UCSF

A fundamental goal of biology is understanding how a limited number of human genes are responsible for governing the cellular response to myriad insults and environmental changes. Relationships between genes, processes, and ontologies are thought to be necessarily plastic to achieve this adaptability, but quantitative determination of gene functional connection is non-trivial and historically difficult at scale. Here, we developed a framework for conditional genetic interaction mapping in human cells to evaluate the plasticity of human genetic architecture upon environmental perturbation using three distinct challenges to cell cycle regulation, genome fidelity, and metabolism as archetypes. For the first time, we systematically and quantitatively discover rewiring of human gene functional connections across conditions, shedding light on how interdependence of ontologies is contingent on their environment. We reproducibly nominate novel context specific complex identities, and propose new putative relationships between established complexes and individual genes. This concept is highlighted in our finding that the TIP60 histone acetyltransferase complex radically alters its interaction profile after inhibition of ATR, moving from a peripheral to a key factor in the regulation of core cellular processes such as cell cycle control and metabolism. We further find that loss of TIP60 function yields a cell state that is refractory to the effects of ATR inhibition at the transcriptional level. Our work here provides a resource for understanding the genetic landscape regulating DNA replication fidelity and metabolism and establishes a scalable framework for measuring the plasticity of human gene function in response to environmental stimulus.