In a paper in Proceedings of the National Academy of Sciences released online Sept. 30, the scientists led by bioengineering professor Jeff Hasty reported that a newly developed computer model shows that a combination of unscripted biochemical variations, or noise, leads to oscillations in gene regulation that couldn't otherwise be predicted. Such noise is routinely described by cell biologists who record large phenotypic differences between supposedly identical cells in a single flask of growth medium.

The mental picture most biologists have of a cell is of a smoothly running Swiss watch," said Hasty. "But our results and the findings of other theorists and computational biologists are proving otherwise. The fine-grain fluctuations we see in the genetic regulation within single cells may lead to new insights about variability at the level of a fly, cat, or human."

Changes in a cell's phenotype may be triggered by environmental factors, by programmed genetic instructions, or more subtly by built-in delays in biochemical pathways that generate oscillations, sometimes in 24-hour circadian periods. Hasty, graduate students Dmitri Bratsun and Dmitri Volfson, and post-doctoral fellow Lev. S. Tsimring modified the Gillespie algorithm, a well known computer model of cellular reactions, by factoring in intrinsic noise and delays. Using the modified Gillespie algorithm and sophisticated mathematical analyses of sets of biochemical reactions, the team discovered how the combination of intrinsic noise and biochemical delays also generates oscillations in phenotype.

"We think an analysis of such fine details of gene regulation explains not only the observed variability of cells, but also, in a larger sense, why identical twins don't necessarily have identical fingerprints," said Hasty. "Given that every potential feature of an organism is ultimately determined at the genetic level, it is important to zoon in on the noisy details of gene expression to explain the variability that we couldn't otherwise account for."

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