Single cell functional genomics reveals the importance of mitochondria in cell-to-cell phenotypic variation

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 >1,500 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 in 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.

即便遗传背景完全一致且所处环境相同，不同个体间的突变表型结果仍常存在显著差异。此外，单个微生物与哺乳动物细胞的增殖速率、应激耐受性及药物耐药性可存在显著差异，这对感染与癌症的临床治疗具有重要指导价值。为探究细胞间增殖异质性的成因，本研究采用高通量自动化显微检测技术，对酵母中超过1500个基因的敲除效应进行定量分析。影响线粒体的突变，其表型结果尤其多变。在突变型与野生型（wild-type）细胞中，线粒体膜电位（mitochondrial membrane potential）而非线粒体数量，在单个细胞间存在显著差异，且可预测细胞间在增殖能力、突变表型结果、应激耐受性以及临床常用抗真菌药物耐药性方面的异质性。上述结果表明，细胞器状态的细胞间差异在单细胞表型变异中发挥着关键作用。