May 27, 2004
"Noisy" Genes Can Have Big Impact
Experiments by Howard Hughes Medical Institute (HHMI) researchers
have revealed it might be possible for randomness in gene expression to
lead to differences in cells — or people, for that matter — that are
genetically identical.
The researchers, HHMI investigator Erin K.
O'Shea and colleague Jonathan M. Raser, both at the University of
California, San Francisco, published their findings May 27, 2004, in
Science Express, the online edition of the journal
Science.
“While processes such as gene expression involved in the development of organisms proceed in a very orderly fashion, paradoxically, they depend on chemical reactions that are inherently probabilistic.”
Erin K. O'Shea
According to O'Shea, the original notion that random noise in gene
expression — the processes by which proteins are synthesized from the
information contained in DNA — arose from a paradox. “While
processes such as gene expression involved in the development of
organisms proceed in a very orderly fashion, paradoxically, they depend
on chemical reactions that are inherently probabilistic, like flipping
a coin,” said O'Shea. “And since these processes involve
small numbers of molecules, they should be significantly affected by
chance, just as flipping a coin a few times will be more heavily
affected than flipping it many times.”
Earlier experiments by Michael Elowitz, who is now at the California
Institute of Technology, and his colleagues at The Rockefeller
University demonstrated that this type of random noise existed in the
common bacterium E. coli. In later experiments, Raser and O'Shea
set out to explore the mechanism underlying random noise in gene
expression in a higher organism — choosing the most primitive animal,
yeast.
Raser and O'Shea used an indicator technique developed by Elowitz to
detect noise in gene expression. They engineered yeast cells to produce
blue and yellow fluorescent indicator proteins under the control of the
same “promoter” — the segment of the gene regulating its
expression. In this scheme, if there were no noise, every cell would
appear the same mix of blue and yellow color under the microscope.
However, if any noise crept in, it would produce a variation in
colors among the cells. This color variation could then be measured to
determine the amount of noise that was present. This method eliminated
any influence of external environmental factors or variables such as
differences in cell type, since the two genes were operating inside the
same cell.
After using this technique to study the function of various
promoters, the scientists concluded that noise did, indeed, affect gene
expression in the yeast cells. They also found that different promoters
produced different amounts of noise.
Based on their studies, Raser and O'Shea believe they have
identified the source of a major portion of the random noise they
observed. “Our experiments suggest that for the promoters we
studied, a major source of noise is the act of preparing the promoter
DNA, the regulatory region, to be competent for transcription,”
said O'Shea. This preparation, she said, involves
“remodeling” the protective structure, called the
nucleosome, which enfolds the regulatory region of the gene so that the
transcription machinery can access it. “And the step that is
generating noise is this act of removing the nucleosomes, in order to
allow access of the transcription machinery and the regulatory
proteins,” she said.
Remodeling is particularly slow, O'Shea said, and subject to
significant probabilistic variation. This variation would likely have
an affect on the amount of mRNA produced for each marker-tagged gene
and thus the level of a given protein in the cell — affecting its
color.
According to O'Shea, randomness in gene express could have important
evolutionary and biological implications, both advantageous for cells
and deleterious. For example, mutations in genes could change their
“noisiness” independent of the effect of the mutation
itself. Noise in essential genes could be deleterious for a cell.
However, noise could also produce diversity in populations of cells
with the same genetic makeup, and this diversity could make them more
adaptable to changes.
Another effect of randomness in gene expression might be observed,
for example, in cells with two slightly different copies of the same
gene, where one might be noisier than the other. Such noise might also
produce variability among cells that might offer evolutionary
advantages.
Noise in genes might also be a trigger for the formation of tumors,
said O'Shea. In cases where cells lose one copy of a gene through
mutation, the reduction in gene number increases the noise in gene
expression. This increase in noise makes it more likely that the
remaining gene might alter its activity to trigger uncontrolled
proliferation.
Noise could be necessary for normal development of some biological
systems, said O'Shea. For example, when olfactory neurons in the
developing embryo are “deciding” which of a multitude of
possible odorant receptors they will produce — a choice that is final
— random noise in gene expression might be necessary to enable this
decision, she said.
O'Shea said that her group plans to continue this line of research
and hopes to identify in which cases such randomness is beneficial to
an organism. Then, they will alter the level of noise and determine how
it affects the fitness of the organism. They also want to follow noise
production in a single cell over time — rather than in populations of
cells — to explore in more detail how noise is produced.
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