Ann. N.Y. Acad. Sci.xxxx ISSN 0077-8923

A N N A L S O F T H E N E W Y O R K A C A D E M Y O F SC I E N C E S Issue: DNA Habitats and Their RNA Inhabitants

DNA and RNA editing of retrotransposons accelerate mammalian genome evolution Binyamin A. Knisbacher and Erez Y. Levanon The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel Address for correspondence: Erez Y. Levanon, The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan 52900, Israel. [email protected]

Genome evolution is commonly viewed as a gradual process that is driven by random mutations that accumulate over time. However, DNA- and RNA-editing enzymes have been identified that can accelerate evolution by actively modifying the genomically encoded information. The apolipoprotein B mRNA editing enzymes, catalytic polypeptide-like (APOBECs) are potent restriction factors that can inhibit retroelements by cytosine-to-uridine editing of retroelement DNA after reverse transcription. In some cases, a retroelement may successfully integrate into the genome despite being hypermutated. Such events introduce unique sequences into the genome and are thus a source of genomic innovation. adenosine deaminases that act on RNA (ADARs) catalyze adenosine-to-inosine editing in double-stranded RNA, commonly formed by oppositely oriented retroelements. The RNA editing confers plasticity to the transcriptome by generating many transcript variants from a single genomic locus. If the editing produces a beneficial variant, the genome may maintain the locus that produces the RNA-edited transcript for its novel function. Here, we discuss how these two powerful editing mechanisms, which both target inserted retroelements, facilitate expedited genome evolution. Keywords: RNA editing; DNA editing; ADAR; APOBEC; genome evolution; retrotransposons

Introduction With the exception of infrequent random somatic mutations, it is widely believed that the same genomic content should be fixed in an organism throughout its lifetime. This information will also serve as a template for exact RNA copies. Nevertheless, two endogenous processes that can modify genomic content have been identified in humans and in many other organisms: (1) active replication of retrotransposons through a single-stranded RNA intermediate, which is reverse transcribed and integrated into the host genome; and (2) editing of either RNA or DNA involving the alteration of particular nucleotides into different ones. Surprisingly, a tight linkage between retroelements and both RNA and DNA editing was recently found. Although both processes have the potential to radically alter our view of genomic integrity and complexity, they are still a great mystery, mainly because of the difficulty in studying repetitive sequences comprising

many similar copies in a genome. In this short essay, we discuss the possible impact of DNA editing by apolipoprotein B mRNA editing enzymes, catalytic polypeptide-like 3 (APOBEC3s) and RNA editing by adenosine deaminases that act on RNA (ADARs) of retrotransposons on mammalian evolution. DNA editing DNA editing of retroelements by APOBEC proteins Retroviruses replicate through a single-stranded RNA intermediate, which is then reverse transcribed to DNA and integrated into the host genome. One of the powerful ways mammalian cells can interrupt this process is by inducing a multitude of cytosine-to-uridine (C-to-U) deaminations in the negative strand of the retroviral DNA after reverse transcription. This cytidine deamination, or editing, is carried out predominantly by APOBEC3 proteins (reviewed in Refs. 1 and 2), although APOBEC1s from some nonhuman species have

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been shown to possess this capability as well.3,4 The encounter with APOBEC3 proteins typically results in viral inhibition. However, in some cases, the retrovirus may successfully integrate into the host genome after being edited, bearing numerous guanidine-to-adenine (G-to-A) mutations in its positive strand, as templated by the C-to-U–edited negative strand.5–7 APOBEC3s are very potent restriction factors, not only against retroviruses, but also against endogenous retroelements (Fig. 1A). In addition to restricting long terminal repeat (LTR) retrotransposons,8–10 which are homologous to extant retroviruses, they can also restrict non-LTR retrotransposons (e.g., LINE-1 and Alu).1,11,12 The APOBEC3 locus emerged in placental mammals and greatly expanded through multiple duplications and notable positive selection throughout evolution.13–15 Intriguingly, this expansion is greatest in primates, encoding a total of seven APOBEC3 proteins,13 which is attributed to an ongoing arms race against mutagenic retroelements.15 DNA editing is a powerful mutation mechanism Although the genomic effects of DNA editing have not been sufficiently studied,16 it seems that it is an exceptionally powerful evolutionary mechanism. Two intensively studied mutation mechanisms are random point mutations and de novo insertions of transposable elements (TEs). Both can alter coding sequences, mRNA splicing, and regulatory elements. However, there are great differences in their modes of action and genomic impact. Nucleotide substitutions occur randomly during genome replication, for example, and alter an existing sequence. In contrast, retrotransposition is a source of structural variation where one locus can affect distant ones by creating new insertions. Furthermore, retrotransposons can also shuffle genomic sequence by transducing a neighboring sequence and inserting it along with their own sequence into the site of integration.17,18 Thus, retrotransposons modify the genome at a higher order than point mutations. However, mutation by retrotransposition is limited to the arsenal of preexisting sequences in the genome and cannot generate novel sequences. Intriguingly, DNA editing synergistically combines the distinct dynamic traits of point mutation and retrotransposition by spawning unique sequences that are dispersed throughout the genome. By this means, 2

