DISSEQT—DIStribution-based modeling of SEQuence space Time dynamics†

Rapidly evolving microbes are a challenge to model because of the volatile, complex and dynamic nature of their populations. We developed the DISSEQT pipeline (DIStribution-based SEQuence space Time dynamics) for analyzing, visualizing and predicting the evolution of heterogeneous biological populations in multidimensional genetic space, suited for population-based modeling of deep sequencing and high-throughput data. DISSEQT is openly available on GitHub (https://github.com/rasmushenningsson/DISSEQT.jl) and Synapse (https://www.synapse.org/#!Synapse:syn11425758), covering the entire workflow from read alignment to visualization of results. DISSEQT is centered around robust dimension and model reduction algorithms for analysis of genotypic data with additional capabilities for including phenotypic features to explore dynamic genotype-phenotype maps. We illustrate its utility and capacity with examples from evolving RNA virus populations, which present on of the highest degrees of population heterogeneity found in nature. Using DISSEQT, we empirically reconstruct the evolutionary trajectories of evolving populations in sequence space and genotype-phenotype fitness landscapes. We show that while sequence space is vastly multidimensional, the relevant genetic space of evolving microbial populations is of intrinsically low dimension. In addition, evolutionary trajectories of these populations can be faithfully monitored to identify the key minority genotypes contributing most to evolution. Finally, we show that empirical fitness landscapes, when reconstructed to include minority variants, can predict phenotype from genotype with high accuracy.