Rapid species-level metagenome profiling and containment estimation with sylph

Profiling metagenomes against databases allows for the detection and quantification of microorganisms, even at low abundances where assembly is not possible. We introduce sylph, a species-level metagenome profiler that estimates genome-to-metagenome containment average nucleotide identity (ANI) through zero-inflated Poisson k -mer statistics, enabling ANI-based taxa detection. On the Critical Assessment of Metagenome Interpretation II (CAMI2) Marine dataset, sylph was the most accurate profiling method of seven tested. For multisample profiling, sylph took >10-fold less central processing unit time compared to Kraken2 and used 30-fold less memory. Sylph’s ANI estimates provided an orthogonal signal to abundance, allowing for an ANI-based metagenome-wide association study for Parkinson disease (PD) against 289,232 genomes while confirming known butyrate–PD associations at the strain level. Sylph took <1 min and 16 GB of random-access memory to profile metagenomes against 85,205 prokaryotic and 2,917,516 viral genomes, detecting 30-fold more viral sequences in the human gut compared to RefSeq. Sylph offers precise, efficient profiling with accurate containment ANI estimation even for low-coverage genomes.