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One example is the large number of SARS-CoV-2 genomes available, which are beyond the processing power of many methods, and simulating such large datasets is also proving difficult. Here, we present a new algorithm and software for efficiently simulating sequence evolution along extremely large trees (e.g. &gt; 100, 000 tips) when the branches of the tree are short, as is typical in genomic epidemiology. Our algorithm is based on the Gillespie approach, and it implements an efficient multi-layered search tree structure that provides high computational efficiency by taking advantage of the fact that only a small proportion of the genome is likely to mutate at each branch of the considered phylogeny. Our open source software allows easy integration with other Python packages as well as a variety of evolutionary models, including indel models and new hypermutability models that we developed to more realistically represent SARS-CoV-2 genome evolution.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1010056","type":"journal-article","created":{"date-parts":[[2022,4,29]],"date-time":"2022-04-29T16:25:40Z","timestamp":1651249540000},"page":"e1010056","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":28,"title":["phastSim: Efficient simulation of sequence evolution for pandemic-scale datasets"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1776-8564","authenticated-orcid":true,"given":"Nicola","family":"De 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