TY - JOUR T1 - Inferring Fitness Landscapes and Selection on Phenotypic States from Single-Cell Genealogical Data JF - bioRxiv DO - 10.1101/069260 SP - 069260 AU - Takashi Nozoe AU - Edo Kussell AU - Yuichi Wakamoto Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/08/11/069260.abstract N2 - Recent advances in single-cell time-lapse microscopy have revealed non-genetic heterogeneity and temporal fluctuations of cellular phenotypes. While different phenotypic traits such as abundance of growth-related proteins in single cells may have differential effects on the reproductive success of cells, rigorous experimental quantification of this process has remained elusive due to the complexity of single cell physiology within the context of a proliferating population. We introduce and apply a practical empirical method to quantify the fitness landscapes of arbitrary phenotypic traits, using genealogical data in the form of population lineage trees which can include phenotypic data of various kinds. Our inference methodology for fitness landscapes determines how reproductivity is correlated to cellular phenotypes, and provides a natural generalization of bulk growth rate measures for single-cell histories. Using this technique, we quantify the strength of selection acting on different cellular phenotypic traits within populations, which allows us to determine whether a population responds to environmental perturbations by physiological changes in single cells, through population-level selection, or by a mixture of single-cell and population-level processes. By applying these methods to single-cell time-lapse data of growing bacterial populations that express a resistance-conferring protein under antibiotic stress, we show that selection acts on the resistance protein's production rate rather than on its concentration. Our work provides a unified and practical framework for quantitative measurements of fitness landscapes and selection strength for any statistical quantities definable on lineages, and thus elucidates the adaptive significance of phenotypic states in time series data. The method is applicable in diverse fields, from single cell biology to stem cell differentiation and viral evolution. ER -