Perturbation-driven transcriptional heterogeneity impacts cell fitness

Heterogeneity is inherent to living organisms and it determines cell fate and phenotypic variability1-3. Indeed, even isogenic cell populations vary in quantifiable phenotypes. Here we generated a high-resolution single-cell yeast transcriptome atlas using genotype and clone RNA barcoded deletions to profile 3500 mutants under control and stress conditions in a genome-scale genetic and environmental perturbation screen. We uncovered a myriad of cell states within a population with specific transcriptional architectures that are both intrinsically and extrinsically regulated, thereby suggesting a continuum of cell states. Cell state occupancy and transition can be genetically modulated with specific mutants that act as state attractors, resulting in differential fitness. By exploiting the power of intra-genetic variability, we identified regulators of transcriptional heterogeneity that are functionally diverse and influenced by the environment. One-Sentence SummaryThe yeast single cell-transcriptome atlas based on RNA-traceable genetic perturbations served to map cellular states and define their underlying genetic basis.