Cell-specific expression buffering promotes cell survival and cancer robustness
Functional buffering that ensures biological robustness is critical for maintaining tissue homeostasis, organismal survival, and evolution of novelty. However, the mechanism underlying functional buffering, particularly in multicellular organisms, remains largely elusive. Here, we developed an inference index (C-score) for Cell-specific Expression- BUffering (CEBU), whereby functional buffering is mediated via expression of buffering genes in specific cells and tissues in humans. By computing C-scores across 684 human cell lines using genome-wide CRISPR screens and transcriptomic RNA-seq, we report that C- score-identified putative buffering gene pairs are enriched for members of the same duplicated gene family, pathway, and protein complex. Furthermore, CEBU is especially prevalent in tissues of low regenerative capacity (e.g., bone and neuronal tissues) and is weakest in highly regenerative blood cells, linking functional buffering to tissue regeneration. Clinically, the buffering capacity enabled by CEBU can help predict patient survival for multiple cancers. Our results reveal CEBU as a buffering mechanism contributing to tissue homeostasis and cancer robustness in humans. Summary blurbWe unveil a genome-wide functional buffering mechanism, termed Cell-specific Expression Buffering (CEBU), whereby gene expression contributes to functional buffering in specific cell types and tissues. We link CEBU to genetic interactions, tissue homeostasis and cancer robustness.