Noise in gene expression -...
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Noise in gene expression
Tie Koide, 14 jun 2012
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“Life is a study in contrasts between randomness and determinism: from the chaos of biomolecular interactions to the precise coordination of development, living organisms are able to resolve these two seemingly contradictory aspectsof their internal workings”
Raj & van OudernaardenCell 2008
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Photo credit, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University.
Raser & O'Shea, Science 2005
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When large numbers of molecules are present, chemical reactions may proceed in a predictable manner.
However, when only a few molecules of a specific typeexist in a cell, stochastic effects can become prominent.
Raser & O'Shea, Science 2005
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Stochastic (from the Greek στόχος for aim or guess) is an adjective that refers to systems whose behavior is intrinsically non-deterministic, sporadic and categorically not intermittent.
A stochastic process is one whose behavior is non-deterministic, in that a system's subsequent state is determined both by the process's predictable actions and by a random element.
From Wikipedia
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Why is gene expression considered a stochastic process???
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“Noise” in gene expression refer to the measured level of variation in gene expression among cells, regardless of source, within a supposedly identical population
Raser & O'Shea, 2005
η = σ/μ coefficient of variationEstimate of overall population variability
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Sources of variation in gene expression:
1. inherent stochasticity of biochemical processes that are dependent on infrequent molecular events involving small numbers of molecules
2. variation in gene expression owing to differences in the internal states of a population of cells, either from predictable processes or from a random process
3. subtle environmental differences, such as morphogen gradients in multicellular development
4. ongoing genetic mutation, either random or directed
Raser & O'Shea, 2005
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Gene expression vary from cell to cell
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Gene expression vary from cell to cell
Novick and Weiner, PNAS 1957
Beta-galactosidase production in individual cells: highly variable and randomInduction: increase the proportion of cells expressing the enzyme (not every cell expression level)
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“ (…) In any event, the existence of induced inheritable changes of the kind described here raises the possibility that some differences which arise in a clone of organisms may be the result of changes in cellular systems other than the primary genetic endowment of the cell”
Novick and Weiner, PNAS 1957
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Gene expression vary from cell to cell
Ko et al, Cell 1990
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Theoretical work
McAdams & Arkin, 1997Arkin, 1998
Model gene expression using stochastic formulation
Protein numbers – flutuate within individual cellsLytic-lysogenic cycles of phage lambda – stochastic effects
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Characterization of stochastic gene expression: started with synthetic biology experiments
http://syntheticbiology.org/
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http://partsregistry.org/Main_Page
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Repressilator: artificial clock
Elowitz & Leibler, Nature 2000
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Engineering stability
Becskei & Serrano, Nature 2000
Negative feedback loops to control noise
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How can we study the “noise” in gene expression?
Can we count the total number of molecules in a single cell?
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Experimental developments:single molecule view of gene expression
Protein levels
GFP (and other fluorescent probes)FACS – Fluorescent Activated Cell SortingLive cell microscopy
mRNA levels
Single cell quantitative PCRSingle cell microarrays In situ fluorescent PCRFISH – Fluorescent in situ hybridizationMS2
Microfluidics
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Larson et al, Trends in Cell Biology 2009
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Larson et al, 2009
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RNA mimics of GFPPaige et al, Science 2011
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Microfluidics
http://groups.csail.mit.edu/cag/biostream/
Lin & Levchenko, 2012
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Szita et al, 2010
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http://www.elveflow.com/microfluidic-reviews-and-tutorials/review-microfluidic-for-cell-biology
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So far, we know that noise exists, can be detected and even engineered to be controlled.
...but what are the causes of stochastic gene expression?
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Causes of stochastic gene expression???
Elowitz et al, Science 2002
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Raser & O'Shea, Science 2005
Intrinsic noise
Extrinsic noise
Global noise
Gene or pathway specific noise
Noise in populations
Manipulable extrinsicnoise
Noise of low magnitude and short autocorrelation time
Noise of high magnitude and short autocorrelation time
Noise of high magnitude and long autocorrelation time
Autocorr. Time = time scale over which the protein production rate fluctuates in any given cell
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Raj & van Oudenaarden, 2008
Noise in prokaryotic gene expression
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Raj & van Oudenaarden, 2008
Transcriptional bursts and cell to cell variability
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Advantage of couting molecules
Probability distribution of molecules corresponding to each stage of the central dogma, for a single gene
Larson et al, 2009
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Theoretical models
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Consequences of noise in gene expression
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Control of noise
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Functional roles for noise in genetic circuits
Eldar & Elowitz, Nature, 2010
Afternoon discussion:
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Figure 1: Gene expression noise is ubiquitous, and affects diverse systems at several levels.
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Figure 2: Frequency modulation of stochastic nuclear localization bursts enables coordination of gene regulation.
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Figure 3: Probabilistic differentiation.
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Figure 4: Roles of noise in evolution.