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Noise and Delays Explain Why Some Genes Oscillate in Activity

Jeff Hasty 
While most biologists envision that gene regulation in a healthy cell runs like a Swiss watch, UCSD bioengineering professor Jeff Hasty says the process is full of unexpected variation.
September 30, 2005 -- Geneticists have debated for decades the relative importance of nature versus nurture in determining how an animal looks and behaves, and now UCSD scientists report that the coupling of noise and time delay could also be an important factor in determining the variability in gene expression that may affect phenotype.

In a paper in Proceedings of the National Academy of Sciences released online Sept. 30, the scientists led by bioengineering professor Jeff Hasty and research scientist Lev Tsimring reported that unscripted biochemical variations, or noise, combined with time delays in certain biochemical reactions may lead 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 many biologists have of a healthy cell at the genetic level is of a smoothly running Swiss watch,” said Hasty. “But recent work in several labs around the country 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 the whole organism.”

Changes in a cell 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, Tsimring,  project scientist Dmitri Bratsun, and postdoctoral fellow Dmitri Volfson modified the Gillespie algorithm, a classical method of simulating stochastic chemical reactions, by factoring in time delays. Using the modified Gillespie algorithm, coupled with a sophisticated theoretical analysis, the team discovered how the combination of intrinsic noise and biochemical delays can lead to oscillations in gene expression when such variations are not expected in the absence of delays.

“This analysis of gene regulation extends earlier explanations of the observed variability of cells,” said Hasty. “The phenotype of an organism is largely determined at the genetic level, so it is important to zoom in on the noisy details of gene expression to explain the variability that we couldn’t otherwise account for.”

Given that the coupling of 24-hour biological rhythms and the external environment can be crucial in the survival of an organism, the results may lead to new insights into the importance of the synchronization of noisy genetic oscillations with the day-night cycle.  “Our analysis provides a framework for addressing the role of noise and time delay in the generation of biological rhythms that are extremely important in many contexts,” said Hasty.

Dmitri Bratsun, Dmitri Volfson, Lev S. Tsimring, and Jeff Hasty, "Delay-induced stochastic oscillations in gene regulation" (2005). Proceedings of the National Academy of Sciences.102 (41), pp 14593-14598.

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