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To operate in the extreme cold, ion channels from psychrophiles must have evolved structural changes to compensate for their thermal environment. A reasonable assumption would be that the underlying adaptations lie within the encoding genes. Here, we show that delayed rectifier K⁺ channel genes from an Antarctic and a tropical octopus encode channels that differ at only four positions and display very similar behavior when expressed in Xenopus oocytes. However, the transcribed messenger RNAs are extensively edited, creating functional diversity. One editing site, which recodes an isoleucine to a valine in the channel's pore, greatly accelerates gating kinetics by destabilizing the open state. This site is extensively edited in both Antarctic and Arctic species, but mostly unedited in tropical species. Thus adenosine-to-inosine RNA editing can respond to the physical environment.

Cephalopods are known for their large nervous systems, complex behaviors and morphological innovations. To investigate the genomic underpinnings of these features, we assembled the chromosomes of the Boston market squid, Doryteuthis (Loligo) pealeii, and the California two-spot octopus, Octopus bimaculoides , and compared them with those of the Hawaiian bobtail squid, Euprymna scolopes . The genomes of the soft-bodied (coleoid) cephalopods are highly rearranged relative to other extant molluscs, indicating an intense, early burst of genome restructuring. The coleoid genomes feature multi-megabase, tandem arrays of genes associated with brain development and cephalopod-specific innovations. We find that a known coleoid hallmark, extensive A-to-I mRNA editing, displays two fundamentally distinct patterns: one exclusive to the nervous system and concentrated in genic sequences, the other widespread and directed toward repetitive elements. We conclude that coleoid novelty is mediated in part by substantial genome reorganization, gene family expansion, and tissue-dependent mRNA editing. “Cephalopods are known for their large nervous systems, complex behaviors, and morphological innovations. Here, the authors find that soft-bodied cephalopod genomes are more rearranged than other extant molluscs and that mRNA editing patterns are associated with the nervous system and repetitive elements”.

Adenosine deaminases that act on RNA are a conserved family of enzymes that catalyze a natural process of site-directed mutagenesis. Biochemically, they convert adenosine to inosine, a nucleotide that is read as guanosine during translation; thus when editing occurs in mRNAs, codons can be recoded and the changes can alter protein function. By removing the endogenous targeting domains from human adenosine deaminase that acts on RNA 2 and replacing them with an antisense RNA oligonucleotide, we have engineered a recombinant enzyme that can be directed to edit anywhere along the RNA registry. Here we demonstrate that this enzyme can efficiently and selectively edit a single adenosine. As proof of principle in vitro, we correct a premature termination codon in mRNAs encoding the cystic fibrosis transmembrane conductance regulator anion channel. In Xenopus oocytes, we show that a genetically encoded version of our editase can correct cystic fibrosis transmembrane conductance regulator mRNA, restore full-length protein, and reestablish functional chloride currents across the plasma membrane. Finally, in a human cell line, we show that a genetically encoded version of our editase and guide RNA can correct a nonfunctional version of enhanced green fluorescent protein, which contains a premature termination codon. This technology should spearhead powerful approaches to correcting a wide variety of genetic mutations and fine-tuning protein function through targeted nucleotide deamination.

RNA editing by the ADAR enzymes converts selected adenosines into inosines, biological mimics for guanosines. By doing so, it alters protein-coding sequences, resulting in novel protein products that diversify the proteome beyond its genomic blueprint. Recoding is exceptionally abundant in the neural tissues of coleoid cephalopods (octopuses, squids, and cuttlefishes), with an over-representation of nonsynonymous edits suggesting positive selection. However, the extent to which proteome diversification by recoding provides an adaptive advantage is not known. It was recently suggested that the role of evolutionarily conserved edits is to compensate for harmful genomic substitutions, and that there is no added value in having an editable codon as compared with a restoration of the preferred genomic allele. Here, we show that this hypothesis fails to explain the evolutionary dynamics of recoding sites in coleoids. Instead, our results indicate that a large fraction of the shared, strongly recoded, sites in coleoids have been selected for proteome diversification, meaning that the fitness of an editable A is higher than an uneditable A or a genomically encoded G.

