On the origin, evolution, and maintenance of RNA editing

Abstract

A newly published review by Bendich and Rogers (The biological and evolutionary consequences of competition between DNA sequences that benefit the cell and DNA sequences that benefit themselves. Nucleic Acids Research2025;53:gkaf589.) discusses the origin of RNA editing as a defense against mobile genetic elements (MGEs) and points out that many recent reviews, including ours, failed to recognize this fundamental issue. In this article, we expand on this perspective by examining the mechanistic and theoretical gaps regarding whether RNA editing suppresses or tolerates TE proliferation. We highlight the relevance of constructive neutral evolution (CNE) theory, suggesting that regardless of whether the editing machinery has arisen via CNE, specific editing sites do exhibit CNE signals. Additionally, we explore why certain A-to-I recoding sites are selectively maintained without being replaced with genomic G, reinforcing their indispensable regulatory role. Taken together, while acknowledging the plausibility of the MGE-related origin, we advocate for a broader view of RNA editing that includes multiple fascinating functions like proteome diversification and mutation correction.

Graphical Abstract

Graphical Abstract.

Introduction

The central dogma dictates that the genetic information flows from DNA to RNA to protein with high fidelity [1]. However, RNA editing seems to overturn this notion [2, 3]. RNA editing is a widespread co-transcriptional or post-transcriptional RNA modification found in both prokaryotic and eukaryotic organisms [4–6]. The two most abundant types of RNA editing are A-to-I and C-to-U RNA editing [7, 8]. Since inosines in mRNAs are interpreted as guanosines [3], both types of RNA editing are inherently mutagenic and can recode protein sequences beyond the information encoded in the genome [2, 9, 10]. RNA editing has long been recognized for its multifaceted roles in shaping immunity, development, neurobiology, and behavior in different lineages of species [10–14]. In a recent review published in Nucleic Acids Research, Bendich and Rogers revisited the evolutionary origins of various RNA editing mechanisms [15]. Notably, they proposed that the primary function of RNA editing may have originally emerged as a defense against mobile genetic elements (MGEs), rather than as a mechanism to diversify proteomes or to correct deleterious genomic mutations (Fig. 1).

Figure 1.

Mainstream views on the origin and current functions of RNA editing. A representative reference is cited for each perspective: anti-MGE origin of RNA editing [15], anti-dsRNA origin of RNA editing [20], CNE-origin of RNA editing [40], immune protector function [22], mutation compensator function [7], and proteome diversifier function [18]. Particularly, Bendich and Rogers stress that the evolutionary origin of RNA editing must not be overlooked when evaluating its present functions.

Bendich and Rogers critically point out the prevalent trend in current RNA editing literature to emphasize its “derived adaptive benefits,” particularly proteomic diversification and restorative functions [16–18], often at the expense of ignoring its ancestral role in MGE defense (Fig. 1). They indicate that such narratives may reflect a form of selective reporting and caution that “Emphasis on such derived beneficial effects of editing may have obscured its origin as an instrument for transposon defense, which is not mentioned in recent reviews of editing” [15]. Among the references cited is our own recent contribution to Journal of Molecular Evolution entitled “An ultimate question for functional A-to-I mRNA editing: why not a genomic G?” [19], which calls attention to the deeper evolutionary rationale for RNA editing sites but does not mention the origin of RNA editing.

Moreover, Bendich and Rogers’ discussion acknowledges the relevance of the both constructive neutral evolution (CNE) framework and adaptive hypotheses, the two conceptual models that also form the foundation of our ongoing investigations. In this commentary, we aim to extend and refine several of the arguments raised by Bendich and Rogers, offering perspectives shaped by empirical and theoretical insights from our and other’s research works in the field. While we recognize the plausibility of the MGE-related origin suggested by Bendich and Rogers, we propose a more expansive perspective on RNA editing, one that encompasses various intriguing functions such as proteome diversification and mutation correction.

