Excess of mutational jackpot events in expanding populations revealed by spatial Luria–Delbrück experiments

Fusco, Diana; Gralka, Matti; Kayser, Jona; Anderson, Alex; Hallatschek, Oskar

doi:10.1038/ncomms12760

Cited by 125 publications

(221 citation statements)

References 46 publications

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“…The most compelling evidence for neutral evolution in human cancers is based on the observation that the mutation frequency distributions of many tumours resemble the null distribution predicted by a non-spatial neutral model [8]. However, in the present study we have extended previous work [28] showing that, even in the neutral case, spatial structure is expected to distort mutation frequency distributions in solid tumours, potentially obscuring signatures of selection. Although we find that evolution may be effectively neutral within a few specific tumour types, our results are generally consistent with extensive selection, in line with findings from pan-cancer comparative genomics [9].…”

Section: Discussionsupporting

confidence: 57%

Spatial structure governs the mode of tumour evolution

Noble

Burri

Kather

et al. 2019

Preprint

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Characterizing the mode -the way, manner, or pattern -of evolution in tumours is important for clinical forecasting and optimizing cancer treatment. DNA sequencing studies have inferred various modes, including branching, punctuated and neutral evolution, but it is unclear why a particular pattern predominates in any given tumour [1]. Here we propose that differences in tumour architecture alone can explain the variety of observed patterns. We examine this hypothesis using spatially explicit population genetic models and demonstrate that, within biologically relevant parameter ranges, tumours are expected to exhibit diverse evolutionary modes including four archetypal "oncoevotypes": rapid clonal expansion (predicted in leukaemia); progressive diversification (in colorectal adenomas and early-stage colorectal carcinomas); branching evolution (in invasive glandular tumours); and almost neutral evolution (in certain non-glandular and poorly differentiated solid tumours). We thus provide a simple, mechanistic explanation for a wide range of empirical observations. Oncoevotypes are driven by differences in cell dispersal and cell-cell interactions, which we show are essential for accurately characterizing, forecasting and controlling tumour evolution.A tumour is a product of somatic evolution in which interacting processes of mutation, selection, genetic drift, and cell dispersal generate a patchwork of cell subpopulations (clones) with varying degrees of aggressiveness and treatment sensitivity [2]. A primary goal of modern cancer research is to characterize this evolutionary process, so as to enable precise, patient-specific prognostic forecasts and to optimize targeted therapy regimens.Much progress has been made in revealing the evolutionary features of particular cancers, yet these findings raise as many questions as they answer. Why do different tumour types exhibit different modes of evolution [1,3,4,5,6]? What conditions sustain the frequently observed pattern of branching evolution, in which several clones diverge and evolve in parallel [1,7]? And why do some pan-cancer analyses indicate that many tumours evolve neutrally [8], whereas others support extensive selection [9]?Factors proposed as contributing to intra-tumour evolution include microenvironmental heterogeneity, niche construction, and positive ecological interactions between clones [10, 2]. However, because such factors have not been well characterized across human cancer types, it remains unclear how they might relate to evolutionary modes.On the other hand, it is well established that tumours exhibit a wide range of architectures. In leukaemia, for example, mutated stem cells in semi-solid bone marrow produce cancer cells that mix and proliferate in the bloodstream (Figure 1a). Colorectal adenomas and early-stage colorectal carcinomas, by contrast, inherit 1

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Section: Discussionsupporting

confidence: 57%

Spatial structure governs the mode of tumour evolution

Noble

Burri

Kather

et al. 2019

Preprint

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“…The concept of "allele surfing" (Edmonds, Lillie, & Cavalli-Sforza, 2004; Klopfstein, Currat, & Excoffier, 2006) has emerged as having key explanatory power in modelled populations experiencing geographic range expansion, and the phenomenon has been observed both in cultured bacteria (e.g., Fusco, Gralka, Kayser, Anderson, & Hallatschek, 2016;Gralka et al, 2016;Hallatschek, Hersen, Ramanathan, & Nelson, 2007) and in eukaryotes in their natural environments (Becheler et al, 2016;François et al, 2010;Graciá et al, 2013;Peischl, Dupanloup, Bosshard, & Excoffier, 2016;Pierce et al, 2014;Streicher et al, 2016). Surfing allows rare alleles in a population to reach high frequency through repeated founder events and to become more widespread at the leading edge of population expansion (sometimes referred to as the wave front), where population density is especially low (Excoffier & Ray, 2008).…”

mentioning

confidence: 99%

Loss of genetic diversity, recovery and allele surfing in a colonizing parasite, Geomydoecus aurei

