Location of Repository

A method of predicting changes in human gene splicing induced by genetic variants in context of cis-acting elements

By Alexander Churbanov, Igor Vorechovsky and Chindo Hicks

Abstract

Background: polymorphic variants and mutations disrupting canonical splicing isoforms are among the leading causes of human hereditary disorders. While there is a substantial evidence of aberrant splicing causing Mendelian diseases, the implication of such events in multi-genic disorders is yet to be well understood. We have developed a new tool (SpliceScan II) for predicting the effects of genetic variants on splicing and cis-regulatory elements. The novel Bayesian non-canonical 5’GC splice site (SS) sensor used in our tool allows inference on non-canonical exons. <br/>Result: our tool performed favorably when compared with the existing methods in the context of genes linked to the Autism Spectrum Disorder (ASD). SpliceScan II was able to predict more aberrant splicing isoforms triggered by the mutations, as documented in DBASS5 and DBASS3 aberrant splicing databases, than other existing methods. Detrimental effects behind some of the polymorphic variations previously associated with Alzheimer’s and breast cancer could be explained by changes in predicted splicing patterns. <br/>Conclusions: we have developed SpliceScan II, an effective and sensitive tool for predicting the detrimental effects of genomic variants on splicing leading to Mendelian and complex hereditary disorders. The method could potentially be used to screen resequenced patient DNA to identify de novo mutations and polymorphic variants that could contribute to a genetic disorde

Topics: QH426
Year: 2010
OAI identifier: oai:eprints.soton.ac.uk:72043
Provided by: e-Prints Soton