On the anti-MGE origin of RNA editing

We fully concur with Bendich and Rogers’ proposition that the evolutionary origin of RNA editing might be closely linked to transposable elements (TEs) [15]. Indeed, Zhang et al. (2023) already explicitly stated that “metazoan A-to-I editing might first emerge as a safeguard mechanism against repeat-derived dsRNA (double-stranded RNA) and was later co-opted into diverse biological processes due to its mutagenic nature” [20]. Their conclusion was based on the observation of extensive A-to-I RNA editing events within TE-rich regions across a wide range of metazoans (which is also observed in another large-scale transcriptome analysis [21]), as well as on classical studies demonstrating that RNA editing prevents the innate immune sensor MDA5 from erroneously recognizing endogenous dsRNA as “nonself” [22]. This body of evidence suggests an intrinsic relationship between RNA editing and TEs.

However, the function of RNA editing in preventing immune responses triggered by TE-derived dsRNA [22] differs slightly from the model proposed by Bendich and Rogers that RNA editing evolved to suppress the proliferation of TEs that function as an anti-MGE mechanism [15]. This distinction raises several key questions.

First, given that RNA editing attenuates immune responses against endogenous TE-derived dsRNA [22], does editing ultimately suppress TE proliferation, or does it paradoxically protect TEs (Fig. 2)? Without RNA editing, such dsRNAs could activate host immunity and (the individual will) be purged by strong purifying selection. However, the presence of RNA editing cancels the purifying selection and may instead tolerate TE expression and expansion. Indeed, one may argue that RNA editing can disrupt the open reading frame (ORF) of TEs by introducing premature stop codons, thereby reducing their invasiveness. Since the stop codons UAA/UAG/UGA can arise from sense codons only through C-to-U editing, such events are expected to be rare. Moreover, disrupting the ORF of TEs does not prevent TEs from transposition, and this strategy seems less effective than directly disrupting the transposase. Moreover, as we will discuss in a later section, why should the organisms abolish the ORF of TEs by RNA editing rather than genomic mutations? What about the prevalent TEs without ORFs and nonautonomous TEs like miniature inverted-repeat transposable elements (MITEs) [23, 24]?

Figure 2.

Concerns on the anti-MGE origin of RNA editing. (1) Does RNA editing suppress TEs or tolerate the expression of TEs? (2) How does RNA editing suppress TEs? (3) Does ADAR compete or collaborate with RNAi machineries? (4) RNAi mechanism predates the emergence of ADAR, then why do organisms need RNA editing to suppress TEs? (5) Plants do not have ADAR-mediated A-to-I RNA editing but they still manage to control TEs.

Second, apart from the earlier speculations, the mechanistic basis for RNA editing as a TE-silencing pathway remains unclear (Fig. 2). As discussed earlier, altering the RNA of TEs, especially those nonautonomous TEs, contributes little to TE suppression. Most current evidence suggests that A-to-I editing contributes to TE repression indirectly, via interaction with RNA interference (RNAi) pathways. For example, in Caenorhabditis elegans, ADAR-mediated editing collaborates with the ERI-6/7-MOV10 RNAi machinery to silence endogenous retroelements and LTR retrotransposons [25]. Similarly, Drosophila RNA editing has been implicated in heterochromatin-based transposon silencing [26]. These processes likely converge on the shared substrate of dsRNAs (Fig. 2). Then, an open question is, do ADAR and RNAi machineries collaborate to suppress TEs, or do they compete, with ADAR ultimately playing a negative role in TE suppression?

