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

Mariona Nadal-Ribelles (), Carme Solé, Anna Díez-Villanueva, Camille Stephan-Otto Attolini, Yaima Matas, Lars Steinmetz, Eulàlia Nadal () and Francesc Posas ()
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Mariona Nadal-Ribelles: Universitat Pompeu Fabra
Carme Solé: Universitat Pompeu Fabra
Anna Díez-Villanueva: the Barcelona Institute of Science and Technology
Camille Stephan-Otto Attolini: the Barcelona Institute of Science and Technology
Yaima Matas: Universitat Pompeu Fabra
Lars Steinmetz: School of Medicine
Eulàlia Nadal: Universitat Pompeu Fabra
Francesc Posas: Universitat Pompeu Fabra

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-57600-4

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