Complex Evolution of Resistance in Spatially Structured Populations

空间结构群体中抵抗力的复杂演化

• 批准号: 316081223
• 负责人: Dr. Jona Kayser
• 金额: --
• 依托单位: Sächsischer Inkubator für klinische Translation (SIKT)
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/316081223?language=en
• 关键词: Complex; Evolution; Resistance; Spatially; Structured

For many naturally occurring populations, ranging from microbial biofilms to solid tumors, it has been argued that their spatial organization can drastically influence their evolutionary dynamics, and hence the establishment probability of new mutants. This is especially relevant in the context of adaptation to deteriorating environments, such as antibiotic or chemotherapeutic attacks, where the emergence of resistant clones can lead to treatment failure.For many naturally occurring populations, ranging from microbial biofilms to solid tumors, it has been argued that their spatial organization can drastically influence their evolutionary dynamics, and hence the establishment probability of mutant clones. This is especially relevant in the context of adaptation to deteriorating environments, such as antibiotic or chemotherapeutic attacks, where the emergence of resistant clones can lead to treatment failure. Despite its argued importance, the role of spatial organization in evolution remains poorly characterized. I here propose a series of experiments investigating the evolutionary dynamics within spatially structured populations in a quantitative manner. To this end, I will develop a collection of new model systems based on yeast strains that can effectively switch between several successive fitness states in a tunable fashion. These engineered mutations, mediated by recombinase action, are also coupled to a change in fluorescence color, enabling precise spatio-temporal tracking of each individual clone via microscopy. Furthermore, employing CRISPR/Cas9 technology will allow me to significantly increase the number of tracked mutation and hence the complexity of investigated scenarios. Using these setups I will study the evolutionary mechanisms leading to the establishment of resistant clones in spatially structured populations and compare them to the well-mixed cultures of cells. I will specifically assess how the intricate interplay of mutation rate, relative fitness and spatial effects result in complex evolutionary trajectories in clinically-relevant scenarios, such as the crossing of fitness valleys.

对于许多自然发生的种群，从微生物生物膜到实体肿瘤，人们认为它们的空间组织可以极大地影响它们的进化动力学，从而影响新突变体的建立概率。这在适应环境恶化的背景下尤其重要，如抗生素或化疗攻击，其中抗性克隆的出现可能导致治疗失败。对于许多自然发生的种群，从微生物生物膜到实体肿瘤，人们认为它们的空间组织可以极大地影响它们的进化动力学，从而影响突变克隆的建立概率。这在适应不断恶化的环境，如抗生素或化疗攻击的背景下尤其重要，其中耐药克隆的出现可能导致治疗失败。尽管其重要性，空间组织在进化中的作用仍然很差的特点。在这里，我提出了一系列的实验调查的空间结构种群的进化动力学定量的方式。为此，我将开发一系列基于酵母菌株的新模型系统，这些系统可以以可调的方式在几个连续的适应状态之间有效地切换。这些由重组酶作用介导的工程突变也与荧光颜色的变化相结合，从而能够通过显微镜精确地时空跟踪每个单独的克隆。此外，采用CRISPR/Cas9技术将使我能够显着增加跟踪突变的数量，从而增加研究场景的复杂性。使用这些设置，我将研究的进化机制，导致建立抗性克隆的空间结构的人口和比较，他们的混合培养的细胞。我将具体评估突变率、相对适应度和空间效应之间复杂的相互作用如何在临床相关场景中导致复杂的进化轨迹，例如穿越适应度山谷。

项目成果

Impact of crowding on the diversity of expanding populations

• DOI: 10.1101/743534
• 发表时间: 2019-08
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: C. Schreck;D. Fusco;Yuya Karita;Stephen Martis;Jona Kayser;Marie-Cécilia Duvernoy;O. Hallatschek

SCWISh network is essential for survival under mechanical pressure

• DOI: 10.1073/pnas.1711204114
• 发表时间: 2017-12-19
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Delarue, Morgan;Poterewicz, Gregory;Hallatschek, Oskar
• 通讯作者: Hallatschek, Oskar