DNA editing can confer extraordinary plasticity to the genome and foster accelerated evolution19 (Fig. 2A). DNA editing is widespread in mammalian genomes Previously, experiments in cultured cells demonstrated that APOBEC3-mediated restriction of LTR retrotransposons involves or even relies on DNA editing.8,9,20,21 However, the impact of DNA editing on genome variability was not yet explored. Therefore, a recent study endeavored to delineate the effects of DNA editing on genome evolution and found that it is a frequent event in various retrotransposon families across mammalian reference genomes.19 Carmi et al.19 screened genomic sequence for DNA-edited retrotransposons, specifically identifying those that were inserted in the germ line or during early embryonic development. It is worth noting that the plausibility of such events is supported by the expression of various APOBEC3s in ovaries and testes,22,23 suggesting that many retrotransposons undergo DNA editing during mobilization in the germ line. Genomes of the primate (human, chimp, orangutan, rhesus, marmoset) and rodent (mouse, rat) lineages were analyzed, all of which contained signs of DNA editing. Aside from extensive DNA editing of the immediate suspects, LTR retrotransposons, an abundance of DNA editing in primate SVA and mammalian LINE-1 retrotransposons was identified. The latter was unexpected, because restriction of non-LTR retrotransposons was thought to be independent of DNA editing. This in silico observation was supported by a recent experimental study in which the Moran group showed that APOBEC3A restricts LINE-1 elements through DNA editing.24 Therefore, the DNA editing detected in mammalian LINE-1 elements could be associated with APOBEC3A or another editing-competent APOBEC. DNA-edited elements are exapted by the genome Carmi et al.19 identified an abundance of DNAedited retrotransposons in mammalian genomes. In total, thousands of edited elements, containing tens of thousands of G-to-A edited sites, were found. The retroelement restriction by DNA editing was evident in many of the edited elements, as reflected by the numerous editing sites in retroelement open reading frames (ORFs) that change amino acids or introduce

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Figure 1. DNA and RNA editing of retrotransposons. (A) C-to-U DNA editing of a retroelement during retrotransposition (mobilization). DNA editing creates diversity in retroelement sequences and accelerates genome evolution. In this process, a retroelement (gray box) in genomic DNA (paired black lines) is transcribed to RNA (blue line), which is reverse transcribed, creating an RNA–DNA hybrid. The RNA is degraded, releasing ssDNA (black line) of the retroelement’s minus strand. The APOBECs (typically APOBEC3), whose preferred substrate is ssDNA, convert cytidines to uridines in the retroelement DNA, typically inducing its degradation. However, retrotransposition may be completed by successful synthesis of the second DNA strand and integration into the genome at a new locus (the pink box is the inserted edited element). The C-to-U editing on the minus strand results in G-to-A mutations in the retroelement’s positive strand. (B) A-to-I RNA editing of retroelements and its effect on mRNA transcript diversity. RNA containing two retroelements in opposite orientation (gray arrow boxes) is transcribed and the complementary retroelement sequences form a stable double-stranded RNA (dsRNA) structure. dsRNA is the preferred substrate for editing by ADARs, which convert one or more adenosines to inosines. ADARs can produce a large number of mRNA isoforms, as a function of the set of adenosines edited in each transcript (pink arrow boxes). For simplicity, RNA editing of only one of the two complementary retroelements is shown, but both could be edited, increasing the potential number of mRNA products.

