title: Determinants of Genetic Diversity of Spontaneous Drug Resistance in Bacteria.
abstract: Any pathogen population sufficiently large is expected to harbor spontaneous drug-resistant mutants, often responsible for disease relapse after antibiotic therapy. It is seldom appreciated, however, that while larger populations harbor more mutants, the abundance distribution of these mutants is expected to be markedly uneven. This is because a larger population size allows early mutants to expand for longer, exacerbating their predominance in the final mutant subpopulation. Here, we investigate the extent to which this reduction in evenness can constrain the genetic diversity of spontaneous drug resistance in bacteria. Combining theory and experiments, we show that even small variations in growth rate between resistant mutants and the wild type result in orders-of-magnitude differences in genetic diversity. Indeed, only a slight fitness advantage for the mutant is enough to keep diversity low and independent of population size. These results have important clinical implications. Genetic diversity at antibiotic resistance loci can determine a population's capacity to cope with future challenges (i.e., second-line therapy). We thus revealed an unanticipated way in which the fitness effects of antibiotic resistance can affect the evolvability of pathogens surviving a drug-induced bottleneck. This insight will assist in the fight against multidrug-resistant microbes, as well as contribute to theories aimed at predicting cancer evolution.
authors.affiliation: Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Cientffícas, 28049 Madrid, Spain Unité Mixte de Recherche 1137 (IAME-Institut National de la Santé et de la Recherche Médicale), 75018 Paris, France alejandro.couce@inserm.fr.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Couce
authors.affiliation: Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Cientffícas, 28049 Madrid, Spain Institut für Biologie, Freie Universität Berlin, 14195, Germany.
authors.forename: Alexandro
authors.initials: A
authors.lastname: Rodríguez-Rojas
authors.affiliation: Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Cientffícas, 28049 Madrid, Spain Instituto de Biomedicina de Sevilla, 41013, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Blázquez
mesh_terms: D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D005075:Biological Evolution; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008957:Models, Genetic; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics*
chemical_list: D000900:Anti-Bacterial Agents
keywords: antibiotic resistance cost; clonal heterogeneity; genetic diversity; mutation; population size