Next, RNAi is a broadly conserved pathway across eukaryotic lineages, whereas ADAR-mediated A-to-I editing appears to be restricted to metazoans, suggesting that RNAi predates RNA editing evolutionarily (Fig. 2). If RNAi was already present and effective at controlling MGEs, what evolutionary pressure necessitated the emergence of RNA editing in metazoans [27, 28]? Furthermore, plants, which lack A-to-I mRNA editing, appear to manage TE activity without this mechanism (Fig. 2). In Drosophila, loss of Adar results in increased gene silencing [26], a phenotype that seems counterintuitive if editing were primarily functioning to inhibit TE mobilization. Collectively, these observations and open questions cast doubt on the hypothesis that RNA editing originated as an anti-MGE defense.

Origin and current functions of RNA editing: beyond a unified theory

In fact, we believe that we do not have to seek a single unified theory to explain the origins of all types of RNA editing. The origin of A-to-I RNA editing appears to be most strongly associated with TEs, whereas plant C-to-U RNA editing and insertion/deletion (indel) types of RNA editing in kinetoplastids seem to have a much weaker correlation with TEs. The difference arises from substrate specificity: ADAR targets dsRNAs linked to inverted repeats, while plant C-to-U editing might favor single-stranded RNAs [29], and mitochondrial RNA editing in kinetoplastids (indel) is guided by gRNAs and editosomes [30, 31], neither showing any biases toward TEs.

Next, it is worth addressing Bendich and Rogers’ assertion that “RNA editing as an MGE-defense mechanism was likely present in the first eukaryotes, and this defense is still its primary function” [15]. We would caution against conflating evolutionary origin with contemporary biological function. Evolutionary processes are dynamic, and functions often shift over time, a concept well captured by the ideas of “pre-adaptation” or “exaptation” [32, 33]. Moreover, defining the “primary function” of RNA editing is inherently challenging. In mice, ADAR1 knockout results in embryonic lethality due to uncontrolled immune activation against TE-derived dsRNA [22], while ADAR2 knockout causes death due to failure in Q > R editing at the GRIA2 locus [34, 35]. Given that both phenotypes are lethal, it seems difficult to define one as more “primary” or essential than the other. This is much like the unnecessary debate over whether the primary duty of DNA is replication or transcription? Without replication, genetic information would not be faithfully transmitted across generations, leading to the eventual extinction of the lineage. Without transcription, however, genetic information would remain inert, with no gene expression and no cellular function. Both processes are indispensable, and it is not meaningful to argue which role is more primary. It is similarly unnecessary to rank one essential function of RNA editing above another. In the following sections, we will explore the current biological functions of RNA editing in greater detail.

In summary, we generally agree with Bendich and Rogers’ notion that RNA editing might have originated in connection with TEs [15], at least for A-to-I RNA editing. However, whether it truly functions to suppress TE expansion, and through what mechanisms, remains an open and compelling question for future investigation. The diverse functions of RNA editing, whether acting as an anti-dsRNA defense, a proteome diversifier, or a mutation compensator, are likely to coexist as equally essential, rather than to be ranked in a hierarchical order. We also suggest that the origins of different types of RNA editing are best explained by multiple, context-dependent processes rather than by a single unifying theory.

Reflections and extensions on the constructive neutral evolution hypothesis of RNA editing

Since Bendich and Rogers have raised opposing opinions to the CNE-origin of RNA editing [15], here we recall this theory and make a little extension. As far as we know, the foundational work on the theory of CNE is attributed to Stoltzfus’ article in 1999, “On the possibility of constructive neutral evolution,” published in Journal of Molecular Evolution [36]. Twenty years later, a similar review was published in the same journal, which reiterated core ideas of CNE [37]. If we understand correctly, the hallmark features of CNE phenomena are: (i) the occurrence of a process that is far more complex than necessary, without the presence of positive selection, and (ii) once a tolerance (e.g. correcting) mechanism emerges, the system becomes increasingly complex, making the organism heavily rely on the correcting mechanism, and thus this evolutionary trajectory is irreversible. This phenomenon is described in detail in our previous review [19] cited by Bendich and Rogers, where we have discussed different examples of CNE, including a classic case of genome arrangement in ciliates (protists) [38, 39].