stop codons. One of the most edited elements was a member of the mouse intracisternal A-particle (IAP) family, which contained 176 G-to-A mutations and only 26 other mismatches, when aligned to its tentative parent in the mouse genome. Such

a mutation load would take millions of years to accumulate by neutral mutation, but DNA editing instantly transforms the retrotransposon sequence, promoting diversity and thereby accelerating evolution (Fig. 2A). Notably, only elements with at least

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Figure 2. DNA and RNA editing of retrotransposons accelerate genome evolution. Black horizontal lines depict DNA and blue ones are RNA. RE, retroelements. (A) Exonization of retroelements may be much faster once DNA editing has occurred. Without DNA editing (top), a de novo retroelement insertion is identical to its progenitor source element. The element will accumulate random mutations over time, which may at length give rise to a functional splice site (or any other functional sequence). In contrast, DNA editing by APOBEC3s can instantly hypermutate the retroelement sequence, thus inserting a transformed sequence into the genome. This mechanism enables the genome to tinker with retroelement sequence and increases the probability of creating new function. The lower panel describes such an event, resulting in immediate exonization. (B) Emergence of a new exon by A-to-I RNA editing. In this process, an adenosine is converted to inosine. The latter is recognized as guanine by the splicing machinery, thus a novel 3 splice junction, which has an AG consensus, may emerge. This process has been observed, for example, in the human NARF gene.73

12 consecutive G-to-A editing sites were considered edited. Thus, this approach only detects hyperedited elements, suggesting that the full scope of DNA editing is much broader. Nonetheless, even with this conservative approach, various effects on genic regions were found. Several edited elements overlapped RefSeq exons: (1) an edited mouse IAP element overlaps the first exon of the AK036462 gene; (2) a mouse LINE-1

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element overlaps the fourth exon of AK132687; and (3) an edited SVA element overlaps a humanspecific exon in a transporter gene (SLC22A20). In the latter, DNA editing modified the G upstream of the 5 splice site, possibly weakening the splicesite recognition by diverging it from the splicing consensus. Indeed, this gene is skipped in an alternatively spliced isoform. An in-depth analysis of mouse IAP elements showed that 35 edited elements

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overlap exons. Moreover, these are not just outstanding examples, but rather reflect a general trend: the edited elements are preferentially transcribed and exonized in comparison to their unedited counterparts. This suggests that DNA editing accelerates the exonization of IAP elements. In addition, as expected from novel exons, the exons derived from edited elements tended to be more alternatively spliced than those derived from unedited elements, which suggests a role in boosting transcript diversity. Although these findings are compelling, their functional impact has yet to be determined. However, these findings raise a question: what is the driving force behind preferential exaptation of edited elements? We would like to propose the following explanation, based on the role of the APOBEC3s in innate immunity. The mutations that DNA editing introduces are meant to inhibit the targeted retroelement by triggering its degradation. In less fortunate cases, at least from the immune system’s point of view, the retroelement will enter the genome, but with an impaired coding capacity.25 These inactivating mutations may be an important leap toward exaptation, because older retroelements, which are more mutated, tend to be less suppressed in the human genome.26 Because host fitness may be reduced by actively transposing retroelements, debilitating them could alleviate their mutagenicity and allow the genome to tolerate their presence and expression. Thus, the edited elements could be preferentially retained in the genome and the regulatory elements they encode can be immediately utilized for genomic function. Furthermore, the heavy mutation load that APOBEC3s can inflict upon a retroelement enables the genome to manipulate its original sequence, increasing the chance of developing a novel regulatory element that will be positively selected. DNA editing can alter retrotransposon-derived regulatory elements Retrotransposons encode regulatory elements important for their transcription and retrotransposition. These include internal promoters, transcription factor–binding sites (TFBS), polyadenylation signals, and more. Evidently, such retrotransposonderived regulatory elements are an important source of genomic innovation,27,28 as the genome could utilize these regulatory elements for necessary

