Abstract
Mutations frequently have outcomes that differ across individuals, even when these individuals are genetically identical and share a common environment. Moreover, individual microbial and mammalian cells can vary substantially in their proliferation rates, stress tolerance, and drug resistance, with important implications for the treatment of infections and cancer. To investigate the causes of cell-to-cell variation in proliferation, we used a high-throughput automated microscopy assay to quantify the impact of deleting >1500 genes in yeast. Mutations affecting mitochondria were particularly variable in their outcome. In both mutant and wild-type cells mitochondrial membrane potential - but not amount - varied substantially across individual cells and predicted cell-to-cell variation in proliferation, mutation outcome, stress tolerance, and resistance to a clinically used anti-fungal drug. These results suggest an important role for cell-to-cell variation in the state of an organelle in single cell phenotypic variation.
Highlights
Isogenic populations often exhibit considerable phenotypic heterogeneity even in an identical environment
We show that mitochondrial membrane potential impacts gene expression and stress tolerance and drug resistance in individual cells
To investigate cell-to-cell variation in proliferation rates, we set up a high-throughput automated time-lapse microscopy assay that measures the proliferation rates of thousands of single-cells per plate as they grow into micro-colonies
Summary
Isogenic populations often exhibit considerable phenotypic heterogeneity even in an identical environment. Recent advances in single-cell techniques are revealing the extent of transcriptomic and metabolic differences among isogenic cells (Dey et al, 2015; Trapnell, 2015) The existence of such heterogeneity in gene expression in isogenic microbial and animal populations has been shown – to some extent – to underlie the variable outcome of mutations (Dickinson et al, 2016; Burga et al, 2011; Raj et al, 2010; Eldar et al, 2009; Horvitz and Sulston, 1980).
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