In Bendich and Rogers’ review, the authors extensively cite a 2012 paper by Gray, which merges CNE theory with RNA editing and explains “how complexity might evolve in the absence of positive selection” [40]. Gray argues that the capacity of RNA editing mechanisms to reverse DNA mutations allowed for the tolerance of numerous otherwise detrimental mutations. Once the repair mechanism by RNA editing has been established, then the mutations in the genome will proliferate, thereby rendering RNA editing mechanisms indispensable. This logic is generally tenable.

Gray also acknowledges certain counterexamples that challenge the CNE origin of RNA editing [40]. Notably, in particular plant species, such as marchantiid liverworts [41, 42], the loss of RNA editing mechanisms does not conform to the CNE theory’s prediction that such a mechanism would “effectively lock in the editing system as an integral part of the genetic information pathway.” To resolve this dilemma, we raise a critical question: How many examples of RNA editing loss have we actually observed? These instances must be underrepresented compared to neutral expectation. It is likely that in the history, most individuals that once lost RNA editing mechanisms were subjected to purifying selection and went extinct. Those that have survived despite the loss of RNA editing likely possess unique adaptive strategies compensating for the loss. This is not surprising given the great biodiversity and species-specificity of organisms. This phenomenon is analogous to how certain viruses infect humans but not infect other animals, and vice versa [43, 44]. We need not to worry about the nonhuman species subjected to human viruses. Similarly, in the case of A-to-I RNA editing, the Q > R recoding site in the GRIA2 gene is deemed indispensable in vertebrates [34, 35], but ironically it is not edited in the orthologous gene in Drosophila [45]. In fact, Gray’s interpretation of this phenomenon, that the species having lost RNA editing mechanism generally had fewer editing sites to begin with, essentially suggests that the harm of editing loss is tolerable in those species. This can also be interpreted as the species being intrinsically resistant to such harm, similar to Drosophila not needing Q > R recoding in GRIA2 gene, reflecting species-specific properties. In addition to the loss of the entire RNA editing mechanism, there are cases of ancestral C-to-U RNA editing sites being replaced with genomic T. For instance, a UCA > UUC (Ser > Leu) recoding site in chloroplast gene rps12 is inferred to have editing at the ancestral node of Solanaceae family, but in tobacco the corresponding genomic position is subsequently replaced with T [46]. These examples of loss of editing mechanism or specific editing sites illustrate how organisms can naturally escape dependence on RNA editing. However, as we will elaborate below, mutations on individual RNA editing sites are not counterexamples to the CNE theory.

Regarding Bendich and Rogers’ disagreement with Gray’s hypothesis on CNE-origin of RNA editing [15], we have a compromise solution (Fig. 3). We need not insist that the RNA editing mechanism itself originated through CNE. In fact, we only need to demonstrate that particular RNA editing site(s) emerged as a result of CNE. The origin of the RNA editing mechanism is instantaneous, having emerged at a specific point in evolutionary history; however, the emergence of individual RNA editing sites is a continuous process, with new sites potentially arising at any time from ancient periods to the present day (Fig. 3). Therefore, discussion on the origin of the entire RNA editing mechanism, namely whether it originated related to TEs or via CNE, remains unresolved but is not essential to the discussion on individual editing sites.

Figure 3.

Schematic diagram for a compromise solution between Bendich and Rogers’ perspective and Gray’s hypothesis. The origin of the RNA editing mechanism is instantaneous, while the emergence of individual RNA editing sites is a continuous process. While the CNE-origin of RNA editing is unresolved, there are specific examples of CNE-derived RNA editing sites that correct DNA mutations [7]. The representative literatures for adaptive editing sites [18] and promiscuous (nonadaptive) editing sites [56] are also provided.

