Neuron 20, — Bono, F. Assembly, disassembly and recycling: the dynamics of exon junction complexes. RNA Biol. Bornstein, P. Interactions between the promoter and first intron are involved in transcriptional control of alpha 1 I collagen gene expression. Pubmed Abstract Pubmed Full Text. Bradnam, K. Longer first introns are a general property of eukaryotic gene structure. Bres, V. Brody, Y. PLoS Biol. Brogna, S. Buchman, A. Comparison of intron-dependent and intron-independent gene expression.
Bullock, S. Conserved signals and machinery for RNA transport in Drosophila oogenesis and embryogenesis. Carmel, L. Evolutionarily conserved genes preferentially accumulate introns.
Patterns of intron gain and conservation in eukaryotic genes. BMC Evol. Three distinct modes of intron dynamics in the evolution of eukaryotes. Cenik, C. Genome Biol. Chang, Y. The nonsense-mediated decay RNA surveillance pathway. Chen, D. RNA 17, — Chen, W.
The organization of nucleosomes around splice sites. Cheng, J. Introns are cis effectors of the nonsense-codon-mediated reduction in nuclear mRNA abundance. Choi, T. A generic intron increases gene expression in transgenic mice. Clark, A. Enhancing the efficiency of transgene expression.
B Biol. Csuros, M. Mclysaght, and D. Huson Dublin: Springer , 47— A detailed history of intron-rich eukaryotic ancestors inferred from a global survey of complete genomes.
PLoS Comput. Culler, S. Functional selection and systematic analysis of intronic splicing elements identify active sequence motifs and associated splicing factors. Damgaard, C. Cell 29, — Das, R. Cell 26, — Demir-Weusten, A. Distribution of different Fibronectin isoforms in the extracellular matrices of human term Placenta. Turk J. Dieci, G. Eukaryotic snoRNAs: a paradigm for gene expression flexibility.
Genomics 94, 83— Diem, M. PYM binds the cytoplasmic exon-junction complex and ribosomes to enhance translation of spliced mRNAs. Dredge, B. Dreyfuss, G. Messenger-RNA-binding proteins and the messages they carry. Durand, C. Filipowicz, W. Biogenesis of small nucleolar ribonucleoproteins. Cell Biol. Fisher, S. Conservation of RET regulatory function from human to zebrafish without sequence similarity. Science , — Fong, Y. Stimulatory effect of splicing factors on transcriptional elongation.
Forget, A. Transcription 2, 86— Fortes, P. Friend, K. Cell 28, — Furger, A. Promoter proximal splice sites enhance transcription.
Furth, P. Gaunitz, F. An intronic silencer element is responsible for specific zonal expression of glutamine synthetase in the rat liver. Hepatology 41, — A silencer element in the first intron of the glutamine synthetase gene represses induction by glucocorticoids. Gilbert, W. The exon theory of genes. Cold Spring Harb.
Gilligan, P. Gilson, P. Gingeras, T. Origin of phenotypes: genes and transcripts. Gonzalez, C. Cell 5, — Graur, D. Fundamentals of Molecular Evolution , 2nd Edn. Sunderland, MA: Sinauer Associates.
Graveley, B. Alternative splicing: increasing diversity in the proteomic world. Trends Genet. Green, R. Widespread predicted nonsense-mediated mRNA decay of alternatively-spliced transcripts of human normal and disease genes. Bioinformatics 19 Suppl. Gruss, P. Splicing as a requirement for biogenesis of functional 16S mRNA of simian virus Gubb, D. Intron-delay and the precision of expression of homoeotic gene products in Drosophila. Gunderson, S. Cell 1, — Involvement of the carboxyl terminus of vertebrate poly A polymerase in U1A autoregulation and in the coupling of splicing and polyadenylation.
Hachet, O. Drosophila Y14 shuttles to the posterior of the oocyte and is required for oskar mRNA transport. Splicing of oskar RNA in the nucleus is coupled to its cytoplasmic localization. Hamer, D. SV40 recombinants carrying rabbit beta-globin gene coding sequences. Cell 17, — Hansen, K. Genome-wide identification of alternative splice forms down-regulated by nonsense-mediated mRNA decay in Drosophila.
