Recoding Genes: How Post-Transcriptional Editing is Giving Squid the Upper Hand

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Natural selection is incredibly good at adapting organisms to their environment, even those environments that are harsh and difficult to live in. But the changes currently happening to the World’s climate, hydrology and land-use may be too rapid for natural selection to act, in most cases. For some species, natural selection has provided the tools to adapt more rapidly, through behavioural or physiological changes. A few species have gone further still, evolving the ability to edit their own genes as they are expressed. Recent research shows this ability is used rampantly by certain species of squid, which may explain why they have responded relatively well to human impacts on the environment so far.

RecodingGenes003The recipe for making a human is contained, and repeated many times, of course, in the 2 billion km of DNA that forms our chromosomes. But how is that recipe turned into the cells, proteins and fats that actually form the human? Genes encoded in DNA are transcribed into RNA molecules, and finally translated into protein. These proteins fold, based on their particular sequence, into enzymes, hormones, structural proteins, neurotransmitters and all the many other proteins that function together to make a human. Change the sequence of nucleotides in the DNA and you chance the mRNA, tRNA and ultimately the protein sequence – the final folded product will be different and have different properties. This is the central dogma of biology. DNA – RNA – Protein. And, although biologists now understand that there are many complex, intricate regulatory processes which interact with this basic backbone of protein production, and a great deal more flexibility in the system than the gene-protein paradigm suggests, the central dogma of biology holds.

Almost all animals (sponges being a notable exception) possess genes designed to edit RNA after it has been transcribed from DNA, but before it is translated into protein. Editing at this stage would allow an animal to alter the final protein produced (whether that’s an enzyme, hormone, structural protein or something else) without altering it’s DNA. This can mean short-term changes in enzyme functionality, protein binding, or practically anything you can think of. But the genes possessed by the organism, the underlying ‘recipe’ remains the same, and future transcriptions of that gene will produce the normal version of the protein, not an edited one. RNA editing is therefore a powerful tool to allow animals to adapt to rapid, short-term changes in their environment. But it isn’t enough to just have RNA editing tools, you also need to be able to direct them to the right place. Only genes with recoding sites reprogrammed into them can be accessed by the editing tools.

Previous studies have found that these recoding sites are quite common in some insects such as fruit flies (Drosophila melanogaster), but far rarer in vertebrates such as mammals. Across all expressed transcripts in mammals, screens have found just 25 or so that have RNA editing sites in mammals, compared to several hundred in Drosophila. Then a few studies began to suggest that RNA editing might be far more still common in squid and octopuses – but this could not be confirmed because scientists lacked published genome sequences for these species.

We still don’t have any genome sequences for the cephalopods (squid, cuttlefish, octopuses, etc), although the Cephalpod Sequencing Consortium has plans to sequence eight species, however a new technique developed by Dr Eli Eisenberg at Tel Aviv University has enabled the most comprehensive survey of RNA editing in squid to date. What this study showed was RNA editing (specifically A-to-I editing, where the nucleotide adenosine is switched to the nucleosideinosine) in the longfin inshore squid, Doryteuthis pealeii, on an unprecedented scale.

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Eisenberg and colleagues sequenced expressed mRNA sequences in the brain and compared them to sequences taken directly from the genome of the same animal. A transcriptome (the entire sequence of all expressed genes) was then assembled from all the expressed mRNA sequences. RecodingGenes002The researchers were then able to identify two type of RNA editing site: sites where the transcriptome differed in sequence from the gene it was transcribed from represented ‘strong editing sites’ – these are edited in the same way almost every time the gene is expressed, and sites where different mRNA sequences differed from each other represented ‘weak editing sites’ – these are occasionally edited, but most mRNAs are the same as the original gene. Amazingly, the team found nearly 88,000 A-to-I recoding sites across the squid transcriptome. Of these, just over 57,000 were non-synonymous, meaning that the change in nucleotide sequence of the RNA would result in a change in the protein sequence. Most genes were only edited occasionally, falling into the ‘weak editing site’ category, however they found 4690 non-synonymous ‘strong editing sites’ – frequently-made nucleotide changes that would result in a change in the structure and function of the final protein. Together function-changing editing sites appear in 6991 genes, representing around 60% of the genome – a finding that Dr Eisenberg described as “astonishing”. RNA editing is an order of magnitude more common in squid than fruit flies, who edit only 3% of their genes.

The type of recoding that occurred depended on which tissue the researchers looked at, but across the whole brain, recoding tended to occur in genes involved in neuronal and cytoskeletal (structural components of cells) genes which may be important in brain physiology. Many genes contained multiple different recoding sites, allowing a single gene to code for multiple related proteins, known as protein isoforms. Furthermore, the researchers found that more of these nucleotide changes resulted in an amino acid and therefore functional change to the protein produced than would be expected through chance alone. This indicates that RNA editing is a carefully directed process enabling specific adaptations to environmental variation, generating plasticity in the brain of the squid. Complementary RNA editing in other parts of the body may further adapt squid to changeable environments, but further studies utilising different tissues will be needed to identify if and where these edits occur.

“Why do squid edit to such an extent? One theory is that they have an extremely complex nervous system, exhibiting behavioral sophistication unusual for invertebrates. They may also utilize this mechanism to respond to changing temperatures and other environmental parameters.” – Dr Eisenberg, Tel Aviv University

The implications of this finding are many. RNA editing this widespread is extremely unexpected. So unexpected that Dr Eisenberg suggests that we need to revise the central dogma itself. He believes this is evidence that RNA editing may be extremely common in nature; if so this could be a strong case for modifying the central dogma. However, evidence for extensive RNA editing in other species is still lacking, and it is possible that editing at this scale is a cephalopod adaptation, rather than a general feature of life on Earth. Either way, there are many other processes by which genes, transcripts and proteins are modified and regulated to expand on the plasticity and diversity offered by the central dogma – alternative splicing, for example, is a process which involves mixing and matching different sections of a single gene to produce multiple different proteins – and yet none of these has led scientists to abandon the simplicity of the central dogma as a theory.

Eisenberg also believes the squid may have something to teach us about ourselves. Many diseases in humans are caused as a result of misfolded proteins. RNA editing on such a large scale as is seen in squid, since it introduces changes to the protein sequence, is likely to increase the frequency of misfolded proteins. So, Eisenberg reasons, the squid must have some pretty efficient mechanisms for fixing protein folding errors so that they don’t cause problems. Studying how RNA editing is regulated and how errors are repaired in squid might offer novel treatments for a wide range of human ailments.

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