September 19, 2010 | David F. Coppedge

Synonymous Codons: Another Gene Expression Regulation Mechanism

Some words in English have alternate spellings, but sound the same.  If the sound is the same, how would a recording device tell them apart?  Would it make any difference?  It shouldn’t, but now scientists are realizing that genetic codons spelled differently can influence the protein formed – even when the spellings, called “synonymous codons”, produce the same amino acid when translated.
    Suppose you are a prompter at a spelling bee.  You read the word “aneurysm” aloud as the next word to be spelled.  One student spells ANEURYSM, the next spells it ANEURISM.  Since both forms are acceptable according to the dictionary (though the first is more common) each student should be graded as correct.  But imagine that the judge, listening to the second spelling and not as familiar with it, has to check the dictionary before announcing her decision.  Now suppose that the slight time delay affects what a reporter has time to write before rushing his story to the press.  The resulting story could differ substantially, even though both spellings are, for all practical purposes, equivalent.  Something like that happens in the genetic code, according to researchers at the University of Pennsylvania, publishing in Science.1 
    There are 64 possible triplet codons in the DNA code (table), but only 20 amino acids they produce (chart).  As one can see, some amino acids can be coded by up to six “synonyms” of triplet codons: e.g., the codes AGA, AGG, CGA, CGC, CGG, and CGU will all yield arginine when translated by the ribosome.  If the same amino acid results, what difference could the synonymous codons make?  The researchers found that alternate spellings might affect the timing of translation in the ribosome tunnel, and slight delays could influence how the polypeptide begins its folding.  This, in turn, might affect what chemical tags get put onto the polypeptide in the post-translational process.
    In the case of actin, the protein that forms transport highways for muscle and other things, the researchers found that synonymous codons produced very different functional roles for the “isoform” proteins that resulted in non-muscle cells – beta-actin progressing to the sites of cell movement at the membrane, and gamma-actin staying in the interior, “in dense non-branched networks and long contractile stress fibers that impart morphological stability and support cell adhesion.”  Though both forms got “arginylated” with an arginine tag after translation, the beta-form appeared to start folding earlier, producing a slightly different shape that affected other post-translational modifications, thus affecting its functional role in the cell.  The gamma form also got tagged with ubiquitin, targeting it for earlier degradation in the proteasome.
    The authors proved that it was the different codon spellings that produced these changes by modifying the codons in both genes with their look-alike synonyms and watching the outcomes.  Sure enough, the beta-actin gene produced a protein that acted like gamma-actin when spelled the gamma way, and the gamma-actin gene produced a beta-actin-like protein when spelled the beta way.  The authors extended the principle they discovered to say, in conclusion, “This mechanism may be used not only with actin isoforms but also with other closely homologous but selectively arginylated proteins.”  As a result, an alternate spelling difference in the DNA code can result in different functional outcomes for two isoforms of actin, even though their amino acid sequences are essentially identical (98%).  This amounts to a new mechanism for regulation of the genome and proteome (the set of proteins in the cell).
    Ivana Weygand-Durasevic [U of Zagreb, Croatia] and Michael Ibba [Ohio State], commenting on this finding in the same issue of Science,2 recognized it as a fundamental discovery: “This is an unexpected example of proteins whose properties are determined at the nucleotide rather than the amino acid level, forcing a reassessment of what defines a synonymous change in a gene sequence.”  In their conclusion, they repeated, “Whatever the exact mechanism, the discovery of Zhang et al. that synonymous codon changes can so profoundly change the role of a protein adds a new level of complexity to how we interpret the genetic code.”
    For other recently-discovered regulatory mechanisms in the genome and epigenetic factors affecting function, see 08/09/2010 bullet 2, 08/02/2010, 07/31/2010, 07/24/2010, and 06/24/2010, or search for the words regulation, gene expression, or epigenetic in the Search Bar.

1.  Zhang, Saha, Shabalina and Kashina, “Differential Arginylation of Actin Isoforms Is Regulated by Coding Sequence�Dependent Degradation,” Science, 17 September 2010: Vol. 329. no. 5998, pp. 1534-1537, DOI: 10.1126/science.1191701.
2.  Ivana Weygand-Durasevic and Michael Ibba, “Cell Biology: New Roles for Codon Usage,” Science, 17 September 2010: Vol. 329. no. 5998, pp. 1473-1474, DOI: 10.1126/science.1195567.

The mismatch of 64 codons to 20 amino acids has struck some geneticists as wasteful.  “Degenerate” is the term used to describe mismatched codes that do not show a one-to-one correspondence.  The finding described above may change that view.  Perhaps all those synonyms have functional purposes after all.  If so, it suggests that synonymous mutations might be more destructive than thought, even though the same amino acid sequence is produced in translation, and even though there may be some tolerance to synonymous mutations (i.e., they might not result in the death of the organism).  Design theorists might find some functional role for adaptation at the micro-evolutionary level (where no new genetic information is added) where synonymous mutations might be switched on by epigenetic factors from cues in the environment.  There are several ways this finding can enlighten design thinking while causing new strains for evolutionary theory.
    The authors did not comment on how this regulatory system might have evolved, other than to state that the two forms of actin are “homologous,” or presumably descended from a common ancestral form.  But that’s a circular argument for common descent, because it assumes that sequence similarity is evidence of common descent.  It could be evidence of common design.  An ancestral cell would need the two functions simultaneously: motility at the cell membrane, and network maintenance in the interior.  Arguing that one evolved from the other begs the question of how the functions arose in the first place.
    Each “reassessment” of our knowledge of the genetic code leads to more functional complexity.  That’s not evidence for evolution, but for intelligent design. 

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