Interplay between pleiotropy and secondary selection determines rise and fall of mutators in stress response

Dramatic rise of mutators has been found to accompany adaptation of bacteria in response to many kinds of stress. Two views on the evolutionary origin of this phenomenon emerged: the pleiotropic hypothesis positing that it is a byproduct of environmental stress or other specific stress response mechanisms and the second order selection which states that mutators hitchhike to fixation with unrelated beneficial alleles. Conventional population genetics models could not fully resolve this controversy because they are based on certain assumptions about fitness landscape. Here we address this problem using a microscopic multiscale model, which couples physically realistic molecular descriptions of proteins and their interactions with population genetics of carrier organisms without assuming any a priori fitness landscape. We found that both pleiotropy and second order selection play a crucial role at different stages of adaptation: the supply of mutators is provided through destabilization of error correction complexes or fluctuations of production levels of prototypic mismatch repair proteins (pleiotropic effects), while rise and fixation of mutators occur when there is a sufficient supply of beneficial mutations in replication-controlling genes. This general mechanism assures a robust and reliable adaptation of organisms to unforeseen challenges. This study highlights physical principles underlying physical biological mechanisms of stress response and adaptation

Adapting the engine to the fuel: mutator populations can reduce the mutational load by reorganizing their genome structure

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Bringing Molecules Back into Molecular Evolution

Much molecular-evolution research is concerned with sequence analysis. Yet these sequences represent real, three-dimensional molecules with complex structure and function. Here I highlight a growing trend in the field to incorporate molecular structure and function into computational molecular-evolution work. I consider three focus areas: reconstruction and analysis of past evolutionary events, such as phylogenetic inference or methods to infer selection pressures; development of toy models and simulations to identify fundamental principles of molecular evolution; and atom-level, highly realistic computational modeling of molecular structure and function aimed at making predictions about possible future evolutionary events

The Advantage of Arriving First: Characteristic Times in Finite Size Populations of Error-Prone Replicators

We study the evolution of a finite size population formed by mutationally isolated lineages of error-prone replicators in a two-peak fitness landscape. Computer simulations are performed to gain a stochastic description of the system dynamics. More specifically, for different population sizes, we compute the probability of each lineage being selected in terms of their mutation rates and the amplification factors of the fittest phenotypes. We interpret the results as the compromise between the characteristic time a lineage takes to reach its fittest phenotype by crossing the neutral valley and the selective value of the sequences that form the lineages. A main conclusion is drawn: for finite population sizes, the survival probability of the lineage that arrives first to the fittest phenotype rises significantly

Breaking the weakest link: Evolution and ecology of antibiotic tolerance in cross-feeding bacterial communities

University of Minnesota Ph.D. dissertation.May 2019. Major: Microbiology, Immunology and Cancer Biology. Advisor: William Harcombe. 1 computer file (PDF); ix, 231 pages.Microbes frequently rely on metabolites excreted by other bacterial species, but little is known about how this cross-feeding influences the effect of antibiotics. We hypothesized that when species rely on each other for essential metabolites, the minimum inhibitory concentration (MIC) for all species will drop to that of the "weakest link"— the species least resistant in monoculture. We tested this hypothesis in an obligate cross-feeding system that was engineered between Escherichia coli, Salmonella enterica, and Methylobacterium extorquens. The effect of tetracycline and ampicillin were tested on both liquid and solid media. In all cases, resistant species were inhibited at significantly lower antibiotic concentrations in the cross-feeding community than in monoculture or a competitive community. However, deviation from the "weakest link" hypothesis was also observed in cross-feeding communities apparently as a result of changes in the timing of growth and cross-protection. Comparable results were also observed in a clinically relevant system involving facultative cross-feeding between Pseudomonas aeruginosa and an anaerobic consortium found in the lungs of cystic fibrosis patients. P. aeruginosa was inhibited by lower concentrations of ampicillin when cross-feeding than when grown in isolation. These results suggest that cross-feeding significantly alters tolerance to antibiotics in a variety of systems

Evolution in Space and Time: The Second Synthesis between Ecology, Evolutionary Biology, and the Philosophy of Biology