We should fully recognize that there are indeed observations that some RNA editing sites conform to the predictions of CNE theory. For example, in plant mitochondria and chloroplasts, the start codons of certain ORFs mutate from AUG to ACG, necessitating C-to-U RNA editing to correct this mutation [7]. Without the C-to-U editing mechanism, such genomic mutations would be purged and be unlikely to become fixed during evolution. It is precisely because of the existence of the C-to-U editing system that these otherwise harmful DNA mutations can occur and become fixed, further entrenching the reliance of the organism on the C-to-U mechanism. Although plant mitochondria and chloroplasts generally exhibit low mutation rates in nature [47], RNA editing nevertheless can function as a pre-existing mechanism that corrects and tolerates DNA mutations within these organelles. This then raises the question of why animals did not evolve a comparable correction system for their mitochondria (where mutation rates are generally higher than in plants)? According to the “evolutionary tinkering” perspective [48], organisms innovate by modifying what is already available, and this repertoire itself is often shaped by the influence of random drift. Consequently, “why not” questions in evolutionary biology are not applicable to the origin of complex systems and are more appropriately posed only for relatively simple processes [19], such as those discussed in the next section.

According to our compromise solution earlier, the question of whether RNA editing mechanism originated via CNE is less clear than the recognition that the emergence of specific editing sites aligns with the CNE model. We argue that Bendich and Rogers’ position that the initial purpose of RNA editing was not to diversify the proteome or correct DNA mutations [15] actually supports the notion that those later-emerged restorative editing sites align with CNE. If RNA editing mechanism originated for a purpose related to anti-TE defense, then it would later tolerate the occurrence and fixation of harmful DNA mutations. This scenario exactly fits the “harm-permitting model” proposed by George Zhang [49]. Consider another scenario, if harmful mutations existed at first, and then RNA editing emerged specifically to correct these mutations, then this would not align with CNE but with adaptive origin of RNA editing [50].

Notably, we should mention that the genome itself has the capacity to repair unfavorable mutations. During photosynthesis, plant chloroplasts generate large amounts of reactive oxygen species (ROS) [51], which readily oxidize guanine to form 8-oxoguanine (8-oxoG). In addition to pairing correctly with C, 8-oxoG can mispair with A, leading to the incorporation of T during replication and ultimately resulting in a G > T point mutation [52]. In the base excision repair (BER) pathway, the key glycosylases MutY and OGG1 recognize such lesions, excise the mismatched base, and restore the correct G:C pair [53]. Similarly, cytosines that undergo methylation can be deaminated to thymine, giving rise to C > T transitions, which are also subject to repair by the plant BER system [54]. Importantly, BER activity has been documented in both nuclear and organellar genomes [55], underscoring its role as the first line of defense against mutagenesis. However, BER is not omnipotent. For instance, BER is unlikely to repair T > C mutations. In such cases, C-to-U RNA editing may act as a second line of defense, providing a compensatory mechanism to maintain functional coding capacity and also allowing the fixation of otherwise detrimental DNA mutations.

A potential concern is that if RNA editing became fixed through CNE, the process itself must have required a compensatory safeguard to ensure accurate gene expression. If RNA editing originally arose as a defense against TEs, one might then ask what mechanism provided this backup to maintain transcriptional fidelity? We contend that this concern relies on an assumption that exonic or CDS mutations inherently disrupt gene expression. However, both theoretical considerations and in silico analyses indicate that this is rarely the case. Conceivably, mutations in intergenic regulatory regions are far more likely to influence transcription, whereas CNE-derived RNA editing events in coding regions generally do not. Consistent with this view, our previous differential expression analysis of head transcriptomes from two Adar mutant strains and matched wild-type flies revealed no significant effect of editing status on gene expression [56]. Specifically, edited and unedited genes exhibited comparable log₂fold-changes (mutant/wild-type), with P = .21 for Adar^5G1 (Adar deleted) and P = 0.51 for Adar^E374A (deaminase domain abolished) under Wilcoxon rank sum tests. These facts suggest that RNA editing exerts no broad impact on host gene expression, making the backup mechanism for correcting gene expression unnecessary.

