Determining the fitness of specific microbial genotypes has extensive application in microbial genetics, evolution, and biotechnology. While estimates from growth curves are simple and allow high throughput, they are inaccurate and do not account for interactions between costs and benefits accruing over different parts of a growth cycle. For this reason, pairwise competition experiments are the current “gold standard” for accurate estimation of fitness. However, competition experiments require distinct markers, making them difficult to perform between isolates derived from a common ancestor or between isolates of nonmodel organisms. In addition, competition experiments require that competing strains be grown in the same environment, so they cannot be used to infer the fitness consequence of different environmental perturbations on the same genotype. Finally, competition experiments typically consider only the end-points of a period of competition so that they do not readily provide information on the growth differences that underlie competitive ability. Here, we describe a computational approach for predicting density-dependent microbial growth in a mixed culture utilizing data from monoculture and mixed-culture growth curves. We validate this approach using 2 different experiments with Escherichia coli and demonstrate its application for estimating relative fitness. Our approach provides an effective way to predict growth and infer relative fitness in mixed cultures.

Numerous empirical studies show that stress of various kinds induces a state of hypermutation in bacteria via multiple mechanisms, but theoretical treatment of this intriguing phenomenon is lacking. We used deterministic and stochastic models to study the evolution of stress-induced hypermutation in infinite and finite-size populations of bacteria undergoing selection, mutation, and random genetic drift in constant environments and in changing ones. Our results suggest that if beneficial mutations occur, even rarely, then stress-induced hypermutation is advantageous for bacteria at both the individual and the population levels and that it is likely to evolve in populations of bacteria in a wide range of conditions because it is favored by selection. These results imply that mutations are not, as the current view holds, uniformly distributed in populations, but rather that mutations are more common in stressed individuals and populations. Because mutation is the raw material of evolution, these results have a profound impact on broad aspects of evolution and biology. K E Y W O R D S :Mathematical models/simulations, population genetics, phenotypic plasticity, mutagenesis, genetic variation, evolvability.Hypermutation-an increase in the genomic mutation rate-is a surprising phenomenon, as most mutations are deleterious, so mutators (alleles that induce hypermutation) will usually be surrounded by poor genetic backgrounds and experience a decrease in fitness (Sturtevant 1937;Kimura and Maruyama 1966;Funchain et al. 2000;Montanari et al. 2007). Consequently, selection against mutator alleles should drive the mutation rate to its lower limit (Kimura 1967;Tröbner and Piechocki 1984;Liberman and Feldman 1986;Drake 1991; but also see Dawson 1998;Johnson 1999;Lynch 2010). However, mutations can also help individuals escape stress. Theory (Kimura 1967;Leigh 1970Leigh , 1973Ishii et al. 1989;Sniegowski et al. 2000) and evolutionary experiments in vivo (Gibson et al. 1970;Sniegowski et al. 1997;Oliver 2000;Giraud et al. 2001;Loh et al. 2010;Gentile et al. 2011) and in silico (Taddei et al. 1997;Tenaillon et al. 1999;Heo and Shakhnovich 2010) show that in maladapted populations and in changing environments, mutators can increase in frequency when they "hitchhike" with the beneficial mutations they generate, and therefore the mutation rate evolves to a significantly higher level than the one predicted in well-adapted populations at a mutation-selection balance. Nevertheless, after adaptation is complete and the balance is restored, mutators decrease in frequency due to accumulation of deleterious mutations (Taddei et al. 1997;Sniegowski et al. 1997;Denamur and Matic 2006), thereby restoring the population-wide mutation rate to a lower level.Most models of the evolution of the mutation rate consider only mutators that constitutively increase mutation rates (reviewed in [Sniegowski et al. 2000], but see below for exceptions). Here we focus on stress-induced mutators (SIMs)-alleles that increase the mutation rate in response to...

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Because mutations are mostly deleterious, mutation rates should be reduced by natural selection. However, mutations also provide the raw material for adaptation. Therefore, evolutionary theory suggests that the mutation rate must balance between adaptability-the ability to adapt-and adaptedness-the ability to remain adapted. We model an asexual population crossing a fitness valley and analyse the rate of complex adaptation with and without stress-induced mutagenesis (SIM)-the increase of mutation rates in response to stress or maladaptation. We show that SIM increases the rate of complex adaptation without reducing the population mean fitness, thus breaking the evolutionary trade-off between adaptability and adaptedness. Our theoretical results support the hypothesis that SIM promotes adaptation and provide quantitative predictions of the rate of complex adaptation with different mutational strategies.

Changes in ploidy are relatively rare, but play important roles in the development of cancer and the acquisition of long-term adaptations. Genome duplications occur across the tree of life, and can alter the rate of adaptive evolution. Moreover, by allowing the subsequent loss of individual chromosomes and the accumulation of mutations, changes in ploidy can promote genomic instability and/or adaptation. Although many studies have been published in the last years about changes in chromosome number and their evolutionary consequences, tracking and measuring the rate of whole-genome duplications have been extremely challenging. We have systematically studied the appearance of diploid cells among haploid yeast cultures evolving for over 100 generations in different media. We find that spontaneous diploidization is a relatively common event, which is usually selected against, but under certain stressful conditions may become advantageous. Furthermore, we were able to detect and distinguish between two different mechanisms of diploidization, one that requires whole-genome duplication (endoreduplication) and a second that involves mating-type switching despite the use of heterothallic strains. Our results have important implications for our understanding of evolution and adaptation in fungal pathogens and the development of cancer, and for the use of yeast cells in biotechnological applications.