WIREs RNA (WIREs RNA)

Publications in this journal

• Article: Perturbations of RNA helicases in cancer.

  Francis Robert, Jerry Pelletier
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  ABSTRACT: Helicases are implicated in most stages of the gene expression pathway, ranging from DNA replication, RNA transcription, splicing, RNA transport, ribosome biogenesis, mRNA translation, RNA storage and decay. These enzymes utilize energy derived from nucleotide triphosphate hydrolysis to remodel ribonucleoprotein complexes, RNA, or DNA and in this manner affect the information content or output of RNA. Several RNA helicases have been implicated in the oncogenic process-either through altered expression levels, mutations, or due to their role in pathways required for tumor initiation, progression, maintenance, or chemosensitivity. The purpose of this review is to highlight those RNA helicases for which there is significant evidence implicating them in cancer biology. WIREs RNA 2013. doi: 10.1002/wrna.1163 For further resources related to this article, please visit the WIREs website.
  WIREs RNA 05/2013;
• Article: Metabolite sensing in eukaryotic mRNA biology.

  Carina C Clingman, Sean P Ryder
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  ABSTRACT: All living creatures change their gene expression program in response to nutrient availability and metabolic demands. Nutrients and metabolites can directly control transcription and activate second-messenger systems. More recent studies reveal that metabolites also affect post-transcriptional regulatory mechanisms. Here, we review the increasing number of connections between metabolism and post-transcriptional regulation in eukaryotic organisms. First, we present evidence that riboswitches, a common mechanism of metabolite sensing in bacteria, also function in eukaryotes. Next, we review an example of a double stranded RNA modifying enzyme that directly interacts with a metabolite, suggesting a link between RNA editing and metabolic state. Finally, we discuss work that shows some metabolic enzymes bind directly to RNA to affect mRNA stability or translation efficiency. These examples were discovered through gene-specific genetic, biochemical, and structural studies. A directed systems level approach will be necessary to determine whether they are anomalies of evolution or pioneer discoveries in what may be a broadly connected network of metabolism and post-transcriptional regulation. WIREs RNA 2013. doi: 10.1002/wrna.1167 For further resources related to this article, please visit the WIREs website.
  WIREs RNA 05/2013;
• Article: The role of the DEAD-box RNA helicase DDX3 in mRNA metabolism.

  Ricardo Soto-Rifo, Théophile Ohlmann
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  ABSTRACT: DDX3 belongs to the DEAD-box proteins, a large family of ATP-dependent RNA helicases that participate in all aspects of RNA metabolism. Human DDX3 is a component of several messenger ribonucleoproteins that are found in the spliceosome, the export and the translation initiation machineries but also in different cytoplasmic mRNA granules. DDX3 has been involved in several cellular processes such as cell cycle progression, apoptosis, cancer, innate immune response, and also as a host factor for viral replication. Interestingly, not all these functions require the catalytic activities of DDX3 and thus, the precise roles of this apparently multifaceted protein remain largely obscure. The aim of this review is to provide a rapid and critical overview of the structure and functions of DDX3 with a particular emphasis on its role during mRNA metabolism. WIREs RNA 2013. doi: 10.1002/wrna.1165 For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article.
  WIREs RNA 04/2013;
• Article: RNA synthetic mechanisms employed by diverse families of RNA viruses.

  Sarah M McDonald
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  ABSTRACT: RNA viruses are ubiquitous in nature, infecting every known organism on the planet. These viruses can also be notorious human pathogens with significant medical and economic burdens. Central to the lifecycle of an RNA virus is the synthesis of new RNA molecules, a process that is mediated by specialized virally encoded enzymes called RNA-dependent RNA polymerases (RdRps). RdRps directly catalyze phosphodiester bond formation between nucleoside triphosphates in an RNA-templated manner. These enzymes are strikingly conserved in their structural and functional features, even among diverse RNA viruses belonging to different families. During host cell infection, the activities of viral RdRps are often regulated by viral cofactor proteins. Cofactors can modulate the type and timing of RNA synthesis by directly engaging the RdRp and/or by indirectly affecting its capacity to recognize template RNA. High-resolution structures of RdRps as apoenzymes, bound to RNA templates, in the midst of catalysis, and/or interacting with regulatory cofactor proteins, have dramatically increased our understanding of viral RNA synthetic mechanisms. Combined with elegant biochemical studies, such structures are providing a scientific platform for the rational design of antiviral agents aimed at preventing and treating RNA virus-induced diseases. WIREs RNA 2013. doi: 10.1002/wrna.1164 For further resources related to this article, please visit the WIREs website. Conflict of interest: The author has declared no conflicts of interest for this article.
  WIREs RNA 04/2013;
• Article: Regulation of stress granules and P-bodies during RNA virus infection.

