Natural CRISPR Systems and Targets in the Human Microbiome

Many bacteria resist invasive DNA by incorporating sequences into CRISPR loci, which enable sequence-specific degradation. CRISPR systems have been well-studied from isolate genomes, but culture-independent metagenomics provides a new window into their diversity. We profiled CRISPR loci and cas genes in the body-wide human microbiome using 2,355 metagenomes spanning 265 individuals, yielding functional and taxonomic profiles for 2.9 million spacers. Spacer and repeat profiles agreed qualitatively with those from isolate genomes but expanded their diversity by approximately 20-fold, with the highest spacer load present in the oral microbiome. Taxonomy of spacer carriage paralleled that of the communities in which they were contained, with functional targets enriched for viral elements but also including other microbial structural and enzymatic elements. When coupled with cas gene systems, CRISPR–Cas subtypes were highly site- and taxon-specific. Our analysis provides the first comprehensive collection of natural CRISPR–cas loci and targets in the human microbiome.