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How the Cell Exploits Genetic Code Degeneracy

In the context of making and analyzing codes, the term “degeneracy” refers to having excess codes that produce the same message. A non-degenerate code, like Morse code, is one for one: each code is unique, producing one and only one output. The genetic code, by contrast, is many-to-one in some cases. For instance, six different codons can produce the amino acid leucine. This would be like having six combinations of dots and dashes to produce the letter A in a “degenerate” version of Morse code. Other amino acids can be coded by 4, 3 or 2 codons, while two (methionine and tryptophan) each have only one unique code. Why is this?
One reason is that there are 20 standard amino acids used in living organisms, but 64 possible combinations of codons (4 letters in triplets, 43 = 64). This mismatch creates the degeneracy, but also allows for multiple codons to code for the same amino acid; these are called cognates. Is there a reason for this degeneracy other than happenstance?
In a recent paper in PNAS, a trio of researchers from Harvard and the University of Chicago experimented with E. coli bacteria to study the effects of multiple codons under environmental stress. Here is their explanation of the degeneracy in the genetic code:

The genetic code governing protein synthesis is a highly degenerate system because 18 of the 20 amino acids have multiple synonymous codons and 10 of the 20 amino acids are aminoacylated (charged) onto multiple tRNA [transfer RNA] isoacceptors. (Emphasis added.)

To study the effects of the environment on the code, they first created a library of 29 versions of yellow fluorescent protein genes (yfp) using different cognate forms of the codons for leucine, arginine and serine (each with 6 cognates), proline (4 cognates), isoleucine (3), glutamine (2) and phenylalanine (2).
Under normal conditions, with amino acids plentiful, each of the cognate codes in their gene library produced the same amount of YFP protein. But then they created a supply-and-demand crisis by “starving” the cells of the amino acids, one at a time. What they found was a case of “degeneracy lifting.”

Degenerate states that are indistinguishable under normal conditions can exhibit distinct properties under the action of external perturbations. This effect, called degeneracy lifting, allows degenerate systems to exhibit a wide range of behaviors, depending on the environmental context.

This implies that degenerate systems provide a way to encode extra information; indeed, quantum computing and steganography exploit this capacity. It should be noted that the genetic code is not the only degenerate system in nature:

Degeneracy, the occurrence of distinct states that share a common function, is a ubiquitous property of physical and biological systems. Examples of degenerate systems include atomic spectra, condensed matter, the nervous system, and the genetic code. Degeneracy in physical systems is often associated with underlying symmetries and in biological systems with error minimization, evolvability, and robustness against perturbations.

The question becomes: does E. coli “lift” the degeneracy of the genetic code under stress, and thereby encode environmental information in the extra space? Yes, they found:

Our study suggests that organisms can exploit degeneracy lifting as a general strategy to adapt protein synthesis to their environment.

In a clever series of experiments, they found that the cells divide the cognates into a hierarchy: those that are robust with regard to perturbations, and those that are sensitive. The robust cognates have no effect on protein synthesis levels, whereas the sensitive ones show up to a 100-fold reduction in synthesis rate. These results are independent of tRNA supply and codon usage.

Rather, competition among tRNA isoacceptors for aminoacylation underlies the robustness of protein synthesis. Remarkably, the hierarchy established using the synthetic library also explains the measured robustness of synthesis for endogenous proteins in E. coli. We further found that the same hierarchy is reflected in the fitness cost of synonymous mutations in amino acid biosynthesis genes and in the transcriptional control of ?-factor genes.

The team’s results imply a “strategy” to exploit degeneracy to survive environmental stress. When tRNA isoacceptors are in short supply, the ribosome pauses, and sends feedback to the nucleus to reduce transcription. Other effects include messenger-RNA cleavage and translation recoding — functions induced by the environmental stress to regulate protein supply.
The authors had nothing to say about how evolution produced these regulatory effects that promote robustness in a varying environment. Instead, in concluding, they concentrated on functional design:

Here, we have investigated the effect of a specific environmental perturbation associated with amino acid limitation in the bacterium E. coli. However, this type of perturbation plays a crucial role in the life cycle of other bacteria such as Myxococcus xanthus and Bacillus subtilis that undergo differentiation cued by amino acid limitation. Protein synthesis during such differentiation events might also be regulated by degeneracy lifting of the genetic code. Moreover, degeneracy lifting could be important during protein synthesis in eukaryotes, where clinically important conditions such as neoplastic transformation and drug treatment are often accompanied by a reduction in amino acid supply. Therefore, lifting the degeneracy of the genetic code might emerge as a general strategy for biological systems to expand their repertoire of responses to environmental perturbations.

Feedback, regulation, robustness: When there turns out to be method in what appeared to be madness, it’s reasonable to draw an inference to intelligent design.