Beyond genome sequencing: Lineage tracking with barcodes to study the dynamics of evolution, infection, and cancer

Evolving cellular communities, such as the gut microbiome, pathogenic infections, and cancer, consist of large populations of ~ 107 -1014 cells. Because of their large population sizes, adaptation within these populations can be driven by many beneficial mutations that never rise above extremely low frequencies. Genome sequencing methods such as clonal, single cell, or whole population sequencing are poorly suited to detect these rare beneficial lineages, and, more generally, to characterize which mutations are most important to the population dynamics. Here, we introduce an alternative approach: high-resolution lineage tracking with DNA barcodes. In contrast to whole genome sequencing, lineage tracking can detect a beneficial mutation at an extremely low frequency within the population, and estimate its time of occurrence and fitness effect. Many lineage trajectories can be observed in parallel, allowing one to observe the population dynamics in exquisite detail. We describe some of the technical and analytical challenges to lineage tracking with DNA barcodes and discuss its applications to studies of evolution, infectious disease and cancer.