  Richard E Lloyd
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  ABSTRACT: RNA granules are structures within cells that play major roles in gene expression and homeostasis. Two principle kinds of RNA granules are conserved from yeast to mammals: stress granules (SGs), which contain stalled translation initiation complexes, and processing bodies (P-bodies, PBs), which are enriched with factors involved in RNA turnover. Since RNA granules are associated with silenced transcripts, viruses subvert RNA granule function for replicative advantages. This review, focusing on RNA viruses, discusses mechanisms that manipulate stress granules and P-bodies to promote synthesis of viral proteins. Three main themes have emerged for how viruses manipulate RNA granules; (1) cleavage of key host factors, (2) control of protein kinase R (PKR) activation, and (3) redirecting RNA granule components for new or parallel roles in viral reproduction, at the same time disrupting RNA granules. Viruses utilize one or more of these routes to achieve robust and productive infection. WIREs RNA 2013. doi: 10.1002/wrna.1162 For further resources related to this article, please visit the WIREs website. Conflict of interest: The author has declared no conflicts of interest for this article.
  WIREs RNA 04/2013;
• Article: Intercellular and systemic spread of RNA and RNAi in plants.

  Mohammad Nazim Uddin, Jae-Yean Kim
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  ABSTRACT: Plants possess dynamic networks of intercellular communication that are crucial for plant development and physiology. In plants, intercellular communication involves a combination of ligand-receptor-based apoplasmic signaling, and plasmodesmata and phloem-mediated symplasmic signaling. The intercellular trafficking of macromolecules, including RNAs and proteins, has emerged as a novel mechanism of intercellular communication in plants. Various forms of regulatory RNAs move over distinct cellular boundaries through plasmodesmata and phloem. This plant-specific, non-cell-autonomous RNA trafficking network is also involved in development, nutrient homeostasis, gene silencing, pathogen defense, and many other physiological processes. However, the mechanism underlying macromolecular trafficking in plants remains poorly understood. Current progress made in RNA trafficking research and its biological relevance to plant development will be summarized. Diverse plant regulatory mechanisms of cell-to-cell and systemic long-distance transport of RNAs, including mRNAs, viral RNAs, and small RNAs, will also be discussed. WIREs RNA 2013. doi: 10.1002/wrna.1160 For further resources related to this article, please visit the WIREs website. The authors have declared no conflicts of interest for this article.
  WIREs RNA 03/2013;
• Article: RNA processing and decay in plastids.

  Arnaud Germain, Amber M Hotto, Alice Barkan, David B Stern
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  ABSTRACT: Plastids were derived through endosymbiosis from a cyanobacterial ancestor, whose uptake was followed by massive gene transfer to the nucleus, resulting in the compact size and modest coding capacity of the extant plastid genome. Plastid gene expression is essential for plant development, but depends on nucleus-encoded proteins recruited from cyanobacterial or host-cell origins. The plastid genome is heavily transcribed from numerous promoters, giving posttranscriptional events a critical role in determining the quantity and sizes of accumulating RNA species. The major events reviewed here are RNA editing, which restores protein conservation or creates correct open reading frames by converting C residues to U, RNA splicing, which occurs both in cis and trans, and RNA cleavage, which relies on a variety of exoribonucleases and endoribonucleases. Because the RNases have little sequence specificity, they are collectively able to remove extraneous RNAs whose ends are not protected by RNA secondary structures or sequence-specific RNA-binding proteins (RBPs). Other plastid RBPs, largely members of the helical-repeat superfamily, confer specificity to editing and splicing reactions. The enzymes that catalyze RNA processing are also the main actors in RNA decay, implying that these antagonistic roles are optimally balanced. We place the actions of RBPs and RNases in the context of a recent proteomic analysis that identifies components of the plastid nucleoid, a protein-DNA complex with multiple roles in gene expression. These results suggest that sublocalization and/or concentration gradients of plastid proteins could underpin the regulation of RNA maturation and degradation. WIREs RNA 2013. doi: 10.1002/wrna.1161 For further resources related to this article, please visit the WIREs website. The authors have declared no conflicts of interest for this article.
  WIREs RNA 03/2013;
• Article: CRISPR-Cas systems and RNA-guided interference.

