Analysis and design of RNA sequencing experiments for identifying isoform regulation View Full Text


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Article Info

DATE

2010-12

AUTHORS

Yarden Katz, Eric T Wang, Edoardo M Airoldi, Christopher B Burge

ABSTRACT

Through alternative splicing, most human genes express multiple isoforms that often differ in function. To infer isoform regulation from high-throughput sequencing of cDNA fragments (RNA-seq), we developed the mixture-of-isoforms (MISO) model, a statistical model that estimates expression of alternatively spliced exons and isoforms and assesses confidence in these estimates. Incorporation of mRNA fragment length distribution in paired-end RNA-seq greatly improved estimation of alternative-splicing levels. MISO also detects differentially regulated exons or isoforms. Application of MISO implicated the RNA splicing factor hnRNP H1 in the regulation of alternative cleavage and polyadenylation, a role that was supported by UV cross-linking-immunoprecipitation sequencing (CLIP-seq) analysis in human cells. Our results provide a probabilistic framework for RNA-seq analysis, give functional insights into pre-mRNA processing and yield guidelines for the optimal design of RNA-seq experiments for studies of gene and isoform expression. More... »

PAGES

1009

References to SciGraph publications

  • 2005-05. Understanding alternative splicing: towards a cellular code in NATURE REVIEWS MOLECULAR CELL BIOLOGY
  • 2010-05. Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation in NATURE BIOTECHNOLOGY
  • 2009-06. Cancer-associated regulation of alternative splicing in NATURE STRUCTURAL & MOLECULAR BIOLOGY
  • 2008-07. Mapping and quantifying mammalian transcriptomes by RNA-Seq in NATURE METHODS
  • 2008-11. Alternative isoform regulation in human tissue transcriptomes in NATURE
  • 2009-10. Splice site strength–dependent activity and genetic buffering by poly-G runs in NATURE STRUCTURAL & MOLECULAR BIOLOGY
  • 2010-05. Modeling non-uniformity in short-read rates in RNA-Seq data in GENOME BIOLOGY
  • 2008-03. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth in NATURE
  • 2010-05. Ab initio reconstruction of cell type–specific transcriptomes in mouse reveals the conserved multi-exonic structure of lincRNAs in NATURE BIOTECHNOLOGY
  • 2010-03. Global and unbiased detection of splice junctions from RNA-seq data in GENOME BIOLOGY
  • 2010-10. Alternative expression analysis by RNA sequencing in NATURE METHODS
  • 2008-12. Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing in NATURE GENETICS
  • 2009-03. Ultrafast and memory-efficient alignment of short DNA sequences to the human genome in GENOME BIOLOGY
  • 2008-12. Annotating genomes with massive-scale RNA sequencing in GENOME BIOLOGY
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/nmeth.1528

    DOI

    http://dx.doi.org/10.1038/nmeth.1528

    DIMENSIONS

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    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/21057496


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