Proteobacteria drive significant functional variability in the human gut microbiome

10 While human gut microbiomes vary significantly in taxonomic composition, biological 11 pathway abundance is surprisingly invariable across hosts. We hypothesized that healthy 12 microbiomes appear functionally redundant due to factors that obscure differences in gene 13 abundance across hosts. To account for these biases, we developed a powerful test of gene 14 variability, applicable to shotgun metagenomes from any environment. Our analysis of 15 healthy stool metagenomes reveals thousands of genes whose abundance differs signifi16 cantly between people consistently across studies, including glycolytic enzymes, lipopolysac17 charide biosynthetic genes, and secretion systems. Even housekeeping pathways contain a 18 mix of variable and invariable genes, though most deeply conserved genes are significantly 19 invariable. Variable genes tend to be associated with Proteobacteria, as opposed to taxa 20 used to define enterotypes or the dominant phyla Bacteroidetes and Firmicutes. These re21 sults establish limits on functional redundancy and predict specific genes and taxa that may 22 drive physiological differences between gut microbiomes. 23