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Variability in gene expression underlies incomplete penetrance

Nature volume 463, pages 913–918 (2010)Cite this article

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Abstract

The phenotypic differences between individual organisms can often be ascribed to underlying genetic and environmental variation. However, even genetically identical organisms in homogeneous environments vary, indicating that randomness in developmental processes such as gene expression may also generate diversity. To examine the consequences of gene expression variability in multicellular organisms, we studied intestinal specification in the nematode Caenorhabditis elegans in which wild-type cell fate is invariant and controlled by a small transcriptional network. Mutations in elements of this network can have indeterminate effects: some mutant embryos fail to develop intestinal cells, whereas others produce intestinal precursors. By counting transcripts of the genes in this network in individual embryos, we show that the expression of an otherwise redundant gene becomes highly variable in the mutants and that this variation is subjected to a threshold, producing an ON/OFF expression pattern of the master regulatory gene of intestinal differentiation. Our results demonstrate that mutations in developmental networks can expose otherwise buffered stochastic variability in gene expression, leading to pronounced phenotypic variation.

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Figure 1: Gene expression in the C. elegans intestinal cell fate specification network.
Figure 2: Expression dynamics in wild-type and skn-1 mutant embryos.
Figure 3: High levels of end-1 are required for elt-2 expression in skn-1 mutant embryos.
Figure 4: Chromatin regulators and indirect network connections regulate variability in end-1 expression.

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Acknowledgements

We thank H. R. Horvitz for early discussions and technical assistance. We also thank H. R. Horvitz and J. Gore for a critical reading of the manuscript. This work was funded by a National Institutes of Health (NIH) Director’s Pioneer Award to A.v.O. A.R. was supported by a National Science Foundation MSPRF fellowship DMS-0603392 and a Burroughs-Wellcome Fund Career Award at the Scientific Interface. S.A.R. was supported by an NIH NRSA postdoctoral fellowship 5F32GM080966.

Author Contributions A.R. and S.A.R. performed the experiments. A.R., S.A.R. and E.A. constructed the GFP-labelled skn-1 strains. A.R., S.A.R. and A.v.O. designed the experiments, analysed the data and wrote the manuscript.

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Author notes

  1. Arjun Raj & Scott A. Rifkin

    Present address: Present addresses: Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA (A.R.). Section of Ecology, Behavior, and Evolution, Division of Biology, University of California, San Diego 92093, USA (S.A.R.).,

  2. Arjun Raj and Scott A. Rifkin: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Physics,,

    Arjun Raj, Scott A. Rifkin & Alexander van Oudenaarden

  2. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA,

    Arjun Raj, Scott A. Rifkin, Erik Andersen & Alexander van Oudenaarden

  3. Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey 08544, USA ,

    Erik Andersen

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Correspondence to Alexander van Oudenaarden.

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Raj, A., Rifkin, S., Andersen, E. et al. Variability in gene expression underlies incomplete penetrance. Nature 463, 913–918 (2010). https://doi.org/10.1038/nature08781

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