A single-cell resolved genotype-phenotype map using genome-wide genetic and environmental perturbations

Nadal Ribelles, Mariona, 1984-; Solé, Carme; Díez Villanueva, Pablo; Stephan-Otto Attolini, Camille; Matas, Yaima; Steinmetz, Lars M.; Nadal Clanchet, Eulàlia de; Posas Garriga, Francesc

doi:http://dx.doi.org/10.1038/s41467-025-57600-4

A single-cell resolved genotype-phenotype map using genome-wide genetic and environmental perturbations

Llicència

Citació

Nadal-Ribelles M, Solé C, Díez-Villanueva A, Stephan-Otto Attolini C, Matas Y, Steinmetz L, et al. A single-cell resolved genotype-phenotype map using genome-wide genetic and environmental perturbations. Nat Commun. 2025 Mar 18;16(1):2645. DOI: 10.1038/s41467-025-57600-4

Resum

Heterogeneity is inherent to living organisms and it determines cell fate and phenotypic variability. Despite its ubiquity, the underlying molecular mechanisms and the genetic basis linking genotype to-phenotype heterogeneity remain a central challenge. Here we construct a yeast knockout library with a clone and genotype RNA barcoding structure suitable for genome-scale analyses to generate a high-resolution single-cell yeast transcriptome atlas of 3500 mutants under control and stress conditions. We find that transcriptional heterogeneity reflects the coordinated expression of specific gene programs, generating a continuous of cell states that can be responsive to external insults. Cell state plasticity can be genetically modulated with mutants that act as state attractors and disruption of state homeostasis results in decreased adaptive fitness. Leveraging on intra-genetic variability, we establish that regulators of transcriptional heterogeneity are functionally diverse and influenced by the environment. Our multimodal perturbation-based single-cell Genotype-to-Transcriptome Atlas in yeast provides insights into organism-level responses.