Variability in gene expression underlies incomplete penetrance

By Arjun Raj, Scott A. Rifkin, Erik C. Andersen, Alexander van Oudenaarden. Nature, 2010

698 citations recorded by the source corpus.

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.

Subfields: Aging, Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/77717dfb9c3010904307390dfd224be39307b615

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Citations in the corpus

H3K4me3 breadth is linked to cell identity and transcriptional consistency (2014, background): “Reduction of transcription stochasticity is required for embryo patterning (Lagha et al., 2013; Raj et al., 2010), yet increased transcriptional variability may be permissive for cell-fate decisions (Balázsi et al.”
Cellular Decision-Making and Biological Noise: From Microbes to Mammals (2011, background): “elegans development (Raj et al., 2010) in a regulatory cascade composed of multiple feed-forward loops controlling the expression of elt-2, a self-activating transcription factor critical for intestinal cell-fate specification (Fig.”
Localization and abundance analysis of human lncRNAs at single-cell and single-molecule resolution (2015, methodology): “We performed RNA FISH staining as previously described [24,76].”