasmids) at the nested sub-genomic scale is unlinked from host chromosomes but likely driven by cell type abundance in different habitats. The next horizon of these studies is to establish predictive models for gene flow, including the biological barriers to transmission and coinfection of MGEs that might promote the transmission of plasmid-carrying genes. Graduate student Isaiah Goertz and Rachel Whitaker, in collaboration with Helen Nguyen at UIUC, propose a large genomic study to determine the plasmid distributions and colocalizations within and between E. coli host cells from populations collected longitudinally from wastewater samples over 20 months for COVID surveillance.