Paving the Way Cephalopods: Masters of RNA Recoding

By Iva Fedorka

Even small changes in genetic instructions can affect the proteins an organism produces. Octopuses, squids, and other cephalopods seem to be able to modify their RNA without significantly changing their DNA. This ability to edit their RNA may provide them with options for facing life’s challenges.

What Is RNA Editing?

Instructions for maintaining life are contained in an organism’s DNA. Messenger RNA (mRNA) copies the DNA, which the ribosomes use to create proteins from amino acids. RNA recoding produces a protein that does not include the exact amino acids that the message prescribed.

Almost every multicellular organism has one or more RNA-editing or ADAR enzymes. Scientists have also discovered millions of human RNA locations where editing occurs, but the process rarely affects the protein structure.

Cephalopods most often use adenosine to inosine (A-to-I) editing, enzymatically removing one nitrogen and two hydrogen atoms from adenosine to create inosine. The ribosomes then substitute inosine for guanine when creating proteins.

Recoding in Cephalopods

Humans and other vertebrates typically create these protein variations using copies of a gene, not RNA editing. In contrast, cephalopods have tens of thousands of recoding sites, mostly in their nervous systems. Although it’s been suggested that recoding helps the animals respond more flexibly to their environments, the true evolutionary value is unclear.

Kavita Rangan, a molecular biologist at the University of California, San Diego, has been studying RNA recoding in longfin fish and California market squid (Doryteuthis opalescens).

Although the potential number of editing combinations is large, Rangan and Samara Reck-Peterson, also of UC San Diego, found that certain sites are often edited simultaneously. This restricts the number of potential edits and may offer a way to test protein versions without permanently changing the DNA. These results were reported in a September 2022 preprint post at bioRxiv.org (operated by Cold Spring Harbor Laboratory).

Editing and Evolutionary Advantage

The same thought occurred to Jianzhi Zhang, an evolutionary geneticist at the University of Michigan in Ann Arbor. “It doesn’t make sense to me,” he told Science News in 2023. “If you want a particular amino acid in a protein, you should change the DNA. Why do you change the RNA?”

To test whether the RNA editing offered an evolutionary advantage, Zhang and Daohan Jiang, a former graduate student, compared sites where the edits do not change amino acids with those that do. Their results, published in Nature Communications in 2019, showed that cephalopod recoding is not advantageous or adaptive in most cases.

More Unanswered Questions

Scientists would like to directly test whether recoded RNA has an effect on cephalopod biology, but that requires new tools and creative thinking. Currently, researchers remove tissue and observe it microscopically, but a cell culture line would allow for longitudinal studies.

Zhang is also testing a strain of Baker’s yeast (Saccharomyces cerevisiae) by incorporating a human ADAR enzyme. Other researchers are changing squid genes using CRISPR/Cas9 and have even created an albino squid by disabling its pigment-producing genes.