Together, Bendich and Rogers’ statement that “there are clear examples of how editing is helpful or essential to organism viability; these weigh against the concept of CNE” [15] may not be appropriate. Having or not having essential functions, or being or not being indispensable, has no causal relationship with CNE. Start codon RNA editing events in plants all seem functional and indispensable, but they likely emerged as CNE.

The fascination with A-to-I RNA editing: why not a genomic G?

From Bendich and Rogers’ comments on recent reviews, they seem to advocate that any discussion of the current functional landscape of RNA editing must remain anchored in considerations of its evolutionary origin [15] (Fig. 1). In vascular plants, C-to-U RNA editing currently primarily serves to correct deleterious DNA mutations. In such cases, the RNA-edited state is not evolutionarily more favorable than simply having a genomic T, suggesting that editing is a compensatory rather than an optimizing mechanism [7]. In contrast, in animals, A-to-I RNA editing in coding sequences may serve a regulatory role in expanding proteomic diversity. This raises a compelling question: for particular adaptive A-to-I sites, why have they not been replaced with a genomic G [19]? One may argue that this replacement might have occurred in some individuals but it was not fixed in the population due to genetic drift. However, given the constructively neutral nature of such substitutions, we should expect to observe fixation events at least for a few sites or in a few species.

The logic of CNE theory hinges on the irreversibility of increasingly complex systems. But as mentioned earlier, the irreversibility refers to the entire editing mechanism but does not focus on individual editing sites. We argue that the maintenance of particular RNA editing sites cannot be explained by CNE but should only be plausible under adaptive hypothesis [19].

We first provide a conceptual example in plants. The CNE-driven emergence of a genomic C that is corrected by C-to-U RNA editing does not preclude a subsequent C-to-T DNA mutation. Such point mutations are neither inaccessible nor evolutionarily burdensome. In fact, if the follow-up C-to-T mutation enhances fitness, then natural selection can readily fix it. The substitution from ancestral editing site to a genomic T in tobacco chloroplast gene rps12 is a nice example [46]. CNE does not cancel this possibility. Expecting an entire molecular system to reverse itself may be quixotic, but expecting a single beneficial point mutation to arise and fix it is far more plausible [19].

If restorative C-to-U editing emerged as CNE, then genomic C-to-T replacement on RNA editing sites should be positively selected or at least neutral. In contrast, if RNA editing is adaptive due to other reasons, then genomic replacement on RNA editing sites should be underrepresented. One may argue that if a genome tends to continuously increase its GC content (this trend is more commonly observed in mammals as a result of GC-biased gene conversion [57], but also seen during bacterial evolution [58]), it renders subsequent C-to-T reverse mutation unlikely. However, note that the editable sites constitute only a small fraction of the genome; the benefits of reverse mutations on them might largely exceed their negligible impact on genome-wide GC content.

To assess the overall selective pressure on RNA editing sites, specifically whether they tend to be genomically replaced or maintained as editable, comparative evolutionary analyses in cephalopods and Drosophila have shown that edited adenosines are less likely to be replaced with genomic guanosines than unedited ones [17, 45, 59]. This suggests that evolutionary forces are actively preserving these editing sites, likely due to their functional contribution to proteomic diversification. Supporting this, phenotypic studies in the fungus Fusarium graminearum have demonstrated that the wild-type, editable alleles are superior to both uneditable and fully edited mutants, reinforcing the idea that some editing sites are irreplaceable [16, 18, 50], possibly due to the advantage of temporospatial fine-tuning of protein functions.