  Rodolphe Barrangou
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  ABSTRACT: Clustered regularly interspaced short palindromic repeats (CRISPR) together with associated sequences (cas) form the CRISPR-Cas system, which provides adaptive immunity against viruses and plasmids in bacteria and archaea. Immunity is built through acquisition of short stretches of invasive nucleic acids into CRISPR loci as 'spacers'. These immune markers are transcribed and processed into small noncoding interfering CRISPR RNAs (crRNAs) that guide Cas proteins toward target nucleic acids for specific cleavage of homologous sequences. Mechanistically, CRISPR-Cas systems function in three distinct stages, namely: (1) adaptation, where new spacers are acquired from invasive elements for immunization; (2) crRNA biogenesis, where CRISPR loci are transcribed and processed into small interfering crRNAs; and (3) interference, where crRNAs guide the Cas machinery to specifically cleave homologous invasive nucleic acids. A number of studies have shown that CRISPR-mediated immunity can readily increase the breadth and depth of virus resistance in bacteria and archaea. CRISPR interference can also target plasmid sequences and provide a barrier against the uptake of undesirable mobile genetic elements. These inheritable hypervariable loci provide phylogenetic information that can be insightful for typing purposes, epidemiological studies, and ecological surveys of natural habitats and environmental samples. More recently, the ability to reprogram CRISPR-directed endonuclease activity using customizable small noncoding interfering RNAs has set the stage for novel genome editing and engineering avenues. This review highlights recent studies that revealed the molecular basis of CRISPR-mediated immunity, and discusses applications of crRNA-guided interference. WIREs RNA 2013. doi: 10.1002/wrna.1159 For further resources related to this article, please visit the WIREs website. Conflict of interest: RB is a co-inventor on several patents related to CRISPR use and applications.
  WIREs RNA 03/2013;
• Article: Targeting RNA splicing for disease therapy.

  Mallory A Havens, Dominik M Duelli, Michelle L Hastings
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  ABSTRACT: Splicing of pre-messenger RNA into mature messenger RNA is an essential step for the expression of most genes in higher eukaryotes. Defects in this process typically affect cellular function and can have pathological consequences. Many human genetic diseases are caused by mutations that cause splicing defects. Furthermore, a number of diseases are associated with splicing defects that are not attributed to overt mutations. Targeting splicing directly to correct disease-associated aberrant splicing is a logical approach to therapy. Splicing is a favorable intervention point for disease therapeutics, because it is an early step in gene expression and does not alter the genome. Significant advances have been made in the development of approaches to manipulate splicing for therapy. Splicing can be manipulated with a number of tools including antisense oligonucleotides, modified small nuclear RNAs (snRNAs), trans-splicing, and small molecule compounds, all of which have been used to increase specific alternatively spliced isoforms or to correct aberrant gene expression resulting from gene mutations that alter splicing. Here we describe clinically relevant splicing defects in disease states, the current tools used to target and alter splicing, specific mutations and diseases that are being targeted using splice-modulating approaches, and emerging therapeutics. WIREs RNA 2013. doi: 10.1002/wrna.1158 For further resources related to this article, please visit the WIREs website. The authors have declared no conflicts of interest for this article.
  WIREs RNA 03/2013;
• Article: Nuclear RNA surveillance: role of TRAMP in controlling exosome specificity.

