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The random fluctuations—also known as noise—of gene expression could account for phenotypic variations ranging from the minor—such as different fingerprints in identical twins—to the major, including normal embryonic development, according to a study in the May 27 Science.
The authors, Erin K. O'Shea and Jonathan M. Raser at the Howard Hughes Medical Institute, University of California at San Francisco, say their measurements of noise in single budding yeast cells suggest that noise also provides a means, albeit temporary, of cellular adaptation to the environment.
O'Shea and Raser cloned two—cyan and yellow—fluorescent protein reporter genes under the control of identical budding yeast PHO5 gene promoters to look at cell-to-cell differences in a population of yeast cells. When all cells express similar quantities of the fluorescent proteins at similar times, then little variability—meaning little randomness—in gene expression is occurring, Raser said.
"If we see substantial differences between two independent but identical genes—if the yellow fluorescent protein appears 30 minutes before the cyan appears [in one cell but not in another]—then we can say that's due to randomness, because the cell can't tell the two proteins apart at all," Raser, co-author of the paper, told The Scientist.
Raser said that noise contributes to variability at the population level. "Noisy genes will have highly variable expression at the population level, and genes that are much less noisy will be very consistent at the population level," he said.
The team also identified mutations that could convert a gene from a less to a more noisy state, and vice versa, Raser said, "so it's clearly very possible that this is something that a cellular population can take advantage of: to evolve to better adapt to an environment."
Raser emphasized, however, that noise was not primarily due to a genetic change and was only a temporary means of adaptation. "You can take a genetically identical population, and noise will allow variation to appear in that population, but if you make a mutation, you can convert a very noisy or variable population into a population that is not variable as a whole," he said.
"The amount of randomness is genetic, but the nongenetic part is that different cells of the same genotype will have different phenotypes," said Hunter B. Fraser, at the Department of Molecular and Cell Biology at the University of California, Berkeley. He said that once the range of randomness had been set genetically, the phenotype was still variable within that range.
Many cellular processes are known to show variability, said Michael Elowitz, assistant professor of biology and applied physics in the Biology Division at the California Institute of Technology. "It's not genetic variation, it's what's usually known as epigenetic variation," he said.
Elowitz said he did not believe that noise was necessarily a good thing. "Cells have to learn either to deal with this noise, or suppress the noise, or operate well despite the noise, or use the noise for something—for example, to make decisions to differentiate stochastically," he said.
The possibility of quantifying noise for particular genes, coupled with increasing knowledge of gene networks, means that "now we start to have a real interesting picture of how a chemical circuit works inside the cell," according to Elowitz, who was not involved in the study.
Elowitz said that genetic networks on which the cell is based are like electrical circuits operating inside the cell, showing deterministic regimes and noise among the electronic components. "We want to be able to use this information so we can really understand how the genetic networks operate at the single cell level," he said.
Gene expression is not normally considered to be a random process, said Hunter, who was not involved in the study. "You [only] get this idea because most studies use large populations of cells and they take a population average, which loses any signal of stochasticity. You have to look at individual cells to see the stochasticity—and that's what they've done."
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