PLoS Genet. Hartmann, B. Havlioglu, N. An intronic signal for alternative splicing in the human genome. Hillman, R. An unappreciated role for RNA surveillance. Hinske, L. BMC Genomics 11, Hood, J. In or out? Regulating nuclear transport. Horne-Badovinac, S. Dynein regulates epithelial polarity and the apical localization of stardust A mRNA. Huang, Z. Genome-wide analyses of two families of snoRNA genes from Drosophila melanogaster , demonstrating the extensive utilization of introns for coding of snoRNAs.
Jin, Y. EMBO J. Jobert, L. EMBO Rep. Juneau, K. Introns regulate RNA and protein abundance in yeast. Genetics , — Kaida, D.
Khodor, Y. II, and Rosbash, M. Nascent-seq indicates widespread cotranscriptional pre-mRNA splicing in Drosophila. Kim, Y. Processing of intronic microRNAs. Ko, B. Identification of new poly A polymerase-inhibitory proteins capable of regulating pre-mRNA polyadenylation. Kohler, A. Exporting RNA from the nucleus to the cytoplasm. Koonin, E. The origin of introns and their role in eukaryogenesis: a compromise solution to the introns-early versus introns-late debate? Direct 1, Intron-dominated genomes of early ancestors of eukaryotes.
Kumar, A. An overview of nested genes in eukaryotic genomes. Eukaryotic Cell 8, — Kwek, K. Kyburz, A. Cell 23, — Lane, C. Nucleomorph genome of Hemiselmis andersenii reveals complete intron loss and compaction as a driver of protein structure and function. Lane, N. The energetics of genome complexity. Lareau, L. The evolving roles of alternative splicing. Lauderdale, J. Introns of the chicken ovalbumin gene promote nucleosome alignment in vitro. Le Hir, H. The exon-exon junction complex provides a binding platform for factors involved in mRNA export and nonsense-mediated mRNA decay.
Pseudogenes in yeast? Cell 49 : 5—6. Gilbert W Why genes in pieces? The exon theory of genes. Go M Correlation of DNA exonic regions with protein structural units in haemoglobin. Nature : 90— Gray MW Evolution of organellar genomes. Curr Opin Genet Dev 9 : — Mitochondrial evolution. Patterns of intron sequence evolution in Drosophila are dependent upon length and GC content. Genome Biol 6 : R Imprinted genes have few and small introns.
Nat Genet 12 : — Retrotransposition of the Ll. Mol Microbiol 46 : — Pre-mRNA splicing: awash in a sea of proteins. Mol Cell 12 : 5— Functional constraints and frequency of deleterious mutations in noncoding DNA of rodents. Conservation, regulation, synteny, and introns in a large-scale C. Genome Res 10 : — Lambowitz AM, Zimmerly S Mobile group II introns. Annu Rev Genet 38 : 1— Determinants of plant Udependent intron splicing efficiency. Plant Cell 16 : — Intron presence-absence polymorphism in Drosophila driven by positive Darwinian selection.
Lynch M Intron evolution as a population-genetic process. Lynch M, Kewalramani A Messenger RNA surveillance and the evolutionary proliferation of introns. Mol Biol Evol 20 : — Lynch M, Richardson AO The evolution of spliceosomal introns. Curr Opin Genet Dev 12 : — Majewski J, Ott J Distribution and characterization of regulatory elements in the human genome.
Maniatis T, Reed R An extensive network of coupling among gene expression machines. Mourier T, Jeffares DC Eukaryotic intron loss. Science : Patterns of intron gain and loss in fungi. PLoS Biol 2 : e Nilsen TW The spliceosome: the most complex macromolecular machine in the cell?
Bioessays 25 : — The recent origins of introns. Curr Opin Genet Dev 1 : — Parsch J Selective constraints on intron evolution in Drosophila. Genetics : — Length distribution of long interspersed nucleotide elements LINEs and processed pseudogenes of human endogenous retroviruses: implications for retrotransposition and pseudogene detection.
The Opisthokonta and the Ecdysozoa may not be clades: stronger support for the grouping of plant and animal than for animal and fungi and stronger support for the Coelomata than Ecdysozoa. Mol Biol Evol 22 : — Multigene analyses of bilaterian animals corroborate the monophyly of Ecdysozoa, Lophotrochozoa, and Protostomia. The evolutionary gain of spliceosomal introns: sequence and phase preferences. Mol Biol Evol 21 : — Evolution of evolvability. Ann NY Acad Sci : — Retroids in archaea: phylogeny and lateral origins.
