Impact of crowding on the diversity of expanding populations
Impact of crowding on the diversity of expanding populations
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DOI：
10.1101/743534
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发表时间：
2019-08
影响因子：
11.1
通讯作者：
C. Schreck;D. Fusco;Yuya Karita;Stephen Martis;Jona Kayser;Marie-Cécilia Duvernoy;O. Hallatschek
中科院分区：
文献类型：
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作者：
C. Schreck;D. Fusco;Yuya Karita;Stephen Martis;Jona Kayser;Marie-Cécilia Duvernoy;O. Hallatschek
拥挤效应是致密堆积的细胞组装体（如生物膜、实体瘤和发育中的组织）自组织的关键。当细胞生长和分裂时，它们会相互推开，重塑种群的结构和范围。最近的研究表明，拥挤对自然选择的强度有很大的影响。然而，拥挤对中性过程的影响仍然不清楚，只要它们是罕见的，它就控制着新变体的命运。在这里，我们量化的遗传多样性扩大微生物菌落和发现拥挤的网站频谱的签名。通过结合Luria-Delbrück波动测试，在新型微流体培养箱中进行谱系追踪，基于细胞的模拟和理论建模，我们发现大多数突变发生在扩展的前沿之后，产生了被前面增殖细胞机械地“推出”生长区域的克隆。这些排除体积的相互作用导致克隆大小分布，这完全取决于突变首先出现相对于前面，其特征在于一个简单的幂律为低频克隆。我们的模型预测，分布只取决于一个单一的参数，特征生长层厚度，因此允许在各种拥挤的细胞群体的突变率的估计。结合以前对高频突变的研究，我们的发现提供了在整个频率范围内扩大种群的遗传多样性的统一图景，并提出了一种通过在空间尺度上对种群进行测序来评估生长动态的实用方法。随着细胞增殖和填充空间，生长的细胞群变得密集。拥挤阻止了个体的空间混合，显著改变了混合种群的进化结果。尽管空间和混合种群之间存在根本差异，但对拥挤对遗传多样性的影响知之甚少。在平板上生长的微生物菌落，我们表明，等位基因频谱的特点是由一个简单的幂律低频率。使用基于细胞的模拟和微流体实验，我们确定了这种分布在拥挤的细胞环境中的体积排斥相互作用的起源，使我们能够将这一发现扩展到广泛的密集人群。这项研究强调了细胞拥挤对于罕见遗传变异出现的重要性。
Crowding effects are key to the self-organization of densely packed cellular assemblies, such as biofilms, solid tumors, and developing tissues. When cells grow and divide they push each other apart, remodeling the structure and extent of the population’s range. It has recently been shown that crowding has a strong impact on the strength of natural selection. However, the impact of crowding on neutral processes remains unclear, which controls the fate of new variants as long as they are rare. Here, we quantify the genetic diversity of expanding microbial colonies and uncover signatures of crowding in the site frequency spectrum. By combining Luria-Delbrück fluctuation tests, lineage tracing in a novel microfluidic incubator, cell-based simulations, and theoretical modeling, we find that the majority of mutations arise behind the expanding frontier, giving rise to clones that are mechanically “pushed out” of the growing region by the proliferating cells in front. These excluded-volume interactions result in a clone size distribution that solely depends on where the mutation first arose relative to the front and is characterized by a simple power-law for low-frequency clones. Our model predicts that the distribution only depends on a single parameter, the characteristic growth layer thickness, and hence allows estimation of the mutation rate in a variety of crowded cellular populations. Combined with previous studies on high-frequency mutations, our finding provides a unified picture of the genetic diversity in expanding populations over the whole frequency range and suggests a practical method to assess growth dynamics by sequencing populations across spatial scales. Significance Statement Growing cell populations become densely packed as cells proliferate and fill space. Crowding prevents spatial mixing of individuals, significantly altering the evolutionary outcome from established results for well-mixed populations. Despite the fundamental differences between spatial and well-mixed populations, little is known about the impact of crowding on genetic diversity. Looking at microbial colonies growing on plates, we show that the allele frequency spectrum is characterized by a simple power law for low frequencies. Using cell-based simulations and microfluidic experiments, we identify the origin of this distribution in the volume-exclusion interactions within the crowded cellular environment, enabling us to extend this findings to a broad range of densely packed populations. This study highlights the importance of cellular crowding for the emergence of rare genetic variants.