Metagenome profiling and containment estimation through abundance-corrected k-mer sketching with sylph

Profiling metagenomes against databases allows for the detection and quantification of mi-crobes, even at low abundances where assembly is not possible. We introduce sylph (https://github.com/bluenote-1577/sylph), a metagenome profiler that estimates genome-to-metagenome containment average nucleotide identity (ANI) through zero-inflated Poisson k-mer statistics, enabling ANI-based taxa detection. Sylph is the most accurate method on the CAMI2 marine dataset, and compared to Kraken2 for multi-sample profiling, sylph takes 10x less CPU time and uses 30x less memory. Sylphs ANI estimates provide an orthogonal signal to abundance, enabling an ANI-based metagenome-wide association study for Parkinsons disease (PD) against 289,232 genomes while confirming known butyrate-PD associations at the strain level. Sylph takes < 1 minute and 16 GB of RAM to profile against 85,205 prokaryotic and 2,917,521 viral genomes, detecting 30x more viral sequences in the human gut compared to RefSeq. Sylph offers precise, efficient profiling with accurate containment ANI estimation for even low-coverage genomes.