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  • Review Article
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Challenges in measuring and understanding biological noise

Nature Reviews Genetics volume 20, pages 536–548 (2019)Cite this article

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An Author Correction to this article was published on 03 June 2019

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Abstract

Biochemical reactions are intrinsically stochastic, leading to variation in the production of mRNAs and proteins within cells. In the scientific literature, this source of variation is typically referred to as ‘noise’. The observed variability in molecular phenotypes arises from a combination of processes that amplify and attenuate noise. Our ability to quantify cell-to-cell variability in numerous biological contexts has been revolutionized by recent advances in single-cell technology, from imaging approaches through to ‘omics’ strategies. However, defining, accurately measuring and disentangling the stochastic and deterministic components of cell-to-cell variability is challenging. In this Review, we discuss the sources, impact and function of molecular phenotypic variability and highlight future directions to understand its role.

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Fig. 1: Regulatory features controlling noise.
Fig. 2: Regulation of noise forms single-gene and coupled variability.
Fig. 3: Variability versus mean expression relationship.
Fig. 4: The role of biological noise in cellular systems.

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  • 03 June 2019

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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Acknowledgements

We thank B. Simons for critically reading and commenting on the manuscript. We also thank D. Grün for providing the smFISH counts for serum-grown mouse embryonic stem cells in figure 3. N.E. was supported by the European Molecular Biology Laboratory (EMBL) International PhD Programme. M.D.M. was supported by Wellcome Trust grant 105045/Z/14/Z to J.C.M. J.C.M. was supported by core funding from EMBL and Cancer Research UK (award number 17197).

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Authors and Affiliations

  1. European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, UK

    Nils Eling & John C. Marioni

  2. Wellcome Sanger Institute, Welcome Genome Campus, Hinxton, UK

    Nils Eling, Michael D. Morgan & John C. Marioni

  3. Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK

    John C. Marioni

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  1. Nils Eling
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  2. Michael D. Morgan
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Glossary

Single-molecule fluorescence in situ hybridization

(smFISH). Spatial detection of individual RNA molecules by hybridization with fluorescently labelled DNA probes and imaging.

MS2 stem loop system

Spatial detection of individual RNA molecules by binding of the GFP-tagged MS2 bacteriophage protein to MS2 RNA-binding sequences inserted in the non-coding regions of target RNA molecules.

CpG islands

(CGIs). Computationally defined genomic regions of more than 200 bases with a high CpG dinucleotide content, typically defined as being greater than the genome-wide average.

Bivalent promoters

Gene promoters with both repressive and activating chromatin marks.

Technical noise

Variation in measured components (for example, mRNA or proteins) that arises during data acquisition.

Sporulation

A process during which the cell’s vegetative growth ends, leading to the formation of endospores that survive the altered environment.

Competence

Competent bacteria have the ability to take up DNA from the environment.

Symmetry breaking

The emergence of asymmetry regarding the distribution of factors influencing developmental potency.

Paracrine and autocrine signalling

Autocrine hormone signalling affects the hormone-producing cell, whereas paracrine hormone signalling affects nearby cells.

Autodepletion

Depletion of precursor RNAs by their protein product.

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Eling, N., Morgan, M.D. & Marioni, J.C. Challenges in measuring and understanding biological noise. Nat Rev Genet 20, 536–548 (2019). https://doi.org/10.1038/s41576-019-0130-6

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