Session Q05: Ecological and Evolutionary Dynamics IV

Metabolic fitness landscapes predict the evolution of antibiotic resistance

Bacteria evolve resistance to antibiotics by a multitude of mechanisms. A central, yet unsolved question is how resistance evolution affects cell growth at different drug levels. Here, we develop a fitness model that predicts growth rates of common resistance mutants from their effects on cell metabolism. The model maps metabolic effects of resistance mutations in drug-free environments and under drug challenge; the resulting fitness trade-off defines a Pareto surface of resistance evolution. We predict evolutionary trajectories of growth rates and resistance levels, which characterize Pareto resistance mutations emerging at different drug dosages. We also predict the prevalent resistance mechanism depending on drug and nutrient levels: low-dosage drug defence is mounted by regulation, evolution of distinct metabolic sectors sets in at successive threshold dosages. Evolutionary resistance mechanisms include membrane permeability changes and drug target mutations. These predictions are confirmed by empirical growth inhibition curves and genomic data of Escherichia coli populations. Our results show that resistance evolution, by coupling major metabolic pathways, is strongly intertwined with systems biology and ecology of microbial populations.   

Noisy metabolism can drive the evolution of microbial cross-feeding

Cross-feeding, the exchange of nutrients between organisms, is ubiquitous in microbial communities. Despite its importance in natural and engineered microbial systems, our understanding of how cross-feeding arises is incomplete, with existing theories limited to specific scenarios. Here, we introduce a novel theory for the evolution of cross-feeding, which we term noise-averaging cooperation (NAC). NAC is based on the idea that, due to their small size, bacteria are prone to noisy regulation of metabolism which limits their growth rate. To compensate, related bacteria can share metabolites with each other to 'average out' noise and improve their collective growth. This metabolite sharing among kin then allows for the evolution of metabolic interdependencies via gene deletions (this can be viewed as a generalization of the Black Queen Hypothesis). We first characterize NAC in a simple model of cell metabolism, showing that metabolite leakage can in principle substantially increase growth rate in a community context. Next, we develop a generalized framework for estimating the potential benefits of NAC among real bacteria. Using single-cell protein abundance data, we predict that bacteria suffer from substantial noise-driven growth inefficiencies, and may therefore benefit from NAC.   

Emergent evolutionary forces in spatial models of luminal growth in the human gut microbiota

 The spatial organization of microbial communities can strongly influence their ecological and evolutionary dynamics. Previous work has shown that gut microbiota are structured over a range of length- and time-scales. Yet little is known about how this heterogeneity impacts the long-term genetic turnover of these communities. In this talk, we describe a mathematical framework which demonstrates how evolutionary forces emerge from simple models of growth in the intestinal lumen. Our model shows how fluid flow and nutrient availability combine to shape the frequencies of mutations in sequenced fecal samples, yielding quantitative estimates for the effective selection strengths, generation times, and rates of genetic drift. These results provide a starting point for understanding the evolution of the gut microbiota in its native context.   

Inheritance of broadcast enzymes enables high dispersal of chitin-associated marine bacteria

Insoluble in water, chitin, one of the most abundant biopolymers, sinks through the ocean and sediments as small particles termed ‘marine snow’. The biodegradation of these particles is central to the global carbon and nitrogen cycles. We studied the degradation of chitin by a marine bacterium of the Vibrio species. We found that two co-existing, exponentially growing sub-populations emerged: a minority attached to the particles and a dispersed planktonic majority. We demonstrated that while planktonic cells could not replicate, their increase was due to the detachment of the replicating cells resident on the particles. Proteomic analysis showed that chitin degrading enzymes were “broadcast” extra-cellularly by the entire population and accumulated on the particles. The resident minority thus “inherited” these enzymes, which enabled its fast replication, sustaining the overall growth of the population. This “inheritance” effect allows the level of chitinase synthesis to dictate the population growth rate, irrespective of the number of attached cells and thus of the dispersal rate. It provides a novel mechanism through which small growing colonies can be maintained on particles while the majority of the population is shed. Evolutionary rationales favoring the eager dispersal of cells from their sole nutrient source will be discussed.   

