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Abstract

Metagenomics has revolutionized environmental and human-associated microbiome studies. However, the limited fraction of proteins with known biological process and molecular functions presents a major bottleneck. In prokaryotes and viruses, evolution favors keeping genes participating in the same biological processes co-localized as conserved gene clusters. Conversely, conservation of gene neighborhood indicates functional association. Spacedust is a tool for systematic, de novo discovery of conserved gene clusters. To find homologous protein matches it uses fast and sensitive structure comparison with Foldseek. Partially conserved clusters are detected using novel clustering and order conservation P-values. We demonstrate Spacedust’s sensitivity with an all-vs-all analysis of 1 308 bacterial genomes, identifying 72 843 conserved gene clusters containing 58% of the 4.2 million genes. It recovered recover 95% of antiviral defense system clusters annotated by a specialized tool. Spacedust’s high sensitivity and speed will facilitate the large-scale annotation of the huge numbers of sequenced bacterial, archaeal and viral genomes.