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A Genetic Snooze Button: How Synonymous Codons Regulate the Biological Clock

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The genetic code is a "degenerate" code, meaning it's not strictly one-for-one. Three different bases (called synonymous codons), for instance, can code for the same amino acid, proline: CCA, CCG and CCC. Why is this? On the basis of simple arithmetic, there are 4 bases in triplets, allowing for 4 x 4 x 4 arrangements, 64 codons in all. But there are only 20 amino acids used by most living things. Because of this oversupply of possible codons, some amino acids can allow more than one codon to designate them.

Initially, this "degeneracy" seemed a bit wasteful, but evidence has been accumulating that the synonymous codons actually do behave differently, leading to different functional outcomes (see ENV's coverage, here and here). The first clues came from observations that different synonymous codons affected the rate of translation in the ribosome. Apparently there is an "optimal" codon that translates quickly, while others cause a bit of delay.

It turns out those delays can have functional consequences. Vanderbilt University researchers claim that the synonyms allow for a new kind of regulation. The example they give involves circadian rhythms (the biological clock). Faster translation is not always better, they found, contrary to an evolutionary expectation:

It turns out that there is a reason for this redundancy. Some codons are faster and easier for cells to process and assemble into proteins than others. Recognition of this difference led to the concept of optimal codons and the hypothesis that natural selection should drive organisms - particularly fast growing ones - to use genes that use optimal codons to make critical proteins that need to be highly abundant or synthesized rapidly in cells.
cyanobacteria biological clock molecules.

The problem with this hypothesis was shown by Johnson and Rokas' study of the effect of changing codon usage on the simple biological clock found in single-celled cyanobacteria (blue-green algae) and a similar study of the more complex biological clock found in bread mold performed by a team led by Professor Yi Liu of University of Texas Southwestern Medical Center that were published together.

"What the Liu team found was that optimizing all the codons used by the fungal biological clock knocked the clock out, which was totally unexpected! Those researchers concluded that clock proteins in the fungus are not properly assembled if they are synthesized too rapidly; it's as if the speed of one's writing affected our ability to read the text," Johnson summarized. (Emphasis added.)

New work at Vanderbilt shows that replacing codons for the biological clock in cyanobacteria with the most optimal ones had "a more subtle, but potentially as profound effect: It significantly reduced cell survival at certain temperatures." In other words, the ability to switch between synonymous codons gives the bacteria a toolkit to adapt to changing environmental conditions. Referring again to the writing analogy, Professor Antonis Rokas says, "In cyanobacteria, it's as if writing speed changes the meaning."
Like many written languages, the genetic code is filled with synonyms: differently spelled "words" that have the same or very similar meanings. For a long time, biologists thought that these synonyms, called synonymous codons, were in fact interchangeable. Recently, they have realized that this is not the case and that differences in synonymous codon usage have a significant impact on cellular processes, so scientists have advanced a wide variety of ideas about the role that these variations play.
That's where the "snooze button" comes in. The biological clock is central to many biological processes, "including sleeping and feeding patterns, core body temperature, brain activity, hormone production and cell regeneration." The ability to affect the rate of translation is another way for an organism to adapt:
"This work shows how organisms can ignore the clock under certain circumstances -- much like hitting a biological snooze button on the internal timepiece--and enhance their survival in the face of ever-changing circumstances."
This new understanding of synonymous codons allows researchers to consider new ways to engineer bacteria for optimal production of desirable substances like biofuels merely by tuning the synonyms used in translation. Rokas said, "It is now clear that variations in codon usage is a fundamental and underappreciated form of gene regulation."

The news release from Vanderbilt promises without elaboration that this discovery represents an "important advance in understanding evolution at the molecular level." But how? According to the evolutionary hypothesis, "natural selection should drive organisms -- particularly fast growing ones -- to use genes that use optimal codons," they say. Apparently it does not. The finding that synonymous codons can have functional roles is more in accordance with intelligent design: it's another level of regulation that can nuance the outcomes of translation, much as English synonyms become tools of the writer's craft to enhance meaning.

The ability to "fine tune" expression according to the needs of the environment suggests planning by an intelligent cause -- one that could foresee the need of organisms to adapt to a changing world. Mechanisms for robustness (the ability to tolerate change) are built into the genetic code. Whenever we see robust systems like fault-tolerant software or earthquake-proof buildings, we know intuitively that intelligence was responsible. The same reasoning can be applied to biological systems. Finding a snooze button on the biological clock, one must admit, is pretty cool.

Image credit: Anthony!!/Flickr.