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Genetic screens are tools used to identify genes and mutations responsible for phenotypes of interest. Genetic screens help identify individuals or a group of people at risk of developing  genetic diseases and help them with early intervention, targeted therapy, and reproductive options.
Forward genetic screens
Forward or “classical” genetic screens involve creating random mutations in an organism’s DNA using radiation, mutagens, or insertion of additional bases, which...
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A single-cell resolved genotype-phenotype map using genome-wide genetic and environmental perturbations.

Mariona Nadal-Ribelles1,2, Carme Solé3,4, Anna Díez-Villanueva4

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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.