Newswise – DURHAM, NC – A new study into the way different tissues read information from genes has found that the brain and testes are extremely open to using many different types of code to produce a particular protein.
In fact, the testicles of both fruit flies and humans appear to be enriched with protein products from these rarely used pieces of genetic code. The researchers say using rare bits of code could be another control layer in the genome that could be essential for fertility and evolutionary innovation.
A decade after solving the structure of DNA as a double helix of bases A, C, T and G, Francis Crick deciphered the intermediate step by which three of these letters are translated into a ‘codon’, the recipe for a single amino acid, the building block of proteins.
What stood out at the time, and is still somewhat puzzling, is that this layer of the life code used 61 different three-letter codons to produce just 20 amino acids, meaning many codons were used to describe the same thing.
“We learned in our biology classes that if you change from one version of the codon to another, and you don’t change the amino acid, that’s called a silent mutation. And that means it doesn’t matter,” said Don Fox. , associate professor of pharmacology and cancer biology at Duke School of Medicine.
“But when researchers sequenced all these different organisms, they found a hierarchy,” Fox said. “Some codons are very common and some are really rare.” And that distribution of codons can vary from one type of tissue in an organism to another.
Fox wondered if the rarities play 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 the rare codons with their preferred model Drosophila melanogaster, the laboratory fruit fly. A growing body of work has shown that disparate tissues have different ‘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 many of these rare codons make far fewer proteins,” Fox said.
Fox worked with colleague Christopher Counter, the George Barth Geller Distinguished Professor of Pharmacology at Duke to understand a gene called KRAS, which is known to be a bad factor in pancreatic cancer especially, and contains many rare codons. Why, they wondered, would a cancerous mutation have slowed down protein production, when a cancerous mutation normally makes more of something.
“It turns out that the way KRAS is designed, it should be really hard to make anything out of it,” Fox said.
Fox’s team developed a new way to analyze tissue-specific codon usage to see where and how rare codons might be used in the fruit fly, which may have the best-known genome in science. They conducted a series of experiments to vary which codons were included in the KRAS gene and found that rare codons had a dramatic effect on how KRAS regulates signaling between cells.
“I realized through this cancer collaboration that we could take similar approaches and apply them to my primary research question, which is how tissues know what they are,” Fox said.
In further experiments, they found that testes in flies — and in humans — are more tolerant of a wide variety of codons, but fly ovaries are not. The fly brain was also more tolerant of various codons. Work appeared on May 6 in the open access journal eLife†
One particular gene with a large number of rare codons, RpL10Aa, is evolutionarily newer and helps build the ribosome, the protein assembly machinery in the cell. Fox said it appears that the rare codons of this gene serve to limit its activity to just the more tolerant testicles, which in turn could be something crucial for fertility.
“The way the testicles seem to allow almost any gene to be expressed may make it a breeding ground for new genes,” Fox said. “The testes seem to be a place where younger genes are expressed first. So we think it’s kind of a more permissive tissue, and it allows new genes to take over.”
“What we think we see is that rare codons are a way to limit the activity of this evolutionarily young gene to the testicles,” Fox said. “That would make rare codons a new layer of control and fine-tuning of the genes.”
The editorial of eLife said, “the work is groundbreaking in identifying codon usage as the basis for tissue-specific gene expression in animals.”
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)
CITATION: “Different responses to rare codons in Select Drosophila Tissues,” Scott R Allen, Rebeccah K Stewart, Michael Rogers, Ivan Jimenez Ruiz, Erez Cohen, Alain Laederach, Christopher M Counter, Jessica K Sawyer, Donald T Fox. eLifeMay 6, 2022. DOI: 10.7554/eLife.76893 https://elifesciences.org/articles/76893
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