HERACLES for fast and accurate likelihood-based reconstruction of massive lineages

HERACLES reconstructs CRISPR lineage phylogenies for 150,000-cell lineages in about four hours on a single GPU, improving accuracy via hyperbolic coordinate optimization.

• Why it matters: Likelihood-based CRISPR phylogenies are accurate but computationally heavy, while distance-only methods can introduce unknown biases because distances may not reflect the editing process.
• What they did: HERACLES optimizes cell coordinates in hyperbolic space using a quartet-based composite likelihood with an explicit CRISPR editing evolutionary model, avoiding repeated full tree searches.
• The result: In simulated benchmarks it improves reconstruction accuracy, and on KP-tracer and PEtracer it yields trees consistent with anatomical annotations and temporal markers, also improving simulated DNA Typewriter lineages with sequential editing.

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