The most abundant form of RNA editing in metazoa is the deamination of adenosines into inosines (A-to-I), catalyzed by ADAR enzymes. Inosines are read as guanosines by the translation machinery, and thus A-to-I may lead to protein recoding. The ability of ADARs to recode at the mRNA level makes them attractive therapeutic tools. Several approaches for Site-Directed RNA Editing (SDRE) are currently under development. A major challenge in this field is achieving high on-target editing efficiency, and thus it is of much interest to identify highly potent ADARs. To address this, we used the baker yeast Saccharomyces cerevisiae as an editing-naïve system. We exogenously expressed a range of heterologous ADARs and identified the hummingbird and primarily mallard-duck ADARs, which evolved at 40–42°C, as two exceptionally potent editors. ADARs bind to double-stranded RNA structures (dsRNAs), which in turn are temperature sensitive. Our results indicate that species evolved to live with higher core body temperatures have developed ADAR enzymes that target weaker dsRNA structures and would therefore be more effective than other ADARs. Further studies may use this approach to isolate additional ADARs with an editing profile of choice to meet specific requirements, thus broadening the applicability of SDRE.

Chromatophore organs in cephalopod skin are known to produce ultra-fast changes in appearance for camouflage and communication. Light-scattering pigment granules within chromatocytes have been presumed to be the sole source of coloration in these complex organs. We report the discovery of structural coloration emanating in precise register with expanded pigmented chromatocytes. Concurrently, using an annotated squid chromatophore proteome together with microscopy, we identify a likely biochemical component of this reflective coloration as reflectin proteins distributed in sheath cells that envelop each chromatocyte. Additionally, within the chromatocytes, where the pigment resides in nanostructured granules, we find the lens protein Ω- crystallin interfacing tightly with pigment molecules. These findings offer fresh perspectives on the intricate biophotonic interplay between pigmentary and structural coloration elements tightly co-located within the same dynamic flexible organ - a feature that may help inspire the development of new classes of engineered materials that change color and pattern. Chromatophores in cephalopod skin are known for fast changes in coloration due to light-scattering pigment granules. Here, authors demonstrate structural coloration facilitated by reflectin in sheath cells and offer insights into the interplay between structural and pigmentary coloration elements.

RNA editing by adenosine deamination alters genetic information from the genomic blueprint. When it recodes mRNAs, it gives organisms the option to express diverse, functionally distinct, protein isoforms. All eumetazoans, from cnidarians to humans, express RNA editing enzymes. However, transcriptome-wide screens have only uncovered about 25 transcripts harboring conserved recoding RNA editing sites in mammals and several hundred recoding sites in Drosophila. These studies on few established models have led to the general assumption that recoding by RNA editing is extremely rare. Here we employ a novel bioinformatic approach with extensive validation to show that the squid Doryteuthis pealeii recodes proteins by RNA editing to an unprecedented extent. We identify 57,108 recoding sites in the nervous system, affecting the majority of the proteins studied. Recoding is tissue-dependent, and enriched in genes with neuronal and cytoskeletal functions, suggesting it plays an important role in brain physiology. For living cells to create a protein, a genetic code found in its DNA must first be ‘transcribed’ to create a corresponding molecule of messenger RNA (mRNA). DNA and RNA are both made from smaller molecules called nucleotides that are linked together into long chains; the information in both DNA and RNA is contained in the sequence of these molecules. The mRNA nucleotides coding for proteins are ‘translated’ in groups of three, and most of these nucleotide triplets instruct for a specific amino acid to be added to the newly forming protein. DNA sequences were thought to exactly correspond with the sequence of amino acids in the resulting protein. However, it is now known that processes called RNA editing can change the nucleotide sequence of the mRNA molecules after they have been transcribed from the DNA. One such editing process, called A-to-I editing, alters the ‘A’ nucleotide so that the translation machinery reads it as a ‘G’ nucleotide instead. In some—but not all—cases, this event will change, or ‘recode’, the amino acid encoded by this stretch of mRNA, which may change how the protein behaves. This ability to create a range of proteins from a single DNA sequence could help organisms to evolve new traits. Evidence of amino acid recoding has only been found to a very limited extent in the few species investigated so far. There has been some evidence that suggests that recoding might occur more often, and alter more proteins, in squids and octopuses. However, this could not be confirmed as the genomes of these species have not been sequenced, and these sequences were required to investigate RNA recoding using existing techniques. Alon et al. have now developed a new approach that allows the recoding sites to be identified in organisms whose genomes have not been sequenced. Using this technique—which compares mRNA sequences with the DNA sequence they have been transcribed from—to examine the squid nervous system revealed over 57,000 recoding sites where an ‘A’ nucleotide had been modified to ‘G’ and thereby changed the coded amino acid. Many of the identified mRNA molecules had been recoded in more than one place, and many more of these than expected changed the amino acid sequence of the protein translated from them. Alon et al. therefore suggest that RNA editing may have been crucial in the evolution of the squid's nervous system, and suggest that recoding should be considered a normal part of the process used by squids to make proteins.

