Document Type

Article

Publication Date

3-14-2023

Identifier

DOI: 10.1073/pnas.2208361120

Abstract

Crowding effects critically impact 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. Recent work has shown that crowding has a strong impact on the strength of natural selection. However, the impact of crowding on neutral processes, which controls the fate of new variants as long as they are rare, remains unclear. 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 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.

Journal Title

Proceedings of the National Academy of Sciences of the United States of America

Volume

120

Issue

11

First Page

2208361120

Last Page

2208361120

MeSH Keywords

Animals; Biofilms; Gastropoda; Microfluidics; Mutation; Mutation Rate

Keywords

biofilms; clone size distribution; genetic variation; intratumor heterogeneity

Comments

This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).

Publisher's Link: https://doi.org/10.1073/pnas.2208361120

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