Remarkable interkingdom conservation of intron positions and massive, lineage-specific intron loss and gain in eukaryotic evolution. Curr Biol 13 : — Roy SW, Gilbert W a. The pattern of intron loss. Roy SW, Gilbert W b. Nuclear introns can also be important in a process called alternative splicing, which can produce multiple types of messenger RNA from a single gene. Although these examples demonstrate a constructive role for introns, they cannot explain why introns are so ubiquitous in our genes.
He suggested that introns could speed up evolution by promoting genetic recombinations between exons. This process which he called 'exon shuffling' would be directly associated with formation of new genes. Introns, from this perspective, have a profound purpose. They serve as hot spots for recombination in the formation of new combinations of exons.
In other words, they are in our genes because they have been used during evolution as a faster pathway to assemble new genes. Over the past 10 years, the exon shuffling idea has been supported by data from various experimental approaches.
They are expected to yield a huge amount of information about intron sequences. The new data should solve most of our basic questions about the functions of introns. Newsletter Get smart. Sign up for our email newsletter. Alternative splicing is a controlled molecular mechanism producing multiple variant proteins from a single gene in a eukaryotic cell. One of the remarkable examples of the increasing protein repertoire by alternative splicing is the Drosophila Dscam gene, of which over isoforms can potentially be produced by alternative splicing.
Pan et al. Furthermore, very short introns are selected against because a minimal length of intron is required for the splicing reaction [ 28 ]. It has been noticed that the length of conservations in flanking introns of conserved alternative exons, i. In fact, short cis-acting motifs that are necessary for binding splicing factors have been recognized and named intronic splicing silencers and intronic splicing enhancers.
The expression enhancing effect of introns was first recognized in the experiment using simian virus 40 constructs with or without introns, showing that their protein products were significantly diminished without their introns [ 15 ].
Subsequently, Buchman and Berg [ 48 ] showed that, in a certain condition, constructs with introns were expressed up to times higher than constructs without introns, suggesting that introns can strongly enhance gene expression.
In fact, some introns are designed to be included to construct expression vectors for guaranteeing a higher level of expression [ 49 ]. A large-scale analysis performed in yeast also confirmed that genes with introns tend to have a higher level of gene expression compared to genes without introns [ 50 ].
A similar observation was made in mammals, as well [ 51 ]. Classically, enhancers mediate either direction of expression, up- and down-regulation of genes, and involve both spatial and temporal control of gene expression in a specific cell independent of genomic location [ 52 ].
On the contrary, intron-mediated enhancers IMEs mainly identified in plant generally act in the expression enhancement of genes and are primarily located in the first ordinary intron position within a gene.
In fact, in experiments performed in Arabidopsis, rice, and even mammals, the expression level of a gene with IMEs was increased up to fold [ 29 ]. Genomic location and distance from transcription start site can influence the IME activity unlike the mode of expression regulation performed by the classical enhancers [ 53 ]. Transcription initiation and termination processes are cellular processes that involve introns, as well, which need some sequence elements in introns to be correctly completed.
For instance, some studies showed that specific sequence elements in introns, such as enhancers and silencers, regulate transcription initiation through modulating the function of the promoters of genes [ 30 , 54 ].
Nonsense-mediated decay NMD was originally known as a surveillance mechanism in eukaryotes that selectively removes mRNAs containing erroneously generated premature termination codons PTCs.
However, several recent studies have suggested that NMD may be another normal mechanism of post-transcriptional gene expression regulation [ 34 , 35 , 55 ].
Consistently, a recent study has shown that the levels of the expressions of genes important for plant development are regulated by NMD [ 36 ]. Kalyna et al. It has been reported that spliced transcripts are exported faster from the nucleus to cytoplasm than their unspliced counterparts [ 56 , 57 ] indicating the association between splicing machineries and nuclear export, although there are some contradictory studies [ 58 , 59 ].
A recent experiment using fluorescence in situ hybridization has investigated how intron-bearing and intronless constructs are distributed differently across the nucleus and cytoplasm and showed that intron-bearing transcripts are preferentially located in the cytoplasm [ 31 ]. There are some studies suggesting that introns may have a role in chromatin assembly as well. Recent genome-wide mapping analyses of nucleosome positions have shown that nucleosomes are relatively depleted in intron regions compared to exonic regions [ 32 , 33 ].
