The landscape of novel lateral gene transfer events in the human microbiome

Lateral gene transfer (LGT) is an important mechanism for genomic diversification in microbial populations and communities, including the human microbiome. While previous work has surveyed ancient LGT events in human-associated microbial isolate genomes, the scope, and dynamics of novel LGT events in human microbiomes are not well understood. We addressed this by developing and validating a computational method (Workflow to Annotate Assemblies and Find LGT Events or WAAFLE) to profile novel LGT events from assembled metagenomes.  We assessed WAAFLE on synthetic contigs containing spiked LGTs and identified intergenus LGTs with >91% sensitivity and >99.9% specificity. For more challenging intragenus LGT (due to congeneric overlap), we report a still-respectable 51% sensitivity.  Applying WAAFLE to >2K human metagenomes from diverse body sites, we identified >100K high-confidence putative, novel LGT events. These events were enriched for mobile elements (as expected), as well as restriction-modification and transport functions, both being particularly intriguing areas for further study given their putative role in viral/phage-mediated LGT defense. LGT frequency was quantifiably influenced by biogeography, the phylogenetic similarity of the involved taxa, and the ecological abundance of the involved taxa. Our findings suggest that LGT is an active process in the human microbiome, occurring far more frequently than previously suspected.