biostudies-literatureEble HNIDDK NIH HHSNIH HHSe2300634120https://www.ebi.ac.uk/biostudies/studies/S-EPMC10743376biostudies-literatureUnknown120(51)A longstanding goal of biology is to identify the key genes and species that critically impact evolution, ecology, and health. Network analysis has revealed keystone species that regulate ecosystems and master regulators that regulate cellular genetic networks. Yet these studies have focused on pairwise biological interactions, which can be affected by the context of genetic background and other species present, generating higher-order interactions. The important regulators of higher-order interactions are unstudied. To address this, we applied a high-dimensional geometry approach that quantifies epistasis in a fitness landscape to ask how individual genes and species influence the interactions in the rest of the biological network. We then generated and also reanalyzed 5-dimensional datasProceedings of the National Academy of Sciences of the United States of AmericaMaster regulators of biological systems in higher dimensions.PMC10743376R01 DK128454DP5 OD017851Joswig MLudington WBEble HLamberti LfalseMaster regulators of biological systems in higher dimensions.A longstanding goal of biology is to identify the key genes and species that critically impact evolution, ecology, and health. Network analysis has revealed keystone species that regulate ecosystems and master regulators that regulate cellular genetic networks. Yet these studies have focused on pairwise biological interactions, which can be affected by the context of genetic background and other species present, generating higher-order interactions. The important regulators of higher-order interactions are unstudied. To address this, we applied a high-dimensional geometry approach that quantifies epistasis in a fitness landscape to ask how individual genes and species influence the interactions in the rest of the biological network. We then generated and also reanalyzed 5-dimensional datas2023-01-01T00:00:00Z2023 Dec2025-04-19T16:44:40.3Z2025-04-19T16:44:40.3ZS-EPMC107433763809640910.1073/pnas.2300634120