Schwartz et al. The first intron among all introns within a gene has particularly been a research focus. The first intron is the longest among all other downstream introns within a gene in most species including plants and animals [ 38 ].
Additionally, certain transcription factor binding motifs are enriched in first introns [ 61 ]. Different parts of genes have different average sizes of introns, e. In Drosophila, long introns evolve more slowly than shorter ones and first introns are the longest compared to other introns [ 37 , 63 ]. In Tetrahymena, the introns located closer to the 5' end of genes are more conserved than downstream introns.
Our team also proved in a previous study that first introns are the longest and the most conserved [ 39 ] compared to other downstream introns. Furthermore, we showed that active histone marks, such as H3K4me1, and H3K4me3, are significantly enriched in the first introns, and the size of the first intron of a gene becomes bigger as the number of exons that gene carries increases.
Additionally, we showed in the same paper that the proportions of regulatory histone marks are positively associated with the levels of gene expressions in 12 normal human tissues including kidney, heart, liver, and ovary [ 39 ].
Additionally, a replacement of the second intron with other introns in the beta-globin gene in human led to a reduction of the efficiency of 3'-end formation [ 64 ]. Introns, particularly first introns, have important roles in the correct cytoplasmic localization of some mRNAs, including the Drosophila oskar gene and mRNA export [ 60 , 65 ] as well as in transcriptional and translational regulation [ 61 , 66 , 67 ]. Taken together, first introns among all introns within genes have special functional characteristics, indicating that the existence of introns within genes is highly unlikely to be the product of a random process.
According to Comeron et al. The HR interference was basically described as genetic linkage between two sites under selection in finite populations, leading to decreasing effectiveness of natural selection [ 41 ]. The HR interference model predicts that selection efficiency should be different between genes that differ in exon-intron structures, so that genes with longer introns should be under weaker HR interference by increasing recombination between two sites in two neighboring exons.
In other words, introns may have a role in relaxing intragenic HR interference between sites under the influence of natural selection in finite populations. Recombination gives the opportunity for two independently occurring favorable alleles at linked loci to be located together and thus enhances the efficiency of natural selection [ 40 ], which can be one of the plausible scenarios of how introns have been sustained through the evolutionary history of genes.
Recently, Carvunis et al. According to their model, the short ORFs can evolve into real functional genes through a kind of continuous evolutionary process. In that sense, long non-coding intron regions in higher eukaryotes can be a good reservoir of short and non-functional ORFs.
Genome-wide association study GWAS has been a popular approach to identify trait associated genetic variants so-called single nucleotide polymorphisms SNPs. GWASs compare the allele frequencies of case groups i. If an allele is significantly more frequent in case groups, the allele is said to be a disease-associated allele, or a trait-associated SNP TAS. In theory, TASs are considered to reside near sites of actual disease-causing mutations in genomes.
Investigation of the functional implication of these intron-TASs will thus be an important research subject in the future. For instance, about half of the miRNAs in the human genome are located in introns, and they are usually co-expressed with their host genes regulated by the promoters of host genes [ 44 ].
Similar to miRNAs, some snoRNAs reside in introns, and they are also regulated by host transcriptional and splicing machineries [ 45 ]. Introns are classically degraded after the completion of splicing; however, these ncRNA genes embedded in intron regions are produced upon intron removal [ 2 , 46 ].
Furthermore, they can survive even longer than the intronic host genes [ 2 ]. Considering that the ncRNAs located in introns are co-expressed and co-regulated with their host genes by the promoters and splicing machineries of host genes, they are considered to be involved in auto-regulation of the expression of host genes [ 46 ]. The existence of introns in genome is a real mystery, given the expensive energy cost for a cell to pay for copying the entire length of several introns in a gene and excising them at the exact position, controlled by big RNA and protein complexes after transcription.
Nevertheless, most completely genomes of eukaryotic cells so far carry introns in their genomes [ 69 , 70 ], and some studies even showed that introns had been propagated during eukaryotic lineage evolution [ 3 , 9 , 71 , 72 , 73 ].
The origin of spliceosomal introns in eukaryotic lineage has been attempted to be explained by the massive invasion of group II self-splicing introns from bacteria to eukaryotes [ 3 , 5 ]. It is very hard to understand how and why introns propagate in eukaryotic lineages and what the beneficial effect of introns on cell survival is. We reviewed here putative functional roles of introns in various cellular processes such as splicing, mRNA transport, NMD, and expression regulation.
0コメント