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adaptation. For example, >1500 LTR elements in the human genome encode almost precise p53 binding sites, and LTR elements account for 30% of p53 binding, based on human chromatin immunoprecipitation (ChIP) data.29 These TBFS-encoding retrotransposons have rewired the p53 regulatory network in primates.29 In addition, there are thousands of retrotransposon-derived regions that are conserved and even ultra-conserved in mammals.30,31 The functional implications of many of these elements are unknown, but considering the large mass of conserved elements, it is most probable that many serve important genomic functions yet to be discovered. Thus, another interesting frontier to be studied is the role of DNA editing in modifying such regulatory elements. In the case of TFBSs, even small alterations may profoundly change the affinity of transcription factors to these retrotransposonencoded sequences, possibly modulating expression rates of nearby genes. In addition to altering expression rates, the promoters generated from edited elements may give rise to alternative transcription start sites of coding or noncoding genes, possibly bringing forth new protein isoforms or 5 -UTR–mediated mRNA regulation. Beyond exaptation of regulatory elements initially serving the retrotransposons themselves, another regulatory mechanism influenced by transposable elements is that of microRNAs (miRNAs). Retrotransposons have two complementary effects on this pathway. First, thousands of miRNAs are derived from transposable elements.32 Second, miRNAs target and regulate sequences homologous to themselves. Therefore, the retrotransposonderived miRNAs should, by definition, regulate transcripts containing the same repetitive elements. Indeed, spreading of miRNA targets by repetitive elements is not a new concept.33,34 For instance, exonized Alu elements in the human genome contain putative miRNA targets for 30 distinct miRNAs.33 Interestingly, DNA editing can affect both sides of this equation––the miRNAs and their targets. Typically, the retrotransposon-derived miRNAs emerge from two similar TE sequences present in opposite orientation in the genome. Therefore, editing of either one of these elements can create a slightly altered miRNA, potentially designating a completely new array of targets. However, editing of the putative target element could

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determine if the transcript that harbors it will be regulated by a specific miRNA and modify the strength of this regulation. Genomic DNA editing in cancer and evolution The APOBECs are very powerful DNA mutators.35,36 This attribute is harnessed by the genome for its needs, but encompasses fitness costs as well, as off-target cytidine deamination could be a harmful source of genomic mutation. Activation-induced deaminase (AID), an ancestral member of the AID/APOBEC family,37 catalyzes the process of somatic hypermutation by specific targeting of immunoglobulin genes. AID is highly regulated owing to the potential danger in allowing it to act promiscuously. One means of regulation is nuclear export via an AID-encoded nuclear export signal (NES), which keeps AID at a safe distance from the nuclear DNA. Excision of the NES promotes nuclear localization and off-target mutations of the genome.38 Cellular localization is a trait shared by most APOBEC3s, but some are shuttled back and forth by additionally encoding a nuclear localization signal (NLS).39 The only human APOBEC3 that is primarily nuclear is APOBEC3B (reviewed in Ref. 40), which makes it the most likely APOBEC to cause detrimental mutation of the genome. Indeed, it has been established as a common mutator of genomic DNA in cancer.41–43 In addition, another APOBEC localizing to the nucleus, APOBEC3A, has been shown to be mutagenic as well.44,45 Because APOBEC3A is induced by interferon,46 its upregulation after viral infection may be involved in the prevalence of viral-induced oncogenesis. Another important observation is that multiple APOBEC3s have access to genomic DNA during mitosis and can impede the cell cycle.47 This suggests that the transitions in cell state and regulation during the cell cycle may open a window of opportunity for APOBEC3s to access and mutate genomic DNA in cancer. Future research will determine to what extent DNA editing is a driver of oncogenesis, but, in any event, it is a substantial contributor to genomic mutation in cancer. Tumor progression is commonly viewed as an evolutionary process, where selective pressure drives the survival and proliferation of adequately adapted cancer cells. Reciprocally, mechanisms of evolution in cancer may also provide important insights 6

