A Breakthrough in Gene Expression?

 
When we teach protein synthesis in undergraduate molecule biology classes we cover the main mechanisms regulating the rate of translation.

One of them is the influence of codon bias among synonymous codons. We've known for 35 years that rare codons are translated more slowly that the common codons. Highly expressed genes have a pronounced codon bias in favor of the most common codons. As a result of this phenomenon, it is not true that every codon for leucine, for example, is equal. Some are better than others in some genes. Synonymous codons are not always neutral in their effect. (For a complete description of this phenomenon see: Silent Mutations and Neutral Theory.)

We also teach about the influence of messenger RNA secondary stucture. The classic examples in the E. coli ribosomal protein genes are in all the textbooks, as are the examples of attentuation—especially in the Trp operon. Again, this stuff was standard fair in textbooks and courses beginning in the 1970's.

A press release caught my eye: Penn biologists discover how 'silent' mutations influence protein production. "Cool," I thought, "maybe this is something that I'll have to put into the next edition of my textbook."

Here's the breakthrough.

For biologists, these results fundamentally change the understanding of the role of synonymous mutations, which were previously considered evolutionarily neutral. ....

The silent mutations changed the amount of fluorescent protein by as much as 250-fold, without changing the properties of the protein. Codon bias, the probability that one codon of three adjacent nucleotides will code for one amino acid over another, was previously thought to be the cause for protein expression variance, but it did not correlate with gene expression in these experiments.

"At first we were stumped," Plotkin said. "How were the silent mutations influencing protein levels? Eventually, we looked at mRNA structure and discovered that this was the underlying mechanism."

Imagine that. They've rediscovered what most of my students have been taught for 35 years!

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[Image Credit: The figure is from page 706 of my textbook. Similar figures are in all biochemistry and molecular biology textbooks. The figure shows the secondary mRNA structure around the initiation codon of the S7 ribosomal protein gene in E. coli. The secondary structure inhibits translation initiation. Although in this case the actual codons are not involved in the formation of double-stranded regions, in other cases they are.]