Noise in gene expression: origins, consequences, and control

Abstract

Genetically identical cells and organisms exhibit remarkable diversity even when they have identical histories of environmental exposure. Noise, or variation, in the process of gene expression may contribute to this phenotypic variability. Recent studies suggest that this noise has multiple sources, including the stochastic or inherently random nature of the biochemical reactions of gene expression. In this review, we summarize noise terminology and comment on recent investigations into the sources, consequences, and control of noise in gene expression.

Fig. 1

Examples of possible stochastic influences on phenotype. (A) The fingerprints of identical twins are readily distinguished on close examination. Reprinted from () with permission from Elsevier. (B) Cc, the first cloned cat (left) and Rainbow, Cc's genetic mother (right), display different coat patterns and personalities (). Photo credit, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University.

Fig. 2

Noise definitions and characteristics. (A) Intrinsic noise results in differences between two reporters of the same gene in a single cell. (B) Extrinsic noise affects two reporters of the same gene equally in a single cell but causes differences from cell to cell or in a single cell over time. (C) Global noise affects two distinct genes equally but results in differences from cell to cell or in a single cell over time. (D) Gene- or pathway-specific extrinsic noise affects two reporters of the same gene equally but causes differences from a reporter of a second distinct gene in a single cell. (E to H) Noise in a population; each line represents a different cell. (E) Manipulable extrinsic noise: In a synchronized population of cells, cell cycle progression results in predictable changes in protein abundance over time (red lines); when the cells grow asynchronously, the population displays variability (black lines). (F) Noise of low magnitude and short autocorrelation time. (G) Noise of high magnitude and short autocorrelation time. (H) Noise of high magnitude and long autocorrelation time.

Fig. 3

Consequences of noise. (A) Small differences in gene product abundance affect reproductive fitness. (B) In a heterozygous diploid population, cells display the phenotypes associated with each homozygote as well as the heterozygote. (C) Noise allows simultaneous achievement of multiple steady-state phenotypes in a population. (D) Noise can be transmitted from one gene, in this case a transcription factor, to a downstream target. The intrinsic and global extrinsic noise of the transcription factor can cause extrinsic noise in the downstream gene.

Fig. 4

Control of noise. (A) Infrequent transcription followed by efficient translation results in high intrinsic noise in protein levels (left); frequent transcription and inefficient translation results in low intrinsic noise (right). (B) Infrequent promoter transitions between inactive and active states followed by efficient transcription result in high intrinsic noise in mRNA levels (left); frequent promoter transitions followed by inefficient transcription result in low intrinsic noise (right). (C) Increases in gene copy number through polyploidy (top right) or gene duplication (bottom right) result in decreased intrinsic noise relative to a single gene copy (left). (D) Negative feedback, as when a transcription factor represses its own transcription (right), results in decreased noise relative to a linear pathway (left).