Cell-specific expression buffering promotes cell survival and cancer robustness

Abstract Functional buffering ensures biological robustness critical for cell survival and physiological homeostasis in response to environmental challenges. However, in multicellular organisms, the mechanism underlying cell- and tissue-specific buffering and its implications for cancer development remain elusive. Here, we propose a Cell-specific Expression-BUffering (CEBU) mechanism, whereby a gene’s function is buffered by cell-specific expression of a buffering gene, to describe functional buffering in humans. The likelihood of CEBU between gene pairs is quantified using a C-score index. By computing C-scores using genome-wide CRISPR screens and transcriptomic RNA-seq of 684 human cell lines, we report that C-score-identified putative buffering gene pairs are enriched for members of the same pathway, protein complex and duplicated gene family. Furthermore, these buffering gene pairs contribute to cell-specific genetic interactions and are indicative of tissue-specific robustness. C-score derived buffering capacities can help predict patient survival in multiple cancers. Our results reveal CEBU as a critical mechanism of functional buffering contributing to cell survival and cancer robustness in humans. Summary blurbThis study explores a genome-wide functional buffering mechanism, Cell-specific Expression Buffering (CEBU), where gene expression contributes to functional buffering in specific cell types and tissues. CEBU is prevalent in humans, linking to genetic interactions, tissue homeostasis and cancer robustness.