July 10, 2018
Written by: Barbara Terzic
There’s a good chance you may already be fascinated by octopuses, squids, and their smarts. These deep-sea predators are capable of disconcerting dexterity, communication, and learning: octopuses can open jars, create tools, and escape from tanks; squids have developed their own unique Morse code; and cuttlefish have the highest brain-to-body mass ratio of all invertebrates1. These Coleoid cephalopods, a subclass of the animal kingdom that includes octopuses, squid, and cuttlefish, are the most intelligent invertebrates on our planet. More intriguingly, however, they seem to have developed their mammalian-like acuity via a completely independent mechanism from humans.
As neuroscientists, we are transfixed by the remarkable complexity of the mammalian brain and behavioral sophistication it confers. Since mammals (and vertebrates in general) are thought to be more complicated and intelligent than invertebrates, these clever mollusks leave us somewhat puzzled. (Sidenote: octopuses and squids may not have spines, hence invertebrates, but they do have brains!). How were cephalopods able to achieve such neural sophistication? The answer may be a quirk in how their genes work on a fundamental level.
Back to basics
The central dogma of biology describes how our DNA encodes information that tells each cell of our body what to do (like a blueprint). Genetic information flows from sequences in our DNA to protein products inside of our cell; DNA makes RNA and RNA makes protein (DNA à RNA à Protein). If we imagine DNA as the instruction manual inside each of our cells, proteins are like the small pieces of machinery that execute all the functions our cells need to survive. You can think of RNA as the middle man in this entire process: an important messenger that carries the information from DNA to the parts of the cell that need to translate it. Between generations, DNA can accumulate mutations, leading to natural selection based on altered traits, and thus evolution.
Okay, but what does any of this have to do with squids? Over time, our DNA has gradually accumulated mutations that lead to beneficial adaptions, including behavioral complexity, advanced nervous systems, and intelligence (DNA-based evolution). Recent work, however, suggests that unlike most animals, coleoid cephalopods make extensive use of RNA editing. More specifically, these species have special machinery (proteins) inside their cells that allow them to edit the RNA messages being translated from their DNA blueprint in real time (without editing the core DNA code itself)2. The end result is that modified RNA can create proteins that weren’t originally encoded in the DNA.
Why do cephalopods edit their RNA?
The short answer is adaptability. Being able to edit the information (and thus performance) of your cells in response to environmental changes has its evolutionary advantages. Cephalopods such as octopuses and squids are perhaps more capable of quickly adapting to changing environmental cues or signals, thereby increasing their survival. Since these edits don’t alter the core code of the DNA, they are also only temporary, allowing the organism to turn them on or off when needed.
Another equally important reason is versatility: by editing at the RNA level, these mollusks can curate a pool of edited or unedited versions of their RNA messengers. Now, if we imagine there being multiple ‘edited’ sites on a single sequence of RNA, each capable of a different switch, the number of unique proteins that can be produced from a single strand of RNA increases exponentially.
While RNA editing occurs in cells throughout the body of these coleoids, what’s perhaps most interesting is the fact that these RNA editing events (recodings) appear to happen most frequently in the cells of the nervous system. In fact, editing has been found to affect proteins that are key players in neural signaling, communication, and morphology. The primitive nautiloid cephalophods (i.e. less intelligent cousins of the coleoids) exhibit much less RNA editing throughout their nervous tissues, leaving a curious correlation between RNA editing and intelligence level in these species3.
Ok, so, why aren’t we all editing our RNA?
Rather less exciting for us, RNA editing in mammals is more of the exception than the rule. DNA sequencing studies have revealed that less than 1% of RNAs in humans are recoded; a staggering contrast to the >60% of RNA transcripts that are recoded in squid brain4! The main reason behind this difference is evolutionary flexibility. Editing sites on RNAs require specific surrounding sequences: the structure and code of the RNA sequence around the edit must be preserved to properly target editing machines to that spot. Thus, although RNA editing confers greater diversity in the proteins encoded by a particular organism, it slows the rate of conventional, DNA-level evolution5. The nervous system is one of the most important targets for natural selection since subtle changes can alter behavioral advances. Although RNA editing seems to come at the cost of slower evolution over generations, its persistence in these coleoids over millions of years suggests that it must be worth it in terms of their natural selection.
The bigger picture
Before we began studying cephalopods in greater detail, most scientists viewed RNA recoding as either neutral or detrimental (not beneficial). These recent findings in cephalopods have the potential to completely shift our perspective on how we view RNA editing, and perhaps harness it as a tool for therapeutics in humans.
Our comprehension of complex behavior and intelligence stands to greatly benefit from a clearer understanding of cephalopod intelligence and how it arose due to its reliance on a nervous system fundamentally different from that of vertebrates and humans. At some point in evolution, the coleoids decided to harness RNA editing to develop their complex nervous systems, whereas human intelligence arose from the faster, DNA-based evolutionary path. Although we may be in the lead currently, perhaps these squids are just playing the long game.
1Zullo L, Sumbre G, Agnisola C, Flash T, Hochner B. Nonsomatotopic organization of the higher motor centers in octopus. Curr Biol. 2009; 19(19):1632–6.
2Alon S, Garrett SC, Levanon EY, Olson S, Graveley BR, Rosenthal JJC, and Eisenberg E. The majority of transcripts in the squid nervous system are extensively recoded by A-to-I RNA editing. eLife 2015; 4.
3Liscovitch-Brauer N, Alon S, Porath HT, Elstein B, Unger R, Ziv T, Admon A, Levanon EY, Rosenthal JJC, and Eisenberg E. Trade-off between transcriptome plasticity and genome evolution in cephalopods. Cell 2017; 169, 191-202.
4Ramaswami G, Lin W, Piskol R, Tan MH, Davis C, and Li JB. Accurate identification of human Alu and non-Alu RNA editing sites. Nat. Methods. 2012 9, 579–581.
5Rieder LE, Staber CJ, Hoopengardner B, and Reenan RA. Tertiary stru ctural elements determine the extent and specificity of messenger RNA editing. Nat. Commun. 2013; 4, 2232.
Cover image from Morten Brekkevold ‘Octopus Vulgaris in Palma Aquarium’ via flickr, CC BY-NC-SA 2.0. https://www.flickr.com/photos/lunkwill42/3658339290