Master regulators of evolution and the microbiome in higher dimensions

TL;DR

This paper introduces a high-dimensional geometry method to identify key genes and species acting as master regulators of complex biological interactions, influencing evolution and ecology beyond pairwise relationships.

Contribution

It develops a novel mathematical approach to quantify higher-order interactions and applies it to real datasets, revealing new master regulators in genetic and microbiome networks.

Findings

Identified key genes like rbs locus and pykF as regulators.

Found Lactobacilli species as influential microbiome regulators.

Demonstrated higher-order regulators can shape fitness landscape topography.

Abstract

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 new 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 datasets (two genetic, two microbiome). We identified key genes (e.g. the rbs locus and pykF) and species (e.g. Lactobacilli) that control the interactions of many other genes and species. These higher-order master regulators can induce or suppress evolutionary and ecological diversification by controlling the topography of the fitness landscape. Thus, we provide mathematical intuition and justification for exploration of biological networks in higher dimensions.