The neglected tropical disease schistosomiasis impacts over 700 million people globally. Schistosoma mansoni , the trematode parasite that causes the most common type of schistosomiasis, requires planorbid pond snails of the genus Biomphalaria to support its larval development and transformation to the cercarial form that can infect humans. A greater understanding of neural signaling systems that are specific to the Biomphalaria intermediate host could lead to novel strategies for parasite or snail control. This study examined a Biomphalaria glabrata neural channel that is gated by the neuropeptide FMRF-NH 2 . The Biomphalaria glabrata FMRF-NH 2 gated sodium channel ( Bgl- FaNaC) amino acid sequence was highly conserved with FaNaCs found in related gastropods, especially the planorbid Planorbella trivolvis (91% sequence identity). In common with the P . trivolvis FaNaC, the B . glabrata channel exhibited a low affinity (EC 50 : 3 x 10 −4 M) and high specificity for the FMRF-NH 2 agonist. Its expression in the central nervous system, detected with immunohistochemistry and in situ hybridization, was widespread, with the protein localized mainly to neuronal fibers and the mRNA confined to cell bodies. Colocalization of the Bgl- FaNaC message with its FMRF-NH 2 agonist precursor occurred in some neurons associated with male mating behavior. At the mRNA level, Bgl- FaNaC expression was decreased at 20 and 35 days post infection (dpi) by S . mansoni . Increased expression of the transcript encoding the FMRF-NH 2 agonist at 35 dpi was proposed to reflect a compensatory response to decreased receptor levels. Altered FMRF-NH 2 signaling could be vital for parasite proliferation in its intermediate host and may therefore present innovative opportunities for snail control.

Aging is characterized by the accumulation of proteins that display amyloid-like behavior. However, the molecular mechanisms by which these proteins arise remain unclear. Here, we demonstrate that amyloid-like proteins are produced in a variety of human cell types, including stem cells, brain organoids and fully differentiated neurons by mistakes that occur in messenger RNA molecules. Some of these mistakes generate mutant proteins already known to cause disease, while others generate proteins that have not been observed before. Moreover, we show that these mistakes increase when cells are exposed to DNA damage, a major hallmark of human aging. When taken together, these experiments suggest a mechanistic link between the normal aging process and age-related diseases.

Exposure to arising from solid fuel combustion is estimated to result in million premature deaths and 91 million lost disability-adjusted life years annually. Interventions attempting to mitigate this burden have had limited success in reducing exposures to levels thought to provide substantive health benefits. This paper reports exposure reductions achieved by a liquified petroleum gas (LPG) stove and fuel intervention for pregnant mothers in the Household Air Pollution Intervention Network (HAPIN) randomized controlled trial. The HAPIN trial included 3,195 households primarily using biomass for cooking in Guatemala, India, Peru, and Rwanda. Twenty-four-hour exposures to , carbon monoxide (CO), and black carbon (BC) were measured for pregnant women once before randomization into control ( ) and LPG ( ) arms and twice thereafter (aligned with trimester). Changes in exposure were estimated by directly comparing exposures between intervention and control arms and by using linear mixed-effect models to estimate the impact of the intervention on exposure levels. Median postrandomization exposures of particulate matter (PM) with aerodynamic diameter ( ) in the intervention arm were lower by 66% at the first (71.5 vs. ), and second follow-up visits (69.5 vs. ) compared to controls. BC exposures were lower in the intervention arm by 72% (9.7 vs. ) and 70% (9.6 vs. ) at the first and second follow-up visits, respectively, and carbon monoxide exposure was 82% lower at both visits (1.1 vs. ) in comparison with controls. Exposure reductions were consistent over time and were similar across research locations. Postintervention exposures in the intervention arm were at the lower end of what has been reported for LPG and other clean fuel interventions, with 69% of samples falling below the World Health Organization Annual Interim Target 1 of . This study indicates that an LPG intervention can reduce exposures to levels at or below WHO targets. https://doi.org/10.1289/EHP10295.