arXiv subjects

Kirill S. Korolev

Publications and source records attributed to Kirill S. Korolev.

23 records · Page 2Linked to original sources

arXiv2014

A tug-of-war between driver and passenger mutations in cancer and other adaptive processes

Cancer progression is an example of a rapid adaptive process where evolving new traits is essential for survival and requires a high mutation rate. Precancerous cells acquire a few key mutations that drive rapid population growth and carcinogenesis. Cancer genomics demonstrates that these few 'driver' mutations occur alongside thousands of random 'passenger' mutations-a natural consequence of cancer's elevated mutation rate. Some passengers can be deleterious to cancer cells, yet have been largely ignored in cancer research. In population genetics, however, the accumulation of mildly deleterious mutations has been shown to cause population meltdown. Here we develop a stochastic population model where beneficial drivers engage in a tug-of-war with frequent mildly deleterious passengers. These passengers present a barrier to cancer progression that is described by a critical population size, below which most lesions fail to progress, and a critical mutation rate, above which cancers meltdown. We find support for the model in cancer age-incidence and cancer genomics data that also allow us to estimate the fitness advantage of drivers and fitness costs of passengers. We identify two regimes of adaptive evolutionary dynamics and use these regimes to rationalize successes and failures of different treatment strategies. We find that a tumor's load of deleterious passengers can explain previously paradoxical treatment outcomes and suggest that it could potentially serve as a biomarker of response to mutagenic therapies. Collective deleterious effect of passengers is currently an unexploited therapeutic target. We discuss how their effects might be exacerbated by both current and future therapies.

q-bio.PE↗

arXiv2014

Genetic drift suppresses bacterial conjugation in spatially structured populations

Conjugation is the primary mechanism of horizontal gene transfer that spreads antibiotic resistance among bacteria. Although conjugation normally occurs in surface-associated growth (e.g., biofilms), it has been traditionally studied in well-mixed liquid cultures lacking spatial structure, which is known to affect many evolutionary and ecological processes. Here we visualize spatial patterns of gene transfer mediated by F plasmid conjugation in a colony of Escherichia coli growing on solid agar, and we develop a quantitative understanding by spatial extension of traditional mass-action models. We found that spatial structure suppresses conjugation in surface-associated growth because strong genetic drift leads to spatial isolation of donor and recipient cells, restricting conjugation to rare boundaries between donor and recipient strains. These results suggest that ecological strategies, such as enforcement of spatial structure and enhancement of genetic drift, could complement molecular strategies in slowing the spread of antibiotic resistance genes.

q-bio.QM↗

arXiv2013

The fate of cooperation during range expansions

Cooperation is beneficial for the species as a whole, but, at the level of an individual, defection pays off. Natural selection is then expected to favor defectors and eliminate cooperation. This prediction is in stark contrast with the abundance of cooperation at all levels of biological systems: from cells cooperating to form a biofilm or an organism to ecosystems and human societies. Several explanations have been proposed to resolve this paradox, including direct reciprocity, kin, and group selection. However, our work builds upon an observation that selection on cooperators might depend both on their relative frequency in the population and on the population density. We find that this feedback between the population and evolutionary dynamics can substantially increase the frequency of cooperators at the front of an expanding population, and can even lead to a splitting of cooperators from defectors. After splitting, only cooperators colonize new territories, while defectors slowly invade them from behind. Since range expansions are very common in nature, our work provides a new explanation of the maintenance of cooperation.

q-bio.PE↗

arXiv2013

Radial Domany-Kinzel Models with Mutation and Selection

We study the effect of spatial structure, genetic drift, mutation, and selective pressure on the evolutionary dynamics in a simplified model of asexual organisms colonizing a new territory. Under an appropriate coarse-graining, the evolutionary dynamics is related to the directed percolation processes that arise in voter models, the Domany-Kinzel (DK) model, contact process, etc. We explore the differences between linear (flat front) expansions and the much less familiar radial (curved front) range expansions. For the radial expansion, we develop a generalized, off-lattice DK model that minimizes otherwise persistent lattice artifacts. With both simulations and analytical techniques, we study the survival probability of advantageous mutants, the spatial correlations between domains of neutral strains, and the dynamics of populations with deleterious mutations. "Inflation" at the frontier leads to striking differences between radial and linear expansions. For a colony with initial radius $R_0$ expanding at velocity $v$, significant genetic demixing, caused by local genetic drift, only occurs up to a finite time $t^* = R_0/v$, after which portions of the colony become causally disconnected due to the inflating perimeter of the expanding front. As a result, the effect of a selective advantage is amplified relative to genetic drift, increasing the survival probability of advantageous mutants. Inflation also modifies the underlying directed percolation transition, introducing novel scaling functions and modifications similar to a finite size effect. Finally, we consider radial range expansions with deflating perimeters, as might arise from colonization initiated along the shores of an island.

cond-mat.stat-mech↗

arXiv2011

A Quantitative Test of Population Genetics Using Spatio-Genetic Patterns in Bacterial Colonies

It is widely accepted that population genetics theory is the cornerstone of evolutionary analyses. Empirical tests of the theory, however, are challenging because of the complex relationships between space, dispersal, and evolution. Critically, we lack quantitative validation of the spatial models of population genetics. Here we combine analytics, on and off-lattice simulations, and experiments with bacteria to perform quantitative tests of the theory. We study two bacterial species, the gut microbe Escherichia coli and the opportunistic pathogen Pseudomonas aeruginosa, and show that spatio-genetic patterns in colony biofilms of both species are accurately described by an extension of the one-dimensional stepping-stone model. We use one empirical measure, genetic diversity at the colony periphery, to parameterize our models and show that we can then accurately predict another key variable: the degree of short-range cell migration along an edge. Moreover, the model allows us to estimate other key parameters including effective population size (density) at the expansion frontier. While our experimental system is a simplification of natural microbial community, we argue it is a proof of principle that the spatial models of population genetics can quantitatively capture organismal evolution.

q-bio.PE↗