The Landscape of Genetic Content in the Human Microbiome

Abstract

We have not quantitated the scale of human microbiome genetic diversity, an instrumental task for understanding human-microbe interactions. Here, to do so, we conducted a cross-study meta-analysis of metagenomes from two niches, the mouth and gut, amassing 3,655 samples from 21 studies. We found staggering genetic heterogeneity in our dataset, identifying that 50% of the genes in both datasets were “singletons”, meaning they were unique to specific individuals. We found that singletons arose from individual-specific, instransient, and extremely rare microbial strains. Further, we estimated that the oral and gut microbiomes universally contain 91 and 239 million unique genes, respectively, and that adequately sampling these spaces, such that each new metagenome contains 1% undiscovered genes, will take 6,000 and 20,000 samples. Overall, these results serve as a potential explanation for the large, unexplained heterogeneity observed in microbiome-derived human phenotypes.