about the evolution of genomes and species. The accumulating evidence that APOBEC3s directly mutate non-retroelement genomic DNA in cancer raises the question whether a similar process plays a role in the evolution of species. Whereas the mutagenicity of APOBECs has usually been studied in the context of cancer, we believe that studying their role in genome evolution is promising as well. This idea is especially engaging in light of the complex evolution of the APOBEC3 locus.13 Throughout placental mammal evolution, where the APOBEC3 locus emerged, there were several duplications of this region. It is possible that this process brought about transitional stages that enabled new APOBEC3s to escape cellular regulation and generate genomic mutation, resulting in accelerated speciation. Although this is only a hypothesis at this point, there is still the possibility that genomic DNA editing is a frequent event under normal conditions in the germ line. More and more genomes are becoming available, and comparative genomic approaches have the potential to reveal the extent of this phenomenon. Importantly, DNA editing has been studied almost exclusively in placental mammals. However, APOBECs of other vertebrate lineages are also capable of editing DNA and restricting retroelements.4,48 The study of genomic sequences from a wide spectrum of vertebrate lineages should provide a clearer picture of the prevalence of DNA editing and illuminate its role in genome evolution. A-to-I RNA editing in Alu retroelements Adenosine-to-inosine (A-to-I) RNA editing is a posttranscriptional modification that alters RNA sequences from their original genomic blueprints. The ADARs, an essential family of genes, can edit nucleotides in RNA. Three members of this family are encoded in the mammalian genome: ADAR1 (ADAR), ADAR2 (ADARB1), and ADAR3 (ADARB2), the last of which is thought to be enzymatically dormant.49–52 This protein family can bind to double-stranded RNA structures within a newly made RNA molecule and deaminate several adenosines into inosines. Downstream RNAprocessing enzymes, such as the ribosome and the splicing apparatus, recognize inosine as guanosine, thus changing the outcome of the edited RNA molecules (Fig. 1B).

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In principle, detecting editing events using computational sequence alignments should have been straightforward, as most sequencing reactions also read A-to-I edited sites within cDNA as guanosines. Therefore, one would assume that simply aligning RNA-Seq reads to the genome in search of A-toG mismatches would be sufficient to detect editing events. However, in practice, this is not the case. Mutations, genomic polymorphisms, and duplications that lead to errors in alignment, in addition to common sequencing errors, produce many artificial A-to-G mismatches, which outnumber the true editing events and thus complicate the analysis.53 Only in the past few years has it become possible to identify a large number of editing sites with high specificity, thanks to novel computational approaches and the accumulation of largescale transcriptomic data.54–61 In humans, only several hundreds of editing sites are located within coding sequences and change the protein products, and only a small fraction of these are evolutionary conserved.62 The vast majority of sites, as was found in recent screens, are located within Alu repeats. Up to 100 million adenosines in the human transcriptome can undergo A-to-I editing, and almost all of them reside in these repeats. The Alu repeat, 300 nt in length, is the most abundant primate-specific retroelement. In total, there are over one million Alu copies in the human genome, which make up more than 10% of its mass. Most Alu repeats are located within genes (usually in introns or 3 -UTRs), and are hence transcribed as part of the pre-mRNA transcript of the gene. Owing to the abundance of Alus, it is very probable to find mRNA transcripts containing two nearby Alus in opposite orientation. As the mRNA molecule folds, these two Alus may form secondary RNA structures that are targeted by the double-stranded RNA (dsRNA)–binding ADARs.63–67 Editing of repetitive elements is highly promiscuous, and ranges between a few to tens of nucleotides per element. Several biological functions were proposed for editing. For example, a hyper-edited RNA was shown to be retained in the nucleus68 and released upon cleavage.69 Inosine-containing synthetic dsRNAs were also cleaved at specific sequences.70 In addition, edited transcripts can lead to global downregulation of gene expression71 and to suppression of apoptosis.72 Changes in the RNA sequence, even if outside of coding sequences, can

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also be functional, if, for example, they occur at splice sites73,74 (Fig. 2B) or at miRNA targets.75 However, in general, the biological role of hyperediting has been elusive. Transcripts derived from a single Alu sequence that undergoes editing can be edited at multiple sites, and thus could generate a large number of different transcripts. The most common mechanism for transcript diversification is alternative splicing, with the large majority of genes in the human genome estimated to have more than one variant. An extreme example is the fly DSCAM gene, where up to 38,000 different transcripts are possible. However, RNA editing can bring about much greater diversity, because it can potentially generate billions of different isoforms from a single Alu. In a recent study, an ultra-deep sequencing of several dozen Alus was executed55 (up to 50,000 reads for each Alu), and the number of different isoforms did not reach saturation,76 even with such a high level of transcript representation, indicating that the actual number of different isoforms in just one sample was colossal. There is no evidence that such complexity has any biological meaning, especially because most editing events take place in noncoding regions of the transcriptome. However, several Alus have been exonized during primate evolution into coding parts of genes, and this can contribute to the diversity of the proteome. A notable example is the NARF gene, in which the exonization event itself was demonstrated to be editing dependent73 (Fig. 2B). Such diversity comes with a relatively low evolutionary price, as editing cannot create stop codons. Thus, the freedom to explore the sequence space can be utilized by complex organisms to promote diversity within and across cells.77 Importantly, although RNA editing may, at first glance, seem like a stochastic process with transient effects, this is far from the truth. Phenotypes brought forth by downstream RNA editing can determine the evolutionary fate of genomic mutations that alter the editability77,78 of RNA transcripts. Beneficial alterations may be positively selected, whereas deleterious ones will be selected against. This is highly supported by the existence of 60 RNA-editing sites that have been evolutionarily conserved in mammals.62,79 Thus, the enhanced variation that Alu insertions generate in the germ line, thanks to their dynamic nature, can give rise to novel RNA-editing substrates (dsRNA structures) and facilitate accelerated evolution.

