Phenotype Is Influenced By Nature, Nurture And Noise

In a paper in Proceedings of the National Academy ofSciences released online Sept. 30, the scientists led by bioengineeringprofessor Jeff Hasty and physicist Lev Tsimring reported thatunscripted biochemical variations, or noise, combined with time delaysin certain biochemical reactions may lead to oscillations in generegulation that couldn’t otherwise be predicted. Such noise isroutinely described by cell biologists who record large phenotypicdifferences between supposedly identical cells in a single flask ofgrowth medium.

“The mental picture many biologists have of ahealthy cell at the genetic level is of a smoothly running Swisswatch,” said Hasty. “But recent work in several labs around the countryare proving otherwise. The fine-grain fluctuations we see in thegenetic regulation within single cells may lead to new insights aboutvariability at the level of the whole organism.”

Changes in acell phenotype may be triggered by environmental factors, by programmedgenetic instructions, or more subtly by built-in delays in biochemicalpathways that generate oscillations, sometimes in 24-hour circadianperiods. Hasty, Tsimring, Dmitri Bratsun, and Dmitri Volfsonmodifiedthe Gillespie algorithm, a classical method of simulating stochasticchemical reactions, by factoring in time delays. Using the modifiedGillespie algorithm, coupled with a sophisticated theoretical analysis,the team discovered how the combination of intrinsic noise andbiochemical delays can lead to oscillations in gene expression whensuch variations are not expected in the absence of delays.

“Thisanalysis of gene regulation extends earlier explanations of theobserved variability of cells,” said Hasty. “The phenotype of anorganism is largely determined at the genetic level, so it is importantto zoom in on the noisy details of gene expression to explain thevariability that we couldn’t otherwise account for.”

Given thatthe coupling of 24-hour biological rhythms and the external environmentcan be crucial in the survival of an organism, the results may lead tonew insights into the importance of the synchronization of noisygenetic oscillations with the day-night cycle. “Our analysis provides aframework for addressing the role of noise and time delay in thegeneration of biological rhythms that are extremely important in manycontexts,” 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.