Octopuses Do Something Really Strange to Their Genes
Ed Yong, April 2017, The Atlantic
Octopuses have three hearts, parrot-like beaks, venomous bites, and eight semi-autonomous arms that can taste the world. They squirt ink, contort through the tiniest of spaces, and melt into the world by changing both color and texture. They are incredibly intelligent, capable of wielding tools, solving problems, and sabotaging equipment. As Sy Montgomery once wrote, “no sci-fi alien is so startlingly strange” as an octopus. But their disarming otherness doesn’t end with their bodies. Their genes are also really weird.
It certainly seems that way. Rosenthal and Eisenberg found that RNA editing is especially rife in the neurons of cephalopods. They use it to re-code genes that are important for their nervous systems—the genes that, as Rosenthal says, “make a nerve cell a nerve cell.” And only the intelligent coleoid cephalopods—octopuses, squid, and cuttlefish—do so. The relatively dumber nautiluses do not. “Humans don’t have this. Monkeys don’t. Nothing has this except the coleoids,” says Rosenthal.
It’s impossible to say if their prolific use of RNA editing is responsible for their alien intellect, but “that would definitely be my guess,” says Noa Liscovitch-Brauer, a member of Rosenthal’s team who spearheaded the new study. “It makes for a very compelling hypothesis in my eyes.”
But to what end? RNA editing is still mysterious, and its purpose unclear. Technically, an animal could use it to change the nature of its proteins without altering the underlying DNA instructions. But in practice, this kind of recoding is extremely rare. Only about 3 percent of human genes are ever edited in this way, and the changes are usually restricted to the parts of RNA that are cut out and discarded. To the extent that it happens, it doesn’t seem to be adaptive.
In cephalopods, it’s a different story. Back in 2015, Rosenthal and Eisenberg discovered that RNA editing has gone wild in the longfin inshore squid—a foot-long animal that’s commonly used in neuroscience research. While a typical mammal edits its RNA at just a few hundred sites, the squid was making some 57,000 such edits. These changes weren’t happening in discarded sections of RNA, but in the ones that actually go towards building proteins—the so-called coding regions. They were ten times more common in the squid’s neurons than in its other tissues, and they disproportionately affected proteins involved in its nervous system.
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?
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.”
“It’s a really interesting phenomenon, but it’s unclear why they need so much RNA editing,” says Jianzhi Zhang from the University of Michigan. “It’s not absolutely clear if it has to do with behavior; humans have very complex brains and behaviors and in us, RNA editing is very rare.” The question isn’t just why coleoid cephalopods are unique in embracing RNA editing, but why nothing else has to the same extent.
So far, the team has a lot of correlations—compelling ones, but correlations nonetheless. Rosenthal’s next move is to develop ways of genetically manipulating cephalopods. If he succeeds, he could disable their ADAR enzymes, stop them from editing their RNA, and see what happens.