Sequence analysis Complementary intron sequence motifs associated with human exon repetition : a role for intragenic , inter-transcript interactions in gene expression

Motivation: Exon repetition describes the presence of tandemly repeated exons inmRNA in the absence of duplications in the genome. The regulation of this process is not fully understood. We therefore investigated the entire flanking intronic sequences of exons involved in exon repetition for common sequence elements. Results: A computational analysis of 48 human single exon repetition events identified two common sequence motifs. One of these motifs is pyrimidine-rich and is more common in the upstream intron, whilst the other motif is highly enriched in purines and is more common in the downstream intron. As the two motifs are complementary to each other, they support a model by which exon repetition occurs as a result of trans-splicing between separate pre-mRNA transcripts from the same gene that are brought together during transcription by complementary intronic sequences. The majority of the motif instances overlap with the locations of mobile elements such as Alu elements. We explore the potential importance of complementary intron sequences in a rat gene that undertakes natural exon repetition in a strain specific manner. The possibility that distant complementary sequences can stimulate inter-transcript splicing during transcription suggests an unsuspected new role for potential secondary structures in endogenous genes.

[1]  E. Buratti,et al.  Defective splicing, disease and therapy: searching for master checkpoints in exon definition , 2006, Nucleic acids research.

[2]  Peter F. Stadler,et al.  Partition function and base pairing probabilities of RNA heterodimers , 2006, Algorithms for Molecular Biology.

[3]  Thangavel Alphonse Thanaraj,et al.  ASD: a bioinformatics resource on alternative splicing , 2005, Nucleic Acids Res..

[4]  N. Samani,et al.  A genome-wide survey demonstrates widespread non-linear mRNA in expressed sequences from multiple species , 2005, Nucleic acids research.

[5]  F. Clark,et al.  Understanding alternative splicing: towards a cellular code , 2005, Nature Reviews Molecular Cell Biology.

[6]  E. Buratti,et al.  Influence of RNA Secondary Structure on the Pre-mRNA Splicing Process , 2004, Molecular and Cellular Biology.

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

[8]  N. Samani,et al.  Exon repetition: a major pathway for processing mRNA of some genes is allele-specific. , 2004, Nucleic acids research.

[9]  J. Castle,et al.  Genome-Wide Survey of Human Alternative Pre-mRNA Splicing with Exon Junction Microarrays , 2003, Science.

[10]  D. Black.  Mechanisms of alternative pre-messenger RNA splicing. , 2003, Annual review of biochemistry.

[11]  M. Garcia-Blanco,et al.  5' exon replacement and repair by spliceosome-mediated RNA trans-splicing. , 2003, RNA.

[12]  M. Garcia-Blanco.  Messenger RNA reprogramming by spliceosome-mediated RNA trans-splicing , 2003 .

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

[14]  H. Margalit,et al.  Conserved sequence elements associated with exon skipping. , 2003, Nucleic acids research.

[15]  T. Cooper,et al.  Finding signals that regulate alternative splicing in the post-genomic era , 2002, Genome Biology.

[16]  Bosiljka Tasic,et al.  Alternative pre-mRNA splicing and proteome expansion in metazoans , 2002, Nature.

[17]  Dan Graur,et al.  Alu-containing exons are alternatively spliced. , 2002, Genome research.

[18]  M. Batzer,et al.  Alu repeats and human genomic diversity , 2002, Nature Reviews Genetics.

[19]  A. Furger,et al.  Integrating mRNA Processing with Transcription , 2002, Cell.

[20]  C. Burge,et al.  A computational analysis of sequence features involved in recognition of short introns , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[21]  S. Yanagisawa,et al.  Heterogeneous Sp1 mRNAs in Human HepG2 Cells Include a Product of Homotypic trans-Splicing* , 2000, The Journal of Biological Chemistry.

[22]  J. Jurka,et al.  Inverted Alu repeats unstable in yeast are excluded from the human genome , 2000, The EMBO journal.

[23]  I. Longden,et al.  EMBOSS: the European Molecular Biology Open Software Suite. , 2000, Trends in genetics : TIG.

[24]  N. Samani,et al.  Exon repetition in mRNA. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[25]  M. Garcia-Blanco,et al.  Spliceosome-mediated RNA trans-splicing as a tool for gene therapy , 1999, Nature Biotechnology.

[26]  F. Hegardt,et al.  Natural trans-splicing in carnitine octanoyltransferase pre-mRNAs in rat liver. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[27]  A. Graessmann,et al.  Experimental evidence for RNA trans‐splicing in mammalian cells. , 1995, The EMBO journal.

[28]  Jun S. Liu,et al.  Detecting subtle sequence signals: a Gibbs sampling strategy for multiple alignment. , 1993, Science.

[29]  I. Graham,et al.  Effects of RNA secondary structure on alternative splicing of Pre-mRNA: Is folding limited to a region behind the transcribing RNA polymerase? , 1988, Cell.

[30]  P. Sharp,et al.  Trans splicing of mrna precursors in vitro , 1985, Cell.

[31]  M. Garcia-Blanco,et al.  Partial correction of endogenous ΔF508 CFTR in human cystic fibrosis airway epithelia by spliceosome-mediated RNA trans-splicing , 2002, Nature Biotechnology.

[32]  Christopher J. Lee,et al.  A genomic view of alternative splicing , 2002, Nature Genetics.

[33]  T. Darden,et al.  Biased distribution of inverted and direct Alus in the human genome: implications for insertion, exclusion, and genome stability. , 2001, Genome research.

[34]  Michael Gribskov,et al.  Combining evidence using p-values: application to sequence homology searches , 1998, Bioinform..

[35]  Charles Elkan,et al.  Fitting a Mixture Model By Expectation Maximization To Discover Motifs In Biopolymer , 1994, ISMB.

[36]  D. Haussler,et al.  The Ucsc Genome Browser Database , 2022 .