RNA-editing-mediated exon evolution

BackgroundAlu retroelements are specific to primates and abundant in the human genome. Through mutations that create functional splice sites within intronic Alus, these elements can become new exons in a process denoted exonization. It was recently shown that Alu elements are also heavily changed by RNA editing in the human genome.ResultsHere we show that the human nuclear prelamin A recognition factor contains a primate-specific Alu-exon that exclusively depends on RNA editing for its exonization. We demonstrate that RNA editing regulates the exonization in a tissue-dependent manner, through both the creation of a functional AG 3' splice site, and alteration of functional exonic splicing enhancers within the exon. Furthermore, a premature stop codon within the Alu-exon is eliminated by an exceptionally efficient RNA editing event. The sequence surrounding this editing site is important not only for editing of that site but also for editing in other neighboring sites as well.ConclusionOur results show that the abundant RNA editing of Alu sequences can be recruited as a mechanism supporting the birth of new exons in the human genome.

[1]  Jinhua Wang,et al.  ESEfinder: a web resource to identify exonic splicing enhancers , 2003, Nucleic Acids Res..

[2]  Huanming Yang,et al.  Origin and evolution of new exons in rodents. , 2005, Genome research.

[3]  Victoria Arango,et al.  Altered Editing of Serotonin 2C Receptor Pre-mRNA in the Prefrontal Cortex of Depressed Suicide Victims , 2002, Neuron.

[4]  H. Worman,et al.  Prenylated Prelamin A Interacts with Narf, a Novel Nuclear Protein* , 1999, The Journal of Biological Chemistry.

[5]  Zipora Y. Fligelman,et al.  Systematic identification of abundant A-to-I editing sites in the human transcriptome , 2004, Nature Biotechnology.

[6]  J. Mattick,et al.  Small regulatory RNAs in mammals. , 2005, Human molecular genetics.

[7]  J. Brosius,et al.  On "genomenclature": a comprehensive (and respectful) taxonomy for pseudogenes and other "junk DNA". , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[8]  Eli Eisenberg,et al.  RNA editing level in the mouse is determined by the genomic repeat repertoire. , 2006, RNA.

[9]  Colin N. Dewey,et al.  Initial sequencing and comparative analysis of the mouse genome. , 2002 .

[10]  W. Keller,et al.  Two forms of human double-stranded RNA-specific editase 1 (hRED1) generated by the insertion of an Alu cassette. , 1997, RNA.

[11]  M. O’Connell,et al.  An ADAR that edits transcripts encoding ion channel subunits functions as a dimer , 2003, The EMBO journal.

[12]  G. Carmichael,et al.  SINEs point to abundant editing in the human genome , 2005, Genome Biology.

[13]  Brenda L Bass,et al.  RNA editing by adenosine deaminases that act on RNA. , 2002, Annual review of biochemistry.

[14]  D. Feldmeyer,et al.  Point mutation in an AMPA receptor gene rescues lethality in mice deficient in the RNA-editing enzyme ADAR2 , 2000, Nature.

[15]  J. Brosius,et al.  Alu-SINE exonization: en route to protein-coding function. , 2005, Molecular biology and evolution.

[16]  R. Sorek,et al.  Is abundant A-to-I RNA editing primate-specific? , 2004, Trends in genetics : TIG.

[17]  Noam Shomron,et al.  The Birth of an Alternatively Spliced Exon: 3' Splice-Site Selection in Alu Exons , 2003, Science.

[18]  International Human Genome Sequencing Consortium Initial sequencing and analysis of the human genome , 2001, Nature.

[19]  T. Matise,et al.  Widespread RNA editing of embedded alu elements in the human transcriptome. , 2004, Genome research.

[20]  Daniel R. Clutterbuck,et al.  A bioinformatic screen for novel A-I RNA editing sites reveals recoding editing in BC10 , 2005, Bioinform..

[21]  P. Seeburg,et al.  RNA editing in brain controls a determinant of ion flow in glutamate-gated channels , 1991, Cell.

[22]  B. Bass,et al.  RNA hairpins in noncoding regions of human brain and Caenorhabditis elegans mRNA are edited by adenosine deaminases that act on RNA , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[23]  方福德 单核苷酸多态性(single nucleotide polymorphism) , 2003 .

[24]  Christopher B. Burge,et al.  RESCUE-ESE identifies candidate exonic splicing enhancers in vertebrate exons , 2004, Nucleic Acids Res..

[25]  L. Chasin,et al.  Comparison of multiple vertebrate genomes reveals the birth and evolution of human exons , 2006, Proceedings of the National Academy of Sciences.

[26]  M. Batzer,et al.  Mammalian retroelements. , 2002, Genome research.

[27]  T. Dawson,et al.  Regulation of alternative splicing by RNA editing , 1999, Nature.

[28]  Ichiro Kanazawa,et al.  Glutamate receptors: RNA editing and death of motor neurons , 2004, Nature.

[29]  Alexander Rich,et al.  Widespread A-to-I RNA Editing of Alu-Containing mRNAs in the Human Transcriptome , 2004, PLoS biology.

[30]  R. Reenan,et al.  Nervous System Targets of RNA Editing Identified by Comparative Genomics , 2003, Science.

[31]  Marie Öhman,et al.  RNA editing and alternative splicing: the importance of co‐transcriptional coordination , 2006, EMBO reports.

[32]  G. Ast,et al.  Comparative analysis identifies exonic splicing regulatory sequences--The complex definition of enhancers and silencers. , 2006, Molecular cell.

[33]  E. Levanon,et al.  Identification of RNA editing sites in the SNP database , 2005, Nucleic acids research.

[34]  An editor controlled by transcription , 2006, EMBO reports.

[35]  B. Blencowe Exonic splicing enhancers: mechanism of action, diversity and role in human genetic diseases. , 2000, Trends in biochemical sciences.

[36]  B. Bass,et al.  Inosine exists in mRNA at tissue‐specific levels and is most abundant in brain mRNA , 1998, The EMBO journal.

[37]  R. Emeson,et al.  Regulation of serotonin-2C receptor G-protein coupling by RNA editing , 1997, Nature.

[38]  Michael Q. Zhang,et al.  Regulating Gene Expression through RNA Nuclear Retention , 2005, Cell.

[39]  M Schrey,et al.  Underediting of glutamate receptor GluR-B mRNA in malignant gliomas , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[40]  M. O’Connell,et al.  The many roles of an RNA editor , 2001, Nature Reviews Genetics.

[41]  G. Stormo,et al.  Editing efficiency of a Drosophila gene correlates with a distant splice site selection. , 2005, RNA.

[42]  Richard Wooster,et al.  A survey of RNA editing in human brain. , 2004, Genome research.

[43]  R. Sperling,et al.  RNA editing activity is associated with splicing factors in lnRNP particles: The nuclear pre-mRNA processing machinery , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[44]  Mouse Genome Sequencing Consortium Initial sequencing and comparative analysis of the mouse genome , 2002, Nature.

[45]  E V Koonin,et al.  Origin of alternative splicing by tandem exon duplication. , 2001, Human molecular genetics.

[46]  Dirk Feldmeyer,et al.  Early-Onset Epilepsy and Postnatal Lethality Associated with an Editing-Deficient GluR-B Allele in Mice , 1995, Science.