  Karyn Schmidt, J Scott Butler
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  ABSTRACT: The advent of high-throughput sequencing technologies has revealed that pervasive transcription generates RNAs from nearly all regions of eukaryotic genomes. Normally, these transcripts undergo rapid degradation by a nuclear RNA surveillance system primarily featuring the RNA exosome. This multimeric protein complex plays a critical role in the efficient turnover and processing of a vast array of RNAs in the nucleus. Despite its initial discovery over a decade ago, important questions remain concerning the mechanisms that recruit and activate the nuclear exosome. Specificity and modulation of exosome activity requires additional protein cofactors, including the conserved TRAMP polyadenylation complex. Recent studies suggest that helicase and RNA-binding subunits of TRAMP direct RNA substrates for polyadenylation, which enhances their degradation by Dis3/Rrp44 and Rrp6, the two exosome-associated ribonucleases. These findings indicate that the exosome and TRAMP have evolved highly flexible functions that allow recognition of a wide range of RNA substrates. This flexibility provides the nuclear RNA surveillance system with the ability to regulate the levels of a broad range of coding and noncoding RNAs, which results in profound effects on gene expression, cellular development, gene silencing, and heterochromatin formation. This review summarizes recent findings on the nuclear RNA surveillance complexes, and speculates upon possible mechanisms for TRAMP-mediated substrate recognition and exosome activation. WIREs RNA 2013, 4:217-231. doi: 10.1002/wrna.1155 For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have no conflicts of interest.
  WIREs RNA 03/2013; 4(2):217-31.
• Article: Poly(A) binding proteins: are they all created equal?

  Dixie J Goss, Frida Esther Kleiman
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  ABSTRACT: The PABP family of proteins were originally thought of as a simple shield for the mRNA poly(A) tail. Years of research have shown that PABPs interact not only with the poly(A) tail, but also with specific sequences in the mRNA, having a general and specific role on the metabolism of different mRNAs. The complexity of PABPs function is increased by the interactions of PABPs with factors involved in different cellular functions. PABPs participate in all the metabolic pathways of the mRNA: polyadenylation/deadenylation, mRNA export, mRNA surveillance, translation, mRNA degradation, microRNA-associated regulation, and regulation of expression during development. In this review, we update information on the roles of PABPs and emerging data on the specific interactions of PABP homologs. Specific functions of individual members of PABPC family in development and viral infection are beginning to be elucidated. However, the interactions are complex and recent evidence for exchange of nuclear and cytoplasmic forms of the proteins, as well as post-translational modifications, emphasize the possibilities for fine-tuning the PABP metabolic network. WIREs RNA 2013, 4:167-179. doi: 10.1002/wrna.1151 For further resources related to this article, please visit the WIREs website.
  WIREs RNA 03/2013; 4(2):167-79.
• Article: Making ends meet: coordination between RNA 3'-end processing and transcription initiation.

  Pia K Andersen, Torben Heick Jensen, Søren Lykke-Andersen
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  ABSTRACT: RNA polymerase II (RNAPII)-mediated gene transcription initiates at promoters and ends at terminators. Transcription termination is intimately connected to 3'-end processing of the produced RNA and already when loaded at the promoter, RNAPII starts to become configured for this downstream event. Conversely, RNAPII is 'reset' as part of the 3'-end processing/termination event, thus preparing the enzyme for its next round of transcription-possibly on the same gene. There is both direct and circumstantial evidence for preferential recycling of RNAPII from the gene terminator back to its own promoter, which supposedly increases the efficiency of the transcription process under conditions where RNAPII levels are rate limiting. Here, we review differences and commonalities between initiation and 3'-end processing/termination processes on various types of RNAPII transcribed genes. In doing so, we discuss the requirements for efficient 3'-end processing/termination and how these may relate to proper recycling of RNAPII. WIREs RNA 2013. doi: 10.1002/wrna.1156 For further resources related to this article, please visit the WIREs website.
  WIREs RNA 02/2013;
• Article: RNA dot plots: an image representation for RNA secondary structure analysis and manipulations.

