Biology subjects

Wodarz, D.

Publications and source records attributed to Wodarz, D..

5 recordsLinked to original sources

bioRxiv2018

Multiple infection of cells changes the dynamics of basic viral evolutionary processes

The infection of cells by multiple copies of a given virus can impact virus evolution in a variety of ways, for example through recombination and reassortment, or through intra-cellular interactions among the viruses in a cell, such as complementation or interference. Surprisingly, multiple infection of cells can also influence some of the most basic evolutionary processes, which has not been studied so far. Here, we use computational models to explore how infection multiplicity affects the fixation probability of mutants, the rate of mutant generation, and the timing of mutant invasion. This is investigated for neutral, disadvantageous, and advantageous mutants. Among the results, we note surprising growth dynamics for neutral and disadvantageous mutants: Starting from a single mutant-infected cell, an initial growth phase is observed which is more characteristic of an advantageous mutant and is not observed in the absence of multiple infection. Therefore, in the short term, multiple infection increases the chances that neutral or dis-advantageous mutants are present. Following this initial growth phase, however, the mutant dynamics enter a second phase that is driven by neutral drift or negative selection, respectively, which determines the long-term fixation probability of the mutant. Contrary to the short-term dynamics, the probability of mutant fixation, and thus existence, is lower in the presence compared to the absence of multiple infection, and declines with infection multiplicity. Hence, while infection multiplicity promotes mutant existence in the short term, it makes it less likely in the longer term. Understanding of these dynamics is essential for the investigation of more complex viral evolutionary processes, for which the dynamics described here for the basis. We demonstrate relevance to the interpretation of experiments in the context of published data on phage {varphi}6 evolution at low and high multiplicities.

evolutionary biology↗

bioRxiv2018

Virus and CTL dynamics in the extra-follicular and follicular tissue compartments in SIV-infected macaques

Data from SIV-infected macaques indicate that virus-specific cytotoxic T lymphocytes (CTL) are mostly present in the extrafollicular (EF) compartment of the lymphoid tissue, with reduced homing to the follicular (F) site. This contributes to the majority of the virus being present in the follicle and represents a barrier to virus control. Using mathematical models, we investigate these dynamics. Two models are analyzed. The first assumes that CTL can only become stimulated and expand in the extra-follicular compartment, with migration accounting for the presence of CTL in the follicle. In the second model, follicular CTL can also undergo antigen-induced expansion. Consistent with experimental data, both models predict increased virus compartmentalization in the presence of stronger CTL responses and lower virus loads, and a more pronounced rise of extra-follicular compared to follicular virus during CD8 cell depletion experiments. The models, however, differ in other aspects. The follicular expansion model results in dynamics that promote the clearance of productive infection in the extrafollicular site, with any productively infected cells found being the result of immigration from the follicle. This is not observed in the model without follicular CTL expansion. The models further predict different consequences of introducing engineered, follicular-homing CTL, which has been proposed as a therapeutic means to improve virus control. Without follicular CTL expansion, this is predicted to result in a reduction of virus load in both compartments. The follicular CTL expansion model, however, makes the counter-intuitive prediction that addition of F-homing CTL not only results in a reduction of follicular virus load, but also in an increase in extrafollicular virus replication. These predictions remain to be experimentally tested, which will be relevant for distinguishing between models and for understanding how therapeutic introduction of F-homing CTL might impact the overall dynamics of the infection.

systems biology↗

bioRxiv2017

The role of telomere shortening in carcinogenesis: A hybrid stochastic-deterministic approach

Genome instability is a characteristic of most cancers, contributing to the acquisition of genetic alterations that drive tumor progression. One important source of genome instability is linked to telomere dysfunction in cells with critically short telomeres that lack p53-mediated surveillance of genomic integrity. Here we research the probability that cancer emerges through an evolutionary pathway that includes a telomere-induced phase of genome instability. To implement our models we use a hybrid stochastic-deterministic approach, which allows us to perform large numbers of simulations using biologically realistic population sizes and mutation rates, circumventing the traditional limitations of fully stochastic algorithms. The hybrid methodology should be easily adaptable to a wide range of evolutionary problems. In particular, we model telomere shortening and the acquisition of two mutations: Telomerase activation and p53 inactivation. We find that the death rate of unstable cells, and the number of cell divisions that p53 mutants can sustain beyond the normal senescence setpoint determine the likelihood that the first double mutant originates in a cell with telomere-induced instability. The model has applications to an influential telomerase-null mouse model and p16 silenced human cells. We end by discussing algorithmic performance and a measure for the accuracy of the hybrid approximation.

cancer biology↗

bioRxiv2017

Effect of cellular de-differentiation on the dynamics and evolution of tissue and tumor cells in mathematical models with feedback regulation

Tissues are maintained by adult stem cells that self-renew and also differentiate into functioning tissue cells. Homeostasis is achieved by a set of complex mechanisms that involve regulatory feedback loops. Similarly, tumors are believed to be maintained by a minority population of cancer stem cells, while the bulk of the tumor is made up of more differentiated cells, and there is indication that some of the feedback loops that operate in tissues continue to be functional in tumors. Mathematical models of such tissue hierarchies, including feedback loops, have been analyzed in a variety of different contexts. Apart from stem cells giving rise to differentiated cells, it has also been observed that more differentiated cells can de-differentiate into stem cells, both in healthy tissue and tumors, aspects of which have also been investigated mathematically. This paper analyses the effect of de-differentiation on the basic and evolutionary dynamics of cells in the context of tissue hierarchy models that include negative feedback regulation of the cell populations. The models predict that in the presence of dedifferentiation, the fixation probability of a neutral mutant is lower than in its absence. Therefore, if de-differentiation occurs, a mutant with identical parameters compared to the wild-type cell population behaves like a disadvantageous mutant. Similarly, the process of de-differentiation is found to lower the fixation probability of an advantageous mutant. These results indicate that the presence of de-differentiation can lower the rates of tumor initiation and progression in the context of the models considered here.

evolutionary biology↗

bioRxiv2017

Passenger mutations can accelerate tumor suppressor gene inactivation in cancer evolution

Carcinogenesis is an evolutionary process whereby cells accumulate multiple mutations. Besides the \"driver mutations\" that cause the disease, cells also accumulate a number of other mutations with seemingly no direct role in this evolutionary process. They are called passenger mutations. While it has been argued that passenger mutations render tumors more fragile due to reduced fitness, the role of passenger mutations remains understudied. Using evolutionary computational models, we demonstrate that in the context of tumor suppressor gene inactivation (and hence fitness valley crossing), the presence of passenger mutations can accelerate the rate of evolution by reducing overall population fitness and increasing the relative fitness of intermediate mutants in the fitness valley crossing pathway. Hence, the baseline rate of tumor suppressor gene inactivation might be faster than previously thought. Conceptually, parallels are found in the field of turbulence and pattern formation, where instabilities can be driven by perturbations that are damped (disadvantageous), but provide a richer set of pathways such that a system can achieve some desired goal more readily. This highlights, through a number of novel parallels, the relevance of physical sciences in oncology.

evolutionary biology↗