Having been surprised by one cephalopod, the team decided to study others. Liscovitch-Brauer focused on the common cuttlefish, common octopus, and two-spot octopus. All of these showed signs of extensive RNA editing with between 80,000 to 130,000 editing sites each. By contrast, the nautilus—a ancient cephalopod known for its hard, spiral shell—only had 1,000 such sites.
This distinction is crucial. The nautiluses belong to the earliest lineage of cephalopods, which diverged from the others between 350 and 480 million years ago. They’ve stayed much the same ever since. They have simple brains and unremarkable behavior, and they leave their RNA largely unedited. Meanwhile, the other cephalopods—the coleoids—came to use RNA editing extensively, and while evolving complex brains and extraordinary behavior. Coincidence?
Liscovitch-Brauer also found that around 1,000 of the edited locations were shared between the coleoid species—far more than the 25 or so sites that are shared between humans and other mammals. These sites have been preserved over hundreds of millions of years of evolution. “That’s pretty convincing evidence that these edits are integrated into the wiring of these genomes, and that disrupting this network of edits would be harmful in some way,” says Daniel Rokhsar from the University of California, Berkeley, who was not involved in the study.
Indeed, the edits seem to be so important that cephalopods have gone to unusual lengths to preserve them. To find and edit a particular RNA letter, ADAR enzymes rely on all the surrounding letters for clues. It’s like finding this single ‘A’ by looking for all the words in this paragraph. This means that editing sites effectively cordon off a large chunk of a cephalopod’s genome—between 23 and 41 percent by Rosenthal’s reckoning. Those sites must remain largely unchanged, or the editing enzymes won’t be able to find their targets. And this means that octopus and squid genomes evolve at a slower pace than those of other animals. They may be icons of flexibility and change, but their genomes are rigid and stagnant.
Rosenthal thinks that they pay for this sacrifice with a different kind of flexibility. By changing their RNA rather than their DNA, they might be more effective at adapting to challenges on the fly. From the same gene, they could produce proteins that, say, work better in hot temperatures or cold ones. And such changes would be temporary—the creatures could turn them on or off depending on the circumstance. Rosenthal wonders if they could learn or encode experiences in this way. “I’m working a lot on the squid ADAR enzymes and their distribution between cells,” he says. “It’s mind-blowing how variable they are. One neuron will have high levels but its neighbor will have nothing.”
“This study suggests that RNA editing and recoding is important in the function of the largest invertebrate brains,” says Carrie Albertin from the University of Chicago, who helped to sequence the first cephalopod genome. “By comparing vertebrate and cephalopod brains, we can understand how large nervous systems are put together.”