  Alexander Churkin, Danny Barash
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  ABSTRACT: Dot plots were originally introduced in bioinformatics as dot-containing images used to compare biological sequences and identify regions of close similarity between them. In addition to similarity, dot plots were extended to possibly represent interactions between building blocks of biological sequences, where the dots can vary in size or color according to desired features. In this survey, we first review their use in representing an RNA secondary structure, which has mostly been applied for displaying the output secondary structures as a result of running RNA folding prediction algorithms. Such a result may often contain suboptimal solutions in addition to the optimal one, which can be easily incorporated in the dot plot. We then proceed from their passive use of providing RNA secondary structure snapshots to their active use of illustrating RNA secondary structure manipulations in beneficial ways. While comparison between RNA secondary structures can mostly be done efficiently using a string representation, there are notable advantages in using dot plots for analyzing the suboptimal solutions that convey important information about the structure of the RNA molecule. In addition, structure-based alignment of dot plots has been advanced considerably and the filtering of dot plots that considers chemical and enzymatic data from structure determination experiments has been suggested. We discuss these procedures and how they can be enhanced in the future by using an image representation to analyze RNA secondary structures and examine their manipulations. WIREs RNA 2013. doi: 10.1002/wrna.1154 For further resources related to this article, please visit the WIREs website.
  WIREs RNA 02/2013;
• Article: The GA-minor submotif as a case study of RNA modularity, prediction, and design.

  Wade W Grabow, Zhuoyun Zhuang, Joan-Emma Shea, Luc Jaeger
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  ABSTRACT: Complex natural RNAs such as the ribosome, group I and group II introns, and RNase P exemplify the fact that three-dimensional (3D) RNA structures are highly modular and hierarchical in nature. Tertiary RNA folding typically takes advantage of a rather limited set of recurrent structural motifs that are responsible for controlling bends or stacks between adjacent helices. Herein, the GA minor and related structural motifs are presented as a case study to highlight several structural and folding principles, to gain further insight into the structural evolution of naturally occurring RNAs, as well as to assist the rational design of artificial RNAs. WIREs RNA 2013. doi: 10.1002/wrna.1153 For further resources related to this article, please visit the WIREs website.
  WIREs RNA 02/2013;
• Article: RNAs of the human chromosome 15q11-q13 imprinted region.

  Stormy J Chamberlain
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  ABSTRACT: The human chromosome 15q11-q13 region hosts a wide variety of coding and noncoding RNAs, and is also the site of nearly every imaginable type of RNA processing. To deepen the intrigue, the transcripts in the human chromosome 15q11-q13 region are subject to regulation by genomic imprinting, and some of these transcripts are imprinted in a tissue-specific manner. As the region is critically important for three human neurogenetic disorders, Angelman syndrome, Prader-Willi syndrome, and 15q duplication syndrome, there is intense interest in understanding the types of RNA and RNA processing that occurs among the imprinted genes. This review summarizes what is known about the various RNAs within the imprinted domain, including a novel type of RNA that was only very recently identified. WIREs RNA 2012. doi: 10.1002/wrna.1150 For further resources related to this article, please visit the WIREs website.
  WIREs RNA 12/2012;
• Article: Mutual relationships between transcription and pre-mRNA processing in the synthesis of mRNA.

  Tina Lenasi, Matjaz Barboric
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  ABSTRACT: The generation of messenger RNA (mRNA) in eukaryotes is achieved by transcription from the DNA template and pre-mRNA processing reactions of capping, splicing, and polyadenylation. Although RNA polymerase II (RNAPII) catalyzes the synthesis of pre-mRNA, it also serves as a principal coordinator of the processing reactions in the course of transcription. In this review, we focus on the interplay between transcription and cotranscriptional pre-mRNA maturation events, mediated by the recruitment of RNA processing factors to differentially phosphorylated C-terminal domain of Rbp1, the largest subunit of RNAPII. Furthermore, we highlight the bidirectional nature of the interplay by discussing the impact of RNAPII kinetics on pre-mRNA processing as well as how the processing events reach back to different phases of gene transcription. WIREs RNA 2012. doi: 10.1002/wrna.1148 For further resources related to this article, please visit the WIREs website.
  WIREs RNA 11/2012;
• Article: Long non-coding RNAs in stem cell pluripotency.