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A fascinating example of the utilization of RNA editing for adaptation across evolution was recently described (although not in retroelements). Octopuses from distinct seas, with large differences in sea temperature, share the same potassium channel gene in their genomes. To accommodate the environmental changes, the octopuses fine tune the protein sequence (and therefore its structure and function) by using A-to-I RNA editing of the potassium channel transcript, instead of modifying the genomic sequence.80 In humans, as well, functional changes of a gene’s protein product can be achieved by Alu editing, but are not limited to the Alu sequences themselves, as editing can also take place at locations adjacent to edited Alus. This is the case with the DNA-repair gene Neil1, in which editing changes its lesion specificity.81 In this example, the editing was found to be dependent on a nearby Alu that serves as a docking station for ADARs, which edit the Alu and subsequently shift out of the Alu region and edit a specific location in the Neil1 coding sequence.82 As is the case in DNA editing, cancer seems to take advantage of this rapid process to alter the genomic content. This has been learned from at least one case, AZIN1, where A-to-I editing has been found to progress the cancer phenotype in hepatocellular carcinoma.83 The exceptional level of RNA editing in the primate brain makes it tempting to suggest a role for editing in primate evolution.84,85 Moreover, the overrepresentation of editing in brain tissues and the association of aberrant editing with neurological diseases86 are consistent with a possible connection between editing and brain capabilities. One may thus speculate that the massive editing of brain tissues is responsible, in part, for the brain’s complexity. The accumulating data produced by nextgeneration sequencing of brains and other tissues from many organisms and various biological conditions should enable future research to better understand the contribution of RNA editing to genome evolution. Concluding remarks

Acknowledgments This work was supported by the European Research Council (Grant No. 311257) and the I-CORE Program of the Planning and Budgeting Committee in Israel (Grants Nos. 41/11 and 1796/12). Conflicts of interest The authors declare no conflicts of interest.

Traditionally, it has been assumed that exploring the sequence space in evolution is a very slow process, in which point mutations accumulate randomly until reaching a form that confers beneficial function. In contrast, DNA editing introduces many mutations in parallel, and thus accelerates the evolutionary 8

process by possibly creating a beneficial sequence within a single generation instead of millions of years. This can explain, in part, a basic question in evolution: how do functional sequences emerge when there are no selective advantages for the intermediate steps? By DNA editing, they can simply be skipped. DNA editing can also explain why so many retroelements can become functional, as it can debilitate retroelements, allowing the genome to express the region of insertion at a low fitness cost. Indeed, this is supported by the observation that edited elements are preferentially exonized. It seems likely that refined computational tools will be able to find that many functional retroelements started their way down the road to exaptation with an event of DNA editing. Unlike DNA editing, RNA editing allows the genome to screen several variations of an expressed retroelement in parallel, even in a single cell. As editing cannot create stop codons, the cost of spawning a large number of variants is not very high. Thus, this mechanism for RNA plasticity allows the genome to utilize an invading retroelement to create variation within or near the retroelement. If one of the edited variants is advantageous, the retroelement will be positively selected and retained in the genome. Lastly, cancer is a process of microevolution and, indeed, both RNA and DNA editing are now known to be exploited by tumors for rapid adaptation. We expect the rapid gain of interest in RNA and DNA editing to further our understanding of their substantial contribution to evolution and disease in the near future.

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DNA and RNA editing of retrotransposons accelerate mammalian genome evolution.

Genome evolution is commonly viewed as a gradual process that is driven by random mutations that accumulate over time. However, DNA- and RNA-editing e...
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