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Michael B. Elowitz,12*Arnold J. Levine,1Eric D. Siggia,2Peter S. Swain2
Clonal populations of cells exhibit substantial
phenotypic variation. Such heterogeneity can be essential for many
biologicalprocesses and is conjectured to arise from stochasticity, or
noise,in gene expression. We constructed strains of Escherichia
colithat enable detection of noise and discrimination between thetwo mechanisms by which it is generated. Both stochasticity inherentin
the biochemical process of gene expression (intrinsic noise)and
fluctuations in other cellular components (extrinsic noise)contribute
substantially to overall variation. Transcription rate,regulatory
dynamics, and genetic factors control the amplitudeof noise. These
results establish a quantitative foundation formodeling noise in
genetic networks and reveal how low intracellularcopy numbers of
molecules can fundamentally limit the precisionof gene regulation.
1 Laboratory of Cancer Biology,
2 Center for Studies in Physics and Biology,
Rockefeller University, New York, NY 10021, USA.
*
To whom correspondence should be addressed. E-mail:
elowitm{at}rockefeller.edu
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|Abstract »|Full Text »|PDF »
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|Abstract »|Full Text »|PDF »
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|Abstract »|Full Text »|PDF »
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|Full Text »|PDF »
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|Abstract »|Full Text »|PDF »
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|Abstract »|Full Text »|PDF »
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|Abstract »|Full Text »|PDF »
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|Abstract »|Full Text »|PDF »
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PNAS
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|Abstract »|Full Text »|PDF »
Population robustness arising from cellular heterogeneity.
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|Abstract »|Full Text »|PDF »
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|Abstract »|Full Text »|PDF »