Navigating trade-offs: the adaptive significance of A-to-I RNA editing in fungi, bacteria, and animals

Comparative chloroplast RNA editing analysis in wild and genetically diverse niger (Guizotia abyssinica L.F. Cass) genotypes reveal domestication-driven divergence and wild-specific resilience.

Adenosine-to-inosine (A-to-I) RNA editing, capable of protein recoding, has evolved independently in animals and fungi. This study proposes adaptive hypotheses regarding its origins and phenotypic significance, suggesting that A-to-I editing enhances adaptability by alleviating genetic trade-offs. In metazoans, its emergence may have been driven by a development-defense trade-off associated with transposable element activation during the evolution of multicellularity. Late Devonian cooling and End-Permian warming are hypothesized to have driven the emergence of extensive A-to-I recoding in coleoid nervous systems and Sordariomycete sexual fruiting bodies, respectively. These adaptations may have influenced key evolutionary innovations, including the evolution of metazoan nervous systems, coleoid intelligence, and shell loss, and fungal sexual reproductive structures. Additionally, extensive A-to-I recoding is proposed to facilitate accelerated development and specific life-history strategies in both animals and fungi. This paper provides new perspectives on the evolutionary forces shaping A-to-I RNA editing and its role in phenotypic diversity across taxa.

Simple SummaryAmong the animal species capable of regenerating missing body parts, a species of earthworm, Perionyx excavatus, has the most powerful regeneration capacity, which can completely and regenerate an amputated head and tail. Earthworm regeneration is a form of epimorphosis, a simple mode of development in adults that occurs around the sites of damage rather than throughout the body. In order to achieve this process, the earthworm must have molecular tools via which a variety of cell and tissue types can be precisely recovered from the pluripotent (or possibly totipotent) blastemal cells. Adenosine to inosine (A-to-I) RNA editing catalyzed by adenosine deaminases acting on RNA (ADAR) can generate substantial transcriptome and proteome variability and provide an ideal tool for cell and tissue re-specification. To understand the role of ADAR during earthworm regeneration, the molecular characteristics of an ADAR gene identified from P. excavatus (Pex-ADAR) were analyzed, and its spatial and temporal expression patterns were observed during regeneration. Domain analysis showed that Pex-ADAR is a member of the ADAR1 class. Its expression level primarily increases when and where muscle redifferentiation is actively taking place, suggesting that the RNA-editing enzyme Pex-ADAR is involved in muscle redifferentiation.Adenosine deaminases acting on RNA (ADAR) catalyze the hydrolytic deamination of adenosine (A) to produce inosine (I) in double-stranded RNA substrates. A-to-I RNA editing has increasingly broad physiological significance in development, carcinogenesis, and environmental adaptation. Perionyx excavatus is an earthworm with potent regenerative potential; it can regenerate the head and tail and is an advantageous model system to investigate the molecular mechanisms of regeneration. During RNA sequencing analysis of P. excavatus regenerates, we identified an ADAR homolog (Pex-ADAR), which led us to examine its spatial and temporal expression to comprehend how Pex-ADAR is linked to regeneration. At first, in domain analysis, we discovered that Pex-ADAR only has one double-stranded RNA-binding domain (dsRBD) and a deaminase domain without a Z-DNA-binding domain (ZBD). In addition, a comparison of the core deaminase domains of Pex-ADAR with those of other ADAR family members indicated that Pex-ADAR comprises the conserved three active-site motifs and a glutamate residue for catalytic activity. Pex-ADAR also shares 11 conserved residues, a characteristic of ADAR1, supporting that Pex-ADAR is a member of ADAR1 class. Its temporal expression was remarkably low in the early stages of regeneration before suddenly increasing at 10 days post amputation (dpa) when diverse cell types and tissues were being regenerated. In situ hybridization of Pex-ADAR messenger RNA (mRNA) indicated that the main expression was observed in regenerating muscle layers and related connective tissues. Taken together, the present results demonstrate that an RNA-editing enzyme, Pex-ADAR, is implicated in muscle redifferentiation during earthworm regeneration.

RNA modifications serve as dynamic regulators of neural plasticity through their ability to fine-tune transcript stability and splicing. Pseudouridine (Ψ), an evolutionarily conserved RNA modification catalyzed by pseudouridine synthases, plays established roles in neurodevelopment, yet its functional significance in activity-dependent behavioral adaptation remains poorly defined. Here, we investigate Ψ-mediated epitranscriptomic regulation within the infralimbic prefrontal cortex (ILPFC), a brain region requiring precise synaptic remodeling for the clinically relevant form of fear extinction memory. Combining transcriptome-wide pseudouridylation profiling with behavioral analysis in mice, we identified selective Ψ enrichment at exons of synaptic regulatory genes within ILPFC during fear extinction learning. Fear extinction in the ILPFC drives concomitant exonic Ψ deposition and upregulation of synaptogenic transcripts, processes that involve pseudouridine synthase PUS7. Crucially, PUS7 knockdown in the ILPFC selectively impaired fear extinction memory formation without altering baseline fear expression, establishing a causal link between Ψ-dependent RNA processing and activity-dependent synaptic structural remodeling in this microcircuit. Our findings demonstrate that PUS7-mediated Ψ modification spatiotemporally regulates activity-dependent RNA dynamics in the ILPFC, providing the evidence that epitranscriptomic mechanisms precisely coordinate synaptic gene expression within behaviorally defined brain sub-region. This work bridges molecular RNA biology with systems neuroscience, revealing a novel mechanism for activity-dependent regulation of fear extinction in ILPFC.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13041-025-01250-6.

Dracaena cambodiana, a vulnerable species widely distributed in tropical and subtropical areas, has been recognized as a model plant for studying island conservation biology due to its fragmented habitat, slow growth, and ecological sensitivity. However, its organelle genome evolution and population divergence across different island environments remain poorly understood. In this study, we de novo assembled and annotated the complete chloroplast (cp) and mitochondrial (mt) genomes of two geographically distinct individuals of D. cambodiana from Hainan Island, China: a coastal area (SY) and a mountainous forest area (DF). Both genomes showed conserved circular structures, but comparative analyses revealed key differences. The chloroplast genomes exhibited intergenic hotspot regions such as trnC-GCA-petN, trnL-UAA-trnF-GAA, and psaI-ycf4, which may serve as potential markers for taxonomy, population genetics, phylogeography and conservation biology of D. cambodiana. In the mitochondrial genomes, three genes (nad1, nad5, and rps11) showed the non-synonymous to synonymous substitution rate ratio (Ka/Ks) >1, indicating potential positive selection linked to environmental stress in the coastal population. Over 580 RNA editing sites were identified in each mitochondrial genome, with minor differences between DF and SY. These results suggest that while organelle genome structures are conserved, subtle molecular variations could potentially be associated with environmental differences between populations, although further investigation is needed to confirm adaptive significance. This study provides foundational genomic resources for understanding the adaptive evolution of D. cambodiana and supports conservation strategies in island ecosystems.