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Bioessays. 2016 Feb;38(2):172-80. doi: 10.1002/bies.201500124. Epub 2015 Dec 2.

Variation is function: Are single cell differences functionally important?: Testing the hypothesis that single cell variation is required for aggregate function.

Dueck H1, Eberwine J1,2,3, Kim J1,2,3,4,5.

Author information

Genomics and Computational Biology Graduate Group, University of Pennsylvania, Philadelphia, PA, USA.
Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA.
Penn Program in Single Cell Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Biology, University of Pennsylvania, Philadelphia, PA, USA.
Department of Computer and Information Science, University of Pennsylvania, Philadelphia, PA, USA.


There is a growing appreciation of the extent of transcriptome variation across individual cells of the same cell type. While expression variation may be a byproduct of, for example, dynamic or homeostatic processes, here we consider whether single-cell molecular variation per se might be crucial for population-level function. Under this hypothesis, molecular variation indicates a diversity of hidden functional capacities within an ensemble of identical cells, and this functional diversity facilitates collective behavior that would be inaccessible to a homogenous population. In reviewing this topic, we explore possible functions that might be carried by a heterogeneous ensemble of cells; however, this question has proven difficult to test, both because methods to manipulate molecular variation are limited and because it is complicated to define, and measure, population-level function. We consider several possible methods to further pursue the hypothesis that variation is function through the use of comparative analysis and novel experimental techniques.


bet-hedging; evolution of variation; fractional response; functional variation; single cell transcriptome; single cell variation

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