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

Area of Science:

• Genomics
• Systems Biology
• Cell Biology

Background:

• Biological systems exhibit inherent heterogeneity, influencing cell fate and phenotypic variability.
• Understanding the molecular mechanisms and genetic underpinnings of genotype-phenotype heterogeneity is a significant scientific challenge.

Purpose of the Study:

• To create a high-resolution single-cell yeast transcriptome atlas for genome-scale analyses.
• To investigate the genetic basis of transcriptional heterogeneity and its impact on cell states and fitness.

Main Methods:

• Construction of a yeast knockout library with clone and genotype RNA barcoding.
• Generation of a single-cell transcriptome atlas for 3500 mutants under control and stress conditions.
• Multimodal perturbation-based single-cell analysis.

Main Results:

• Transcriptional heterogeneity reflects coordinated gene programs and continuous cell states responsive to stimuli.
• Cell state plasticity is genetically tunable, with specific mutants acting as state attractors.
• Disruption of cell state homeostasis leads to reduced adaptive fitness.
• Regulators of transcriptional heterogeneity are functionally diverse and environmentally influenced.

Conclusions:

• The yeast Genotype-to-Transcriptome Atlas provides insights into organism-level responses to genetic and environmental perturbations.
• Transcriptional heterogeneity is a key determinant of cell state and adaptive capacity.
• Genetic and environmental factors interact to shape cellular responses and organismal fitness.