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Duke University fly researchers uncover another layer of life’s code

New research has revealed that the brain and testicles appear to be extremely adaptable to using many different types of genetic code to produce a given protein.

Rare bits of genetic code can serve as another way to control cellular machinery.

A new investigation into how different tissues read information from genes has found that the brain and testes seem extraordinarily open to using many different types of codes to produce a given protein.

In fact, the testicles of fruit flies and humans appear to be enriched with the protein products of these rarely used pieces of genetic code. According to the researchers, the use of rare pieces of code could be another layer of control in the genome that could be essential for fertility and evolutionary innovation.

A decade after solving the structure of DNA like a double helix of bases A, C, T and G, Francis Crick went on to decode the intermediate step by which three of these letters are translated into a “codon”, the recipe for a single amino acid. Amino acids are the building blocks of proteins.

What was striking at the time, and still a little confusing, was that this layer of code of life used 61 different three-letter codons to produce only 20


Amino acids are a set of organic compounds used to build proteins. There are about 500 naturally occurring known amino acids, though only 20 appear in the genetic code. Proteins consist of one or more chains of amino acids called polypeptides. The sequence of the amino acid chain causes the polypeptide to fold into a shape that is biologically active. The amino acid sequences of proteins are encoded in the genes. Nine proteinogenic amino acids are called "essential" for humans because they cannot be produced from other compounds by the human body and so must be taken in as food.
" data-gt-translate-attributes="[{" attribute="">amino acidsmeaning that many codons were being used to describe the same thing.

“We are taught in our biology classes that when you switch from one version of the codon to another, and it doesn’t change the amino acid, it’s called a silent mutation. And that implies it doesn’t matter,” said Don Fox, associate professor of cancer pharmacology and biology at Duke School of Medicine.

“Yet when the researchers sequenced all these different organisms, they found a hierarchy,” Fox said. “Some codons are really common and some are really rare.” And this codon distribution can vary from one type of tissue in one organism to another.

Rare codons in the fruit fly embryo

A translucent fruit fly larva glows where a green fluorescent protein (GFP) is expressed by rare codons in the fly’s genome. Only two tissues, the brain (left) and the testes (right) are able to express this version of GFP. Credit: Fox Lab, Duke University

Fox wondered if rarities played a role in how, say, a liver cell does liver things and how a bone cell does bone things.

Fox and his team, led by PhD student Scott Allen, wanted to zoom in on rare codons, using their favorite model Drosophila melanogaster, the laboratory fruit fly. A growing body of work has shown that dissimilar tissues have variable “codon bias”, that is, different frequencies of synonymous codons occurring in different tissues. Rare codons are known to slow down and even stop protein production, and “genes with lots of these rare codons produce much less protein,” Fox said.

Fox was collaborating with his colleague Christopher Counter, professor emeritus of pharmacology George Barth Geller at Duke to understand a gene called KRAS, which is known to be a bad actor in pancreatic cancer in particular, and which carries many rare codons. Why, they wondered, would a cancerous mutation slow protein production, when normally a cancerous mutation does more of something.

“It turns out the way KRAS is designed, it should be very difficult to do anything with it,” Fox said.

Fox’s team developed a new way to analyze tissue-specific codon usage to see where and how rare codons can be used in the fruit fly, which has perhaps the most well-known genome in science. . They conducted a series of experiments to vary the codons included in the KRAS gene and found that rare codons had a dramatic effect on how KRAS controls signaling between cells.

“I realized from this cancer collaboration that we could take similar approaches and apply them to my main research question, which is how tissues know what they are,” Fox said.

In other experiments, they found that the testes in flies – and in humans – are more tolerant of wide codon diversity, but the ovaries of flies are not. The fly brain was also more tolerant of various codons. The work was published on May 6, 2022 in the open access journal eLife.

A particular gene with a high number of rare codons, RpL10Aa, is evolutionarily newer and helps build the ribosome, the protein assembly machinery in the cell. Fox said it appears the rare codons in this gene serve to limit its activity to only the most tolerant testes, which, in turn, may be something critical for fertility.

“The way the testicles seem to allow almost every gene to be expressed, maybe that makes it fertile ground, if you will, for new genes,” Fox said. “The testicles seem to be a place where younger genes tend to express themselves first. So we think it’s a more permissive kind of tissue, and it allows new genes to take hold.

“What we think we’re seeing is that the rare codons are a way of limiting the activity of this young evolutionary gene to the testes,” Fox said. “That would make rare codons another layer of control and fine-tuning in genes.”

eLife editors said “the work breaks new ground in identifying codon usage as the basis for tissue-specific gene expression in animals.”

Reference: “Distinct Rare Codon Responses in Selected Drosophila Tissues” by Scott R Allen, Rebeccah K Stewart, Michael Rogers, Ivan Jimenez Ruiz, Erez Cohen, Alain Laederach, Christopher M Counter, Jessica K Sawyer, Donald T Fox, May 6 2022 , eLife.
DOI: 10.7554/eLife.76893
This research was supported by the American Cancer Society, (RSG-128945) the National Science Foundation and the National Institutes of Health (R01-CA94184, P01-CA203657, R35-GM140844, R01-HL111527)

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