Complex role of space in the crossing of fitness valleys by asexual populations

Komarova, Natalia L.; Shahriyari, Leili; Wodarz, Dominik

doi:10.1098/rsif.2014.0014

Cited by 40 publications

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“…(Interestingly, in the case of slightly advantageous intermediate mutants, the result is the opposite, and spatial interactions tend to slow down the production of m-hit mutants; see ref. 6 for further details. )…”

Section: Resultsmentioning

confidence: 99%

“…For very small neighborhoods, the dynamics are the most localized, and the islands are more pronounced than in systems with larger neighborhood sizes. The degree to which space influences the rate of evolution depends on the parameters (6).…”

Section: Resultsmentioning

confidence: 99%

“…To understand the role of space in the rate of complex phenotype generation, we follow the development presented in ref. 6, where we study the spatial Moran process formulated on a 2D square grid of size N, with periodic boundary conditions. In this process, individuals die at random, independently of their phenotype, and are immediately replaced by the progeny of one of the nearby individuals, selected randomly from the square neighborhood of a fixed size, M. The probability to be selected for reproduction is proportional to the fitness of each phenotype, and mutations happen with a given probability (u) for each of m sites upon reproduction.…”

Section: Resultsmentioning

confidence: 99%

“…In this paper we discuss how this process and its timing depend on the underlying evolutionary dynamics. In particular, we review recent results on the role of the spatial restrictions inherent in the evolving system (6), and the changes in the rate of evolution that may arise as a result of the presence of cooperation among different phenotypes (7). Several applications are discussed.…”

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Spatial interactions and cooperation can change the speed of evolution of complex phenotypes

Komarova

2014

Proc. Natl. Acad. Sci. U.S.A.

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Complex traits arise from the interactions among multiple gene products. In the case where the complex phenotype is separated from the wild type by a fitness valley or a fitness plateau, the generation of a complex phenotype may take a very long evolutionary time. Interestingly, the rate of evolution depends in nontrivial ways on various properties of the underlying stochastic process, such as the spatial organization of the population and social interactions among cells. Here we review some of our recent work that investigates these phenomena in asexual populations. The role of spatial constraints is quite complex: there are realistic cases where spatial constrains can accelerate or delay evolution, or even influence it in a nonmonotonic fashion, where evolution works fastest for intermediate-range constraints. Social interactions among cells can be studied in the context of the division-of-labor games. Under a range of circumstances, cooperation among cells can lead to a relatively fast creation of a complex phenotype as an emerging (distributed) property. If we further assume the presence of cheaters, we observe the emergence of a fully mutated population of cells possessing the complex phenotype. Applications of these ideas to cancer initiation and biofilm formation in bacteria are discussed.mutations | stochastic modeling C omplex traits depend on several genes and their environments, and arise from the interactions among multiple gene products. Much research has been devoted to inheritance patterns of complex traits (1) and to identifying their genetic makeup (2). Here we will concentrate on the evolutionary process of the emergence of complex traits in asexual populations, and review some of our recent results in this context.In some cases, the evolution of complex traits involves the accumulation of several beneficial mutations. In other cases, however, their evolution requires the accumulation of multiple mutations, each of which is individually neutral or deleterious. A fitness advantage is only attained when all mutations have been acquired (sign epistasis). In such cases, evolution involves the crossing of a fitness valley or fitness plateau (3-5). We can talk about a "fitness foothill" when intermediate mutations are very slightly advantageous compared with the wild type, but not nearly as advantageous as the complex trait (Fig. 1). We will denote by m the number of mutations that need to be accumulated to reach the advantageous complex phenotype. Though recombination can bring together all m mutations within an organism, evolution in asexual populations depends on the sequential accumulation of these mutations within a lineage. The process of sequential accumulation (especially if it involves intermediate deleterious types, such as in the case of fitness valleys) can take a very long evolutionary time. In this paper we discuss how this process and its timing depend on the underlying evolutionary dynamics. In particular, we review recent results on the role of the spatial restrictions inherent in th...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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Spatial interactions and cooperation can change the speed of evolution of complex phenotypes

Komarova

2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Our work adds to the growing literature that investigates the dynamics of fitness valley crossing under various conditions [19][20][21]23,[25][26][27][28][42][43][44]. Beyond this immediate discipline, however, it is also interesting to consider our results in a wider scientific sense.…”

Section: Discussionmentioning

confidence: 88%

Passenger mutations can accelerate tumor suppressor gene inactivation in cancer evolution

Wodarz

Newell

Komarova

2017

Preprint

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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.peer-reviewed)

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Modeling Cell Dynamics in Colon and Intestinal Crypts: The Significance of Central Stem Cells in Tumorigenesis

Mahdipour-Shirayeh

Shahriyari

2018

Bull Math Biol

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Colon and intestinal crypts have been widely chosen to study cell dynamics because of their fairly simple structures. In the colon and intestinal crypts, stem cells (SCs) are located at very bottom of the crypt, fully differentiated cells (FDs) are located in the top of the crypt, and transit-amplifying cells (TAs) are in the middle of the crypt between FDs and SCs. Recently, it has been discovered that there are two types of stem cells in the intestinal crypts: central stem cells (CeSCs) and border stem cells. To investigate dynamics of mutants in colon and intestinal crypts, we develop a four-compartmental stochastic model, which includes two SC compartments, and TAs and FDs compartments. We calculate the probability of the progeny of marked or mutant cells located at each of these compartments taking over the entire crypt or being washed out from the crypt. We found that the progeny of CeSCs will take over the entire crypt with a probability close to one. Interestingly, the progeny of advantageous mutant TAs and FDs will be washed out faster than disadvantageous mutants. Saliently, the model predicts that the time that the progeny of wild-type central stem cells will take over the mouse intestinal crypt is around 60 days, which is in perfect agreement with an experimental observation.

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Complex role of space in the crossing of fitness valleys by asexual populations

Cited by 40 publications

References 50 publications

Spatial interactions and cooperation can change the speed of evolution of complex phenotypes

Spatial interactions and cooperation can change the speed of evolution of complex phenotypes

Passenger mutations can accelerate tumor suppressor gene inactivation in cancer evolution

Modeling Cell Dynamics in Colon and Intestinal Crypts: The Significance of Central Stem Cells in Tumorigenesis

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