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July 18th, 2025
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J. Craig Venter Institute
bioinformatics
biorxiv

Leviathan: A fast, memory-efficient, and scalable taxonomic and pathway profiler for next generation sequencing (pan)genome-resolved metagenomics and metatranscriptomics

Espinoza, J. L.Open in Google Scholar

Metagenomic and metatranscriptomic functional profiling is crucial for understanding microbial community capabilities, yet current tools often face challenges in computational efficiency, scalability, and integrated genome-resolved references. Here, I introduce Leviathan, an open-source software package designed to address these limitations. Leviathan implements taxonomic profiling via Sylph and a novel highly optimized functional profiling workflow. The functional profiling workflow uniquely combines the speed of PyKOfamSearch (PyHMMER-accelerated KofamScan implementation) for feature annotation, the accuracy of Salmon for read quantification against genome-resolved reference gene catalogs, and the novel graph-based pathway completeness assessment of the KEGG Pathway Profiler. I demonstrate Leviathan\'s capabilities using the CAMI low, medium, and high complexity datasets. Compared to the widely used tool HUMAnN, Leviathan exhibits significantly reduced runtimes (up to ~72-fold faster) and memory usage (up to ~14-fold lower), while achieving competitive or superior accuracy gains (up to 12%) in identifying functional features at both individual genome and pangenome levels. Notably, Leviathan natively supports and streamlines pangenome-level analysis, a critical aspect for understanding functional redundancy and diversity within microbial communities. Leviathan is available as an open-source software package (Python and CLI APIs) offering a powerful and accessible solution for comprehensive genome-resolved metagenomic profiling.

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