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A longstanding goal of biology is to identify the key genes and species thatcritically impact evolution, ecology, and health. Network analysis has revealedkeystone species that regulate ecosystems and master regulators that regulatecellular genetic networks. Yet these studies have focused on pairwisebiological interactions, which can be affected by the context of geneticbackground and other species present generating higher-order interactions. Theimportant regulators of higher-order interactions are unstudied. To addressthis, we applied a new high-dimensional geometry approach that quantifiesepistasis in a fitness landscape to ask how individual genes and speciesinfluence the interactions in the rest of the biological network. We thengenerated and also reanalyzed 5-dimensional datasets (two genetic, twomicrobiome). We identified key genes (e.g. the rbs locus and pykF) and species(e.g. Lactobacilli) that control the interactions of many other genes andspecies. These higher-order master regulators can induce or suppressevolutionary and ecological diversification by controlling the topography ofthe fitness landscape. Thus, we provide mathematical intuition andjustification for exploration of biological networks in higher dimensions.

Master regulators of evolution and the microbiome in higher dimensions