Effect of migration on Host-Parasitoid Outbreaks

Spatial coupling in dynamical systems undergoing a stable cycle is known to generate a myriad of phase locking behaviors. In the context of ecological populations, phase locking could have both beneficial and detrimental consequences. Synchronized populations are more prone to simultaneous extinction under severe external conditions, like weather, thus making it important to study the conditions leading to phase locking. Here, we introduce a simple discrete time model for a host-parasitoid system with spatial coupling. We explore how migration affects the dynamics of individual oscillators as well as phase locking patterns. Our model by design, has an inherent time lag between the onset and the effects of migration and thus could be relevant more generally in the field of spatially coupled dynamical systems with inherent time lag.   

Evolutionary Dynamics of Branching Cellular Populations

Branching cellular populations, such as the cells of developing kidney ducts, mammary glands, certain microbial colonies, and others, present a unique challenge for evolutionary dynamics: Each branching event increases the effective dividing population size, while branch terminations will prevent propagation of portions of the cellular population. In this work, we develop a basic theory of the evolutionary dynamics of branching populations with tip-driven growth. We compare the theory to simulations of branching tissue and show that branch bifurcations tend to enhance survival probabilities of strains within the population, independently of the details of the bifurcation process. Conversely, branch terminations lead to increased extinction. Our model predicts an optimal branch rate at which mutations arising within the population are more likely to survive as the population grows.   

Slow expanders invade by forming dented fronts in microbial colonies

Most organisms grow in space, whether they are viruses spreading within a host tissue or invasive species colonizing a new continent. Evolution typically selects for higher expansion rates during spatial growth, but it has been suggested that slower expanders can take over under certain conditions. Here, we report an experimental observation of such population dynamics. We demonstrate that the slower mutants win not only when the two types are intermixed at the front but also when they are spatially segregated into sectors. The latter was thought to be impossible because previous studies focused exclusively on the global competitions mediated by expansion velocities but overlooked the local competitions at sector boundaries. We developed a theory of sector geometry that accounts for both local and global competitions and describes all possible sector shapes. In particular, the theory predicted that a slower, but more competitive, mutant forms a dented V-shaped sector as it takes over the expansion front. Such sectors were indeed observed experimentally and their shapes matched up quantitatively with the theory. In simulations, we further explored several mechanism that could provide slow expanders with a local competitive advantage and showed that they are all well-described by our theory. Taken together, our results shed light on previously unexplored outcomes of spatial competition and establish a universal framework to understand evolutionary and ecological dynamics in expanding populations. We will also discuss how the invasion of slow expander may emerge from a microscopic model with frequency-dependent growth.   

Spatial structure alters the allele frequency spectrum produced by hitchhiking

The reduction of genetic diversity due to genetic hitchhiking is widely used to find past selective sweeps from sequencing data, but very little is known about how spatial structure affects hitchhiking. We use mathematical modeling and simulations to find the unfolded allele-frequency-spectrum (AFS) left by hitchhiking in the genomic region of a sweep in a population occupying a one-dimensional range. For such populations, sweeps spread as Fisher waves, rather than logistically. We find that this leaves a characteristic three-part AFS at loci very close to the swept locus. Very low frequencies are dominated by recent mutations that occurred after the sweep and are unaffected by hitchhiking. At moderately low frequencies, there is a transition zone primarily composed of alleles that briefly “surfed” on the wave of the sweep before falling out of the wave front, leaving a spectrum close to that expected in well-mixed populations. However, for moderate-to-high frequencies, there is a distinctive scaling regime of the AFS produced by alleles that drifted to fixation in the wavefront and then were carried throughout the population. For loci slightly farther away from the swept locus on the genome, recombination limits the lifetime of alleles in the wavefront and introduces a fourth scaling regime. We find that these signatures of space can be strong even in apparently well-mixed populations with negligible spatial genetic differentiation, suggesting that space frequently distorts the signatures of hitchhiking in nature.   

