Motivation: The construction of the compacted de Bruijn graph from a large collection of reference genomes is a task of increasing interest in genomic analyses. For example, compacted colored reference de Bruijn graphs are increasingly used as sequence indices for the purposes of alignment of short and long reads. Also, as we sequence and assemble a greater diversity of individual genomes, the compacted colored de Bruijn graph can be used as the basis for methods aiming to perform comparative

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... nomic analyses on these genomes. While algorithms have been developed to construct the compacted colored de Bruijn graph from reference sequences, there is still room for improvement, especially in the memory and the runtime performance as the number and the scale of the genomes over which the de Bruijn graph is built grow. Results: We introduce a new algorithm, implemented in the tool Cuttlefish, to construct the colored compacted de Bruijn graph from a collection of one or more genome references. Cuttlefish introduces a novel modeling scheme of the de Bruijn graph vertices as finite-state automata, and constrains the state-space for the automata to enable tracking of their transitioning states with very low memory usage. Cuttlefish is also fast and highly parallelizable. Experimental results demonstrate that the algorithm scales much better than existing approaches, especially as the number and scale of the input references grow. For example, on a typical shared-memory machine, Cuttlefish constructed the compacted graph for 100 human genomes in less than 7 hours, using ~29 GB of memory; no other tested tool successfully completed this task on the testing hardware. We also applied Cuttlefish on 11 diverse conifer plant genomes, and the compacted graph was constructed in under 11 hours, using ~84 GB of memory, while the only other tested tool able to complete this compaction on our hardware took more than 16 hours and ~289 GB of memory. Availability: Cuttlefish is written in C++14, and is available under an open source license at https://github.com/COMBINE-lab/cuttlefish.