Es un hecho sorprendente que para la mayor parte de la biología evolutiva, rara vez hemos estudiado cómo se desarrolla típicamente la evolución en la naturaleza, en ambientes ecológicos cambiantes, en el espacio y el tiempo. Si bien la ecología desempeñó un papel importante en la eventual aceptación del punto de vista de la evolución genética de poblaciones en la síntesis moderna (alrededor de 1918-1950), desempeñó un papel menor en el desarrollo de la teoría evolutiva hasta la década de 1980, cuando comenzamos a estudiar sistemáticamente la teoría de la evolución. dinámica evolutiva de las poblaciones naturales en el espacio y el tiempo. Como resultado, la teoría evolutiva se construyó inicialmente en un vacío abstracto que no era representativo de la evolución en la naturaleza. Desde entonces, la biología evolutiva ha sufrido un cambio profundo en el pensamiento sobre la evolución impulsado por su reciente síntesis con la ecología. El conocimiento ecológico ha revelado cómo la selección natural varía en fuerza, dirección, forma y, más sorprendentemente, el nivel de organización biológica, todo dependiendo de las condiciones ecológicas. El novedoso concepto de capacidad de evolución juega un papel organizador a lo largo de esta tesis, ya que su reciente ascenso a la popularidad proporciona algunas de las mejores pruebas de cómo los biólogos han descuidado persistentemente la evolución en el espacio y el tiempo. La capacidad de evolución, como una adaptación emergente de las poblaciones cuya manifestación es impulsada por cambios ecológicos, finalmente se reveló dentro de una biología evolutiva que abarcaba la evolución en el espacio y el tiempo. Cómo un proceso tan central como la capacidad de evolución puede pasar relativamente desapercibido en la teoría hasta tiempos recientes destaca las áreas de la biología que justifican un progreso urgente, así como la ciencia en general. En esta tesis, ofrezco una reconstrucción histórica de las fuerzas filosóficas, tecnológicas y naturales que condujeron a la Segunda Síntesis de la biología, con la esperanza de reconocer los avances significativos que han alcanzado a la biología en la última generación. Luego ofrezco mis recomendaciones normativas, prescribiendo una teoría pluralista de la selección natural que puede explicar fenómenos emergentes complejos (como la capacidad de evolución) para finalmente resolver la paradoja de la variación adaptativa. Lo hago construyendo un puente entre la gran biología y la historia/filosofía de la biología, enfocando los principales logros de los historiadores y filósofos durante la última generación y cómo estos avances pueden modernizar el pensamiento biológico.It is a surprising fact that for the majority of evolutionary biology, we have rarely studied how evolution typically unfolds in nature, in changing ecological environments, over space and time. While ecology played a major role in the eventual acceptance of the population genetic viewpoint of evolution in the Modern Synthesis (circa 1918-1950), it held a lesser role in the development of evolutionary theory until the 1980s, when we began to systematically study the evolutionary dynamics of natural populations in space and time. As a result, evolutionary theory was initially constructed in an abstract vacuum that was unrepresentative of evolution in nature.Evolutionary biology has since undergone a profound shift in thinking about evolution spurred by its recent synthesis with ecology. Ecological insight has revealed how natural selection varies in strength, direction, form, and more surprisingly level of biological organization, all dependent on ecological conditions. The novel concept of evolvability plays an organizing role throughout this thesis, since its recent rise to popularity provides some of the best evidence of how biologists have persistently neglected evolution in space and time. Evolvability, as an emergent adaptation of populations whose manifestation is prompted by ecological changes, thus finally became revealed within an evolutionary biology that embraced evolution in space and time. How such a central process as evolvability can go relatively unnoticed in theory until recent times thus highlights the areas of biology that warrant urgent progress, as well as science more generally. In this thesis, I offer an historical reconstruction of the philosophical, technological, and natural forces that led to the Second Synthesis of biology, in hopes of recognizing the significant advancements that have overtaken biology in the past generation. I then offer my normative recommendations, prescribing a pluralistic theory of natural selection that can explain complex emergent phenomena (like evolvability) to finally resolve the paradox of adaptive variation. I do so by building a bridge between greater biology and the history/philosophy of biology, bringing into focus the primary achievements made by historians and philosophers over the past generation and how these advancements can modernize biological thought