Ultrafast Sample Placement on Existing Trees (UShER) Empowers Real-Time Phylogenetics for the SARS-CoV-2 Pandemic.

As the SARS-CoV-2 virus spreads through human populations, the unprecedented accumulation of viral genome sequences is ushering a new era of "genomic contact tracing" - that is, using viral genome sequences to trace local transmission dynamics. However, because the viral phylogeny is already so large - and will undoubtedly grow many fold - placing new sequences onto the tree has emerged as a barrier to real-time genomic contact tracing. Here, we resolve this challenge by building an efficient, tree-based data structure encoding the inferred evolutionary history of the virus. We demonstrate that our approach improves the speed of phylogenetic placement of new samples and data visualization by orders of magnitude, making it possible to complete the placements under real-time constraints. Our method also provides the key ingredient for maintaining a fully-updated reference phylogeny. We make these tools available to the research community through the UCSC SARS-CoV-2 Genome Browser to enable rapid cross-referencing of information in new virus sequences with an ever-expanding array of molecular and structural biology data. The methods described here will empower research and genomic contact tracing for laboratories worldwide. SOFTWARE AVAILABILITY: USHER is available to users through the UCSC Genome Browser at https://genome.ucsc.edu/cgi-bin/hgPhyloPlace . The source code and detailed instructions on how to compile and run UShER are available from https://github.com/yatisht/usher .