  Shi-Yan Ng, Lawrence W Stanton
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  ABSTRACT: Pluripotency refers to the self-renewal of undifferentiated embryonic stem cells (ESCs), and is maintained by a tightly regulated gene regulatory network involving an intricate interplay between transcription factors and their genomic targets, as well as epigenetic processes that influence gene expression. Long non-coding RNAs (lncRNAs) are newly discovered members of gene regulatory networks that govern a variety of cell functions. Defined as RNA transcripts larger than 200 nucleotides, lncRNAs have little or no protein-coding capacity and have been shown to act via various mechanisms, and are important in a variety of biological functions. Recent reports have described the discovery of pluripotent lncRNAs involved in the maintenance and induction of stem cell pluripotency. Here, we discuss how lncRNAs may integrate into the pluripotency network, as well as prominent questions in this emerging field. WIREs RNA 2012. doi: 10.1002/wrna.1146 For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors declare no conflict of interest.
  WIREs RNA 11/2012;
• Article: The curious case of miRNAs in circulation: potential diagnostic biomarkers?

  Radha Duttagupta, Keith W Jones
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  ABSTRACT: The pervasive occurrence of cell-free miRNAs in circulation suggests that these species play an emerging role as regulatory molecules in the secretory environment. Are these molecules released fortuitously with no clear biological intent? Or do they constitute a regulatory architecture that has evolved to modulate gene expression using the highways and byways of the circulatory system? The study of circulating miRNAs continues to increase our understanding of the regulation of genomes. The diversity of acellular miRNAs from a functional perspective is discussed, and in particular we explore their utility in a clinical setting as blood-based biomarkers for diseases. WIREs RNA 2012. doi: 10.1002/wrna.1149 For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors declare no conflict of interest.
  WIREs RNA 11/2012;
• Article: Transfer RNA modifications: nature's combinatorial chemistry playground.

  Jane E Jackman, Juan D Alfonzo
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  ABSTRACT: Following synthesis, tRNAs are peppered by numerous chemical modifications which may differentially affect a tRNA's structure and function. Although modifications affecting the business ends of a tRNA are predictably important for cell viability, a majority of modifications play more subtle structural roles that can affect tRNA stability and folding. The current trend is that modifications act in concert and it is in the context of the specific sequence of a given tRNA that they impart their differing effects. Recent developments in the modification field have highlighted the diversity of modifications in tRNA. From these, the combinatorial nature of modifications in explaining previously described phenotypes derived from their absence has emerged as a growing theme. WIREs RNA 2012. doi: 10.1002/wrna.1144 For further resources related to this article, please visit the WIREs website.
  WIREs RNA 11/2012;
• Article: Whence genes in pieces: reconstruction of the exon-intron gene structures of the last eukaryotic common ancestor and other ancestral eukaryotes.

  Eugene V Koonin, Miklos Csuros, Igor B Rogozin
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  ABSTRACT: In eukaryotes, protein-coding sequences are interrupted by non-coding sequences known as introns. During mRNA maturation, introns are excised by the spliceosome and the coding regions, exons, are spliced to form the mature coding region. The intron densities widely differ between eukaryotic lineages, from 6 to 7 introns per kb of coding sequence in vertebrates, some invertebrates and green plants, to only a few introns across the entire genome in many unicellular eukaryotes. Evolutionary reconstructions using maximum likelihood methods suggest intron-rich ancestors for each major group of eukaryotes. For the last common ancestor of animals, the highest intron density of all extant and extinct eukaryotes was inferred, at 120-130% of the human intron density. Furthermore, an intron density within 53-74% of the human values was inferred for the last eukaryotic common ancestor. Accordingly, evolution of eukaryotic genes in all lines of descent involved primarily intron loss, with substantial gain only at the bases of several branches including plants and animals. These conclusions have substantial biological implications indicating that the common ancestor of all modern eukaryotes was a complex organism with a gene architecture resembling those in multicellular organisms. Alternative splicing most likely initially appeared as an inevitable result of splicing errors and only later was employed to generate structural and functional diversification of proteins. WIREs RNA 2012. doi: 10.1002/wrna.1143 For further resources related to this article, please visit the WIREs website. This article is a U.S. Government work, and as such, is in the public domain in the United States of America.
  WIREs RNA 11/2012;