Demastes

Hafner

et al. 2019

Molecular Ecology

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Understanding the genetic consequences of changes in species distributions has wide‐ranging implications for predicting future outcomes of climate change, for protecting threatened or endangered populations and for understanding the history that has led to current genetic patterns within species. Herein, we examine the genetic consequences of range expansion over a 25‐year period in a parasite (Geomydoecus aurei) that is in the process of expanding its geographic range via invasion of a novel host. By sampling the genetics of 1,935 G. aurei lice taken from 64 host individuals collected over this time period using 12 microsatellite markers, we test hypotheses concerning linear spatial expansion, genetic recovery time and allele surfing. We find evidence of decreasing allelic richness (AR) with increasing distance from the source population, supporting a linear, stepping stone model of spatial expansion that emphasizes the effects of repeated bottleneck events during colonization. We provide evidence of post‐bottleneck genetic recovery, with average AR of infrapopulations increasing about 30% over the 225‐generation span of time observed directly in this study. Our estimates of recovery rate suggest, however, that recovery has plateaued and that this population may not reach genetic diversity levels of the source population without further immigration from the source population. Finally, we employ a grid‐based sampling scheme in the region of ongoing population expansion and provide empirical evidence for the power of allele surfing to impart genetic structure on a population, even under conditions of selective neutrality and in a place that lacks strong barriers to gene flow.

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“…Once the mutant clone reaches the threshold size, the selective advantage of the mutants can deterministically drive them to fixation in the population. During the initial phase, the mutant clone is contained between boundaries with characteristic stochastic properties that are not captured in our one-dimensional model [14]. However, if the threshold size is small, the boundary fluctuations will not have a large impact on the growth of mutant clones.…”

Section: Discussionmentioning

confidence: 99%

Convection shapes the trade-off between antibiotic efficacy and the selection for resistance in spatial gradients

et al. 2017

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Since penicillin was discovered about 90 years ago, we have become used to using drugs to eradicate unwanted pathogenic cells. However, using drugs to kill bacteria, viruses or cancer cells has the serious side effect of selecting for mutant types that survive the drug attack. A key question therefore is how one could eradicate as many cells as possible for a given acceptable risk of drug resistance evolution. We address this general question in a model of drug resistance evolution in spatial drug gradients, which recent experiments and theories have suggested as key drivers of drug resistance. Importantly, our model takes into account the influence of convection, resulting for instance from blood flow. Using stochastic simulations, we study the fates of individual resistance mutations and quantify the trade-off between the killing of wild-type cells and the rise of resistance mutations: shallow gradients and convection into the antibiotic region promote wild-type death, at the cost of increasing the establishment probability of resistance mutations. We can explain these observed trends by modeling the adaptation process as a branching random walk. Our analysis reveals that the trade-off between death and adaptation depends on the relative length scales of the spatial drug gradient and random dispersal, and the strength of convection. Our results show that convection can have a momentous effect on the rate of establishment of new mutations, and may heavily impact the efficiency of antibiotic treatment.

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Excess of mutational jackpot events in expanding populations revealed by spatial Luria–Delbrück experiments

Cited by 125 publications

References 46 publications

Spatial structure governs the mode of tumour evolution

Spatial structure governs the mode of tumour evolution

Loss of genetic diversity, recovery and allele surfing in a colonizing parasite, Geomydoecus aurei

Convection shapes the trade-off between antibiotic efficacy and the selection for resistance in spatial gradients

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