Validity of pioneer dominance in range expansions with long-range dispersal

The pioneers who seed distant satellite colonies can have a disproportionate impact on the evolution of species undergoing range expansions with long-range dispersal. Lattice-based models that focus on the pioneers find that population outcomes are closely tied to the "heaviness" of the tail of the dispersal distance distribution. We used continuous space, individual-based simulations to ascertain when it is valid to use such models. We find that they can capture the structure of range expansions in populations well outside their modeling assumptions, but they can miss important dynamics between coexisting or competing alleles when individuals share resources with many others. Our results highlight the predictive power of simple models of expanding populations and shine a light on where they fall short.   

Population-level properties from single-cell statistics

Thanks to recent advances in single-cell technology, models of bacterial growth, division, and cell-size regulation have become more accurate and more complex. The complexity in these models creates a challenge in understanding what aspects of single-cell statistics affect what properties of the populations. In this talk, I will show that under mild and sensible assumptions, models of growth and division have independent effects on the population dynamics: models of single-cell growth determine the population growth rate independent of the details of cell division, and models of division and cell-size regulation determine the population cell-size distribution independent of details of cellular growth.   

Phage-host dynamics during spatial expansions modulate the rate of genetic diversity loss.

During expansion of a population into a new habitat, individuals at the front have first access to resources and their offspring are more likely to remain at the front of the expansion. As a result, there is generally a rapid decrease in genetic diversity in the colonized region during range expansion. This effect, however, is attenuated in the case of density-dependent growth or dispersal, such as that which occurs in cooperative growth. Recent work reveals that in viral expansions across a host population, an effective density dependent dispersal emerges as an emergent property due the latent period during which viral particles are trapped in the host before cell lysis occurs.

We show that during viral expansions, this effective density dependent dispersal alters the shape of genetic drift, or random sampling of offspring, and subsequently the rate of loss of genetic diversity. Agent-based simulations and an accompanying perturbation analysis of a continuum model both show that the lysis time has a strong impact on the rate of genetic diversity loss. In addition, this rate can be parameterized as an effective population size of the population front, allowing for comparison to previous generic range expansion models, as well as experimental data in the future.   

Population genetics in microchannels

Spatial constraints such as rigid barriers affect the dynamics of cell populations, potentially altering the course of natural evolution. We investigate the population genetics of bacteria Escherichia coli proliferating in microchannels with open ends. We base our analysis on a population model in which reproducing cells push entire lanes of cells towards the open ends of the channel. The model predicts that diversity loss is exponentially fast along the axial direction of the microchannel and at a much slower pace in the transverse direction. These predictions are in quantitative agreement with our experiments. Our theory predicts that two neutral, fluorescently labeled E. coli strains should organize into a regular stripe pattern in the course of a few generations, as we experimentally confirm.  We also demonstrate that random mutations appearing in the middle of the channel and close to its walls are much more likely to reach fixation than those occurring elsewhere.   

Effect of environmental heterogeneity on mutation-selection balance during range expansions

While mutation-selection balance has been extensively studied in well-mixed environments and populations undergoing range expansions in uniform environments, little is known about the effects of environmental structure on the interplay between mutation and selection and on the evolutionary fate of a population.

We consider a system with mutation and selection where individuals with deleterious alleles have an advantage in isolated patches, but a disadvantage everywhere else.

Simulations and theoretical analysis highlight that the deleterious allele can fix at the population front even when the density of patches is below the one guaranteeing spread via percolation. We are able to predict this regime using least-time arguments for front propagation.

Our findings are an example of two sub-critical processes assisting each other to achieve super-criticality. From an applied perspective, it highlights the role of landscape structure during evolution, for example on the emergence of pesticide resistance.