Of note, this line of reasoning applies predominantly to the relatively small subset of recoding A-to-I events. For the vast majority of editing events that occur within TEs in animals, the question becomes: can the edited A in TEs simply be replaced by a genomic G? If A-to-I editing indeed restricts TE proliferation, wouldn’t a permanent A-to-G substitution at the DNA level offer a more efficient and stable solution? Considering that ADAR may resist viral dsRNA by promiscuously altering the viral ORF [8], it raises further questions as to why the same approach is used against endogenous dsRNA? Wouldn’t genomic DNA mutations be a more direct method to disrupt the ORF of TEs? Argument on sustaining genome stability is untenable because the DNA mutations disrupting TEs will only increase, not decrease, genome stability. In addition, disrupting the transposase seems a better choice for the organisms compared to disrupting TEs. All these questions shed concerns on the proposed relationship between RNA editing and anti-MGE role.

Disproportionate focus on the current functions of RNA editing?

It is particularly noteworthy that Bendich and Rogers suggest that other mechanisms, such as repeat-induced point mutation and post-transcriptional gene silencing may serve analogous anti-MGE roles. These systems could, in principle, substitute for RNA editing in the context of TE suppression. In contrast, the proteomic diversification facilitated by A-to-I RNA editing cannot be replaced by genomic G because a permanent DNA mutation will abolish the flexibility. Studying an indispensable mechanism is intuitively more compelling than investigating one that can be replaced, much as single-copy orthologous genes typically receive more attention (such as in phylogenetic analyses) [60], whereas individual members of multi-copy redundant gene families (rather than the family as a whole) tend to attract less average attention [61]. We admit that the ability (or inability) of a function to be substituted by another mechanism is not directly informative of the original evolutionary purpose of this mechanism, nor does it directly quantify its adaptive value. Yet, this might partly explain why many recent studies focus on the currently most eye-catching functionality of RNA editing while overlooking its evolutionary origins [5, 10, 62–64]. This intriguing question of why specific A-to-I RNA editing sites cannot simply be replaced by a genomic G remains at the core of our fascination with RNA editing [19], and is likely a compelling reason why this field as a whole continues to captivate other researchers as well.

Then, another possible reason for the disproportionate attention on recoding events (though it may not be entirely justified) is different recoding sites in different genes can have different functional implications; in contrast, RNA editing at TE-derived dsRNA sites often appears functionally uniform, and expanding the catalog of such editing events adds relatively little to our understanding of the significance of RNA editing [65].

Conclusions and future perspectives

In conclusion, we concur with Bendich and Rogers’ assertion that the origin of RNA editing might be linked to TEs. However, whether RNA editing facilitates or inhibits TE expansion, and the precise molecular mechanisms underlying this relationship, remain open questions that require further investigation. When applying the classic CNE evolutionary theory to the RNA editing field, we need not focus solely on whether the entire RNA editing mechanism itself originated according to the CNE model. Instead, the key focus should be on whether specific RNA editing sites align with the CNE model, particularly C-to-U RNA editing in plants. Moreover, the unresolved origin of RNA editing is largely independent of our fascination with, and continued investigation into, its derived functions such as proteome diversification, mutation compensation, and immune protection.

Certain A-to-I RNA editing sites in animals, which cannot be directly replaced by a genomic G, underscore the advantages and necessity of RNA editing. This highlights the functional indispensability of RNA editing beyond simple genomic substitutions. In future research, we should strive to elucidate the multi-functional properties of RNA editing, rather than confining our understanding to a single functional aspect. Such a comprehensive approach will enhance our understanding of the origin, evolution, and practical value of this post-transcriptional modification mechanism, paving the way for its precise application across different biological contexts.

Conflict of interest

None declared.

Funding

This study is financially supported by the Beijing Natural Science Foundation (Natural Science Foundation of Beijing Municipality, no. 6252012), the Young Elite Scientist Sponsorship Program by CAST (no. 2023QNRC001), the Young Elite Scientist Sponsorship Program by BAST (no. BYESS2023160), and the 2115 Talent Development Program of China Agricultural University.

Data availability

No new data were generated in this research.