Genetics underwater – cephalopod RNA editing

By Larissa Potapova

Cephalopods have intrigued scientists for thousands of years1. Despite being invertebrates, they have unusually large brains and a myriad of complex behaviours2. The most unusual amongst this clade are the coleoids: soft-bodied cephalopods that are widely considered to have the greatest behavioural complexity amongst invertebrates1. Numerous studies have sought to understand their unusual aptitude for problem-solving tool use, and abilities to manipulate the colour of their skin3,4. However, cephalopods hide an even greater secret, and in 2015 a team of researchers5  made a major discovery that changed the way we view adaptation and evolution.

RNA editing occurs in all living organisms and primarily occurs in noncoding regions6. By contrast, nonsynonymous RNA editing (RNA editing resulting in a change in the amino acid sequence of proteins) is relatively rare. The incredibly low numbers of this nonsynonymous RNA editing in humans and other organisms created the misconception that this phenomenon is not evolutionarily successful. However, it was found that RNA editing in coding regions is unprecedently abundant in the coleoids5. Interestingly, this type of RNA editing is not present in nautiloids (the coleoids’ closest relative), possibly due to the vast difference in complexity between these two groups6. The abundance of nonsynonymous RNA editing in coleoids fuels research interest and could explain the mysteries of their genome. 

One of the most common processes of RNA editing is deamination which is the modification of adenosine to inosine (A-to-I) via the removal of an amine group7. Inosine is recognised as guanosine by translational machinery, causing a ‘recoding’ event: a specific change in the amino acid sequence for the protein produced8. This often results in a change in the operation of this new protein. This method is not unique to any group in particular; the enzyme ADAR that catalyses this deamination process is present in all eumetazoans6. In humans, inosine is abundant in RNA however this is largely limited to non-translated regions and therefore does not usually result in modifications in protein structure9. This was assumed to be true for most varieties of life until a study by Alon et al. 5 in 2015 revealed that RNA editing in coleoids was unlike anything previously seen.

Studies investigating RNA editing took place with previously sequenced genomes, such as in humans and fruit flies. Looking at this phenomenon in other groups of organisms such as cephalopods was difficult as cephalopod genomes have not previously been sequenced thus limiting further research in this area5. Using a new approach to identify recoding sites in un-sequenced genomes of organisms, Alon et al. investigated RNA editing sites in the nervous system of squid. It was discovered that almost 60% of mRNAs studied contained recoding sites, and the majority have more than one. These edits took place primarily in coding regions, further separating them from the synonymous RNA editing in other clades, which does not affect protein structure. This resulted in a change in the expression of genetic information, without changing the underlying genetic sequence. 

RNA editing is believed to play a crucial role in the development and function of cephalopod nervous systems. A past study by Rosenthal and Garret10 which investigated the effect of temperature on coleoid proteins further supported this new research. Low temperatures affect the function of certain proteins and in the case of the nervous system, the speed of protein function is crucial. Potassium channels in the cell membrane of neurones allow ions to enter and leave the cell thus making them important in regulating signal transmission.  Colder temperatures slow the closing of these protein channels and hinder the ability of neurons to fire again and so has major effects on the speed of signal transmission11. It was hypothesised octopi that inhabit colder environments have adapted to have modified protein channels which have a lower optimum temperature. What surprised molecular neurophysiologist Joshua Rosenthal and his team was the fact that these changes were not occurring at the level of the gene but rather at an mRNA level.

They compared the genes of two species of octopi that had adapted to different habitats10: the first from the Antarctic seas and the second is native to the Puerto Rican reef. Contrary to the hypothesis, it was found that the potassium channel genes were identical across both species. This was incredibly surprising as if potassium channel proteins from the tropical octopus were in the environment of the Southern Ocean, the channel would close 60 times slower and would be detrimental to the speed of signal transmission. When the researchers genetically modified frog oocytes to contain these genes and express them in their membranes to measure the electrical activity of the channels, they were shocked to find that they functioned in the same way. This phenomenon was explained by RNA editing. Despite having identical genes, they were expressed in different ways causing two different proteins adapted to different temperatures. Each species showed strong editing of RNA. For example, the Antarctic octopus had a changed underlying amino acid sequence of the protein by editing the RNA at nine different sites, and tropical octopus had 10 sites edited with this result. This is just one example of how cephalopods can diversify their neuronal proteome without changing the genetic sequence, and there may be more instances of this that we are not yet aware of.

Unsurprisingly, this unique method of increasing protein diversity has a catch – it slows down the rate of evolution of these species. To maintain the flexibility of RNA editing, these regions must be relatively unchanging6. In order for RNA editing to occur, dsRNA structures must be made for the ADAR enzymes12. The maintenance of these structures requires the underlying DNA sequences to be highly conserved. Thus, although different species appear to have great variations in adaptations, their genomes do not reflect this diversity. These discoveries are examples that our understanding of evolution and adaptation is still vastly incomplete.


1.         Schnell AK, Clayton NS. Cephalopod cognition. Current Biology. 2019 Aug 5;29(15):R726–32. 

2.         Shigeno S, Andrews PLR, Ponte G, Fiorito G. Cephalopod Brains: An Overview of Current Knowledge to Facilitate Comparison With Vertebrates. Frontiers in Physiology [Internet]. 2018;9. Available from:

3.         Amodio P, Boeckle M, Schnell AK, Ostojíc L, Fiorito G, Clayton NS. Grow Smart and Die Young: Why Did Cephalopods Evolve Intelligence? Trends in Ecology & Evolution. 2019 Jan 1;34(1):45–56. 

4.         Mäthger LM, Denton EJ, Marshall NJ, Hanlon RT. Mechanisms and behavioural functions of structural coloration in cephalopods. Journal of The Royal Society Interface. 2008 Dec 15;6(suppl_2):S149–63. 

5.         Alon S, Garrett SC, Levanon EY, Olson S, Graveley BR, Rosenthal JJC, et al. The majority of transcripts in the squid nervous system are extensively recoded by A-to-I RNA editing. Guigó R, editor. eLife. 2015 Jan 8;4:e05198. 

6.         Liscovitch-Brauer N, Alon S, Porath HT, Elstein B, Unger R, Ziv T, et al. Trade-off between Transcriptome Plasticity and Genome Evolution in Cephalopods. Cell. 2017 Apr 6;169(2):191-202.e11. 

7.         Nishikura K. A-to-I editing of coding and non-coding RNAs by ADARs. Nature Reviews Molecular Cell Biology. 2016 Feb 1;17(2):83–96. 

8.         Basilio C, Wahba AJ, Lengyel P, Speyer JF, Ochoa S. Synthetic polynucleotides and the amino acid code, V. Proceedings of the National Academy of Sciences. 1962 Apr 1;48(4):613–6. 

9.         Xu G, Zhang J. Human coding RNA editing is generally nonadaptive. Proceedings of the National Academy of Sciences. 2014 Mar 11;111(10):3769–74. 

10.       Garrett S, Rosenthal JJC. RNA Editing Underlies Temperature Adaptation in K+ Channels from Polar Octopuses. Science. 2012 Feb 17;335(6070):848–51. 

11.       Lee SC, Deutsch C. Temperature dependence of K(+)-channel properties in human T lymphocytes. Biophysical Journal. 1990 Jan 1;57(1):49–62. 

12.       Nishikura K. Functions and Regulation of RNA Editing by ADAR Deaminases. Annu Rev Biochem. 2010 Jun 7;79(1):321–49. 

Leave a Reply

Fill in your details below or click an icon to log in: Logo

You are commenting using your account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s