Suggested articles

Preview

Citations

  1. (2004). 12 Nonclassical splicing mutations in the coding and noncoding regions of the ATM Gene: maximum entropy estimates of splice junction strengths. Hum Mutat doi
  2. (2006). Aberrant 3' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. Nucleic Acids Res doi
  3. (2007). al: Genome-wide association study identifies novel breast cancer susceptibility loci. Nature
  4. (1997). Analysis of donor splice sites in different eukaryotic organisms. doi
  5. (2004). Baraniak AP, Lasda EL: Alternative splicing in disease and therapy. Nat Biotechnol doi
  6. (2002). BLAT--the BLAST-like alignment tool. Genome Res doi
  7. (2004). Brunak S: Analysis and recognition of 5' UTR intron splice sites in human premRNA. Nucleic Acids Res doi
  8. (1996). Brunak S: Splice site prediction in Arabidopsis thaliana pre-mRNA by combining local and global sequence information. Nucleic Acids Res doi
  9. (2004). Burge CB: Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals. doi
  10. (2008). Burge CB: Splicing regulation: from a parts list of regulatory elements to an integrated splicing code. RNA doi
  11. (2004). Burge CB: Systematic identification and analysis of exonic splicing silencers. Cell doi
  12. (2001). CB: A computational analysis of sequence features involved in recognition of short introns. doi
  13. (2008). CB: Alternative isoform regulation in human tissue transcriptomes. Nature doi
  14. (2002). CB: Predictive identification of exonic splicing enhancers in human genes. Science doi
  15. CB: RESCUEESE identifies candidate exonic splicing enhancers in vertebrate exons. doi
  16. (2004). CB: Variation in sequence and organization of splicing regulatory elements in vertebrate genes. doi
  17. (1996). CC: Selection of the bovine papillomavirus type 1 nucleotide 3225 3' splice site is regulated through an exonic splicing enhancer and its juxtaposed exonic splicing suppressor. doi
  18. (2000). Chasin LA: Multiple splicing defects in an intronic false exon. Mol Cell Biol doi
  19. (2005). Common ERBB2 polymorphisms and risk of breast cancer in a white British population: a case-control study. Breast Cancer Res doi
  20. (2006). Commonly studied single-nucleotide polymorphisms and breast cancer: results from the Breast Cancer Association Consortium. doi
  21. (2005). Conboy JG: The splicing regulatory element, UGCAUG, is phylogenetically and spatially conserved in introns that flank tissue-specific alternative exons. Nucleic Acids Res doi
  22. (2006). Contemporary progress in gene structure prediction. Current genomics doi
  23. (2008). DN: Human Gene Mutation Database: towards a comprehensive central mutation database. doi
  24. (1995). Exon recognition in vertebrate splicing. doi
  25. (2006). Fundamentals of Quadruplex Structures. In: Quadruplex Nucleic Acids. Edited by Neidle S, Balasubramanian S. doi
  26. (1998). Gene finding: putting the parts together. In: Guide to human genome computing. doi
  27. (1998). GENIO- A Non-Redundant Eukaryotic Gene Database of Annotated Sites and Sequences. In:
  28. (2000). Genomic sequence, splicing, and gene annotation. doi
  29. (2005). Guigo R: Are splicing mutations the most frequent cause of hereditary disease? FEBS Lett doi
  30. (2005). Guigo R: Comparison of splice sites in mammals and chicken. Genome Res doi
  31. (2004). Haussler D: Ultraconserved elements in the human genome. Science
  32. (2007). Helgason A et al: Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer. Nat Genet doi
  33. (2009). Hicks C: Computational prediction of splicing regulatory elements shared by Tetrapoda organisms. doi
  34. (2001). Human GC-AG alternative intron isoforms with weak donor sites show enhanced consensus at acceptor exon positions. Nucleic Acids Res doi
  35. (2007). Hutchinson A et al: A genome-wide association study identifies alleles in FGFR2 13 associated with risk of sporadic postmenopausal breast cancer. Nat Genet doi
  36. (2005). Incorporation of splice site probability models for non-canonical introns improves gene structure prediction in plants. Bioinformatics doi
  37. (2004). Inferring phylogenies: Sinauer Associates, Inc, doi
  38. (1997). JB: U1 small nuclear RNA-promoted exon selection requires a minimal distance between the position of U1 binding and the 3' splice site across the exon. Mol Cell Biol
  39. (2008). Krainer AR: Antisense masking of an hnRNP A1/A2 intronic splicing silencer corrects SMN2 splicing in transgenic mice. doi
  40. (2002). Krainer AR: Listening to silence and understanding nonsense: exonic mutations that affect splicing. Nat Rev Genet doi
  41. (1990). Lipman DJ: Basic local alignment search tool. doi
  42. (2006). Loyd JE et al: High frequency of BMPR2 exonic deletions/duplications in familial pulmonary arterial hypertension. Am J Respir Crit Care Med doi
  43. (2006). Method of predicting splice sites based on signal interactions. Biol Direct
  44. (1997). Prediction of complete gene structures in human genomic DNA. doi
  45. (2008). Rogozin IB: Accumulation of GC donor splice signals in mammals. Biol Direct doi
  46. (2006). Sachidanandam R: Comprehensive splice-site analysis using comparative genomics. Nucleic Acids Res doi
  47. (2000). Seledtsov IA, Solovyev VV: Analysis of canonical and non-canonical splice sites in mammalian genomes. Nucleic Acids Res doi
  48. (1998). Statistical features of human exons and their flanking regions. Hum Mol Genet doi
  49. (2004). Thomas DC: SNPs, haplotypes, and cancer: applications in molecular epidemiology. Cancer Epidemiol Biomarkers Prev
  50. (1992). Tung CS: Assessment of protein coding measures. doi
  51. (1997). Two methods for improving performance of an HMM and their application for gene finding.
  52. (2009). Vorechovsky I: Ab initio prediction of mutation-induced cryptic splice-site activation and exon skipping. doi
  53. (2007). Vorechovsky I: Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. Nucleic Acids Res doi
  54. (2007). Vorechovsky I: Global control of aberrant splice-site activation by auxiliary splicing sequences: evidence for a gradient in exon and intron definition. Nucleic Acids Res doi
  55. (2006). Vorechovsky I: Position-dependent repression and promotion of DQB1 intron 3 splicing by GGGG motifs. doi
  56. (2004). Zanke B: Predictive models for breast cancer susceptibility from multiple single nucleotide polymorphisms. Clin Cancer Res
  57. (2008). Zhang MQ: RNA landscape of evolution for optimal exon and intron discrimination. doi

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.