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Alternative Isoform Regulation in Human Tissue Transcriptomes

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      Abstract

      Through alternative processing of pre-mRNAs, individual mammalian genes often produce multiple mRNA and protein isoforms that may have related, distinct or even opposing functions. Here we report an in-depth analysis of 15 diverse human tissue and cell line transcriptomes based on deep sequencing of cDNA fragments, yielding a digital inventory of gene and mRNA isoform expression. Analysis of mappings of sequence reads to exon-exon junctions indicated that 92-94% of human genes undergo alternative splicing (AS), ∼86% with a minor isoform frequency of 15% or more. Differences in isoform-specific read densities indicated that a majority of AS and of alternative cleavage and polyadenylation (APA) events vary between tissues, while variation between individuals was ∼2- to 3-fold less common. Extreme or ‘switch-like’ regulation of splicing between tissues was associated with increased sequence conservation in regulatory regions and with generation of full-length open reading frames. Patterns of AS and APA were strongly correlated across tissues, suggesting coordinated regulation of these processes, and sequence conservation of a subset of known regulatory motifs in both alternative introns and 3′ UTRs suggested common involvement of specific factors in tissue-level regulation of both splicing and polyadenylation.

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        Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets.

        We predict regulatory targets of vertebrate microRNAs (miRNAs) by identifying mRNAs with conserved complementarity to the seed (nucleotides 2-7) of the miRNA. An overrepresentation of conserved adenosines flanking the seed complementary sites in mRNAs indicates that primary sequence determinants can supplement base pairing to specify miRNA target recognition. In a four-genome analysis of 3' UTRs, approximately 13,000 regulatory relationships were detected above the estimate of false-positive predictions, thereby implicating as miRNA targets more than 5300 human genes, which represented 30% of our gene set. Targeting was also detected in open reading frames. In sum, well over one third of human genes appear to be conserved miRNA targets.
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          The MicroArray Quality Control (MAQC) project shows inter- and intraplatform reproducibility of gene expression measurements.

          Over the last decade, the introduction of microarray technology has had a profound impact on gene expression research. The publication of studies with dissimilar or altogether contradictory results, obtained using different microarray platforms to analyze identical RNA samples, has raised concerns about the reliability of this technology. The MicroArray Quality Control (MAQC) project was initiated to address these concerns, as well as other performance and data analysis issues. Expression data on four titration pools from two distinct reference RNA samples were generated at multiple test sites using a variety of microarray-based and alternative technology platforms. Here we describe the experimental design and probe mapping efforts behind the MAQC project. We show intraplatform consistency across test sites as well as a high level of interplatform concordance in terms of genes identified as differentially expressed. This study provides a resource that represents an important first step toward establishing a framework for the use of microarrays in clinical and regulatory settings.
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            Author and article information

            Affiliations
            [1 ]Dept. of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139 USA
            [2 ]Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA 02139 USA
            [3 ]Dept. of Cell and Molecular Biology, Karolinska Institutet, 171 77 Stockholm, Sweden
            [4 ]Illumina Inc., 25861 Industrial Boulevard, Hayward, CA 94545 USA
            [5 ]Whitehead Institute for Biomedical Research, Cambridge, MA 02142 USA
            [6 ]National Center for Genome Resources, 2935 Rodeo Park Drive East, Santa Fe, NM 87505 USA
            Author notes
            [7]

            Correspondence should be addressed to: cburge@ 123456mit.edu , Ph: (617) 258-5997, Fax: (617) 452-2936.

            [*]

            These authors contributed equally to this work

            Journal
            0410462
            6011
            Nature
            Nature
            0028-0836
            1476-4687
            6 October 2008
            27 November 2008
            27 May 2009
            : 456
            : 7221
            : 470-476
            2593745
            18978772
            10.1038/nature07509
            nihpa72491
            Funding
            Funded by: National Human Genome Research Institute : NHGRI
            Funded by: National Institute of General Medical Sciences : NIGMS
            Award ID: R01 HG002439-07 ||HG
            Funded by: National Human Genome Research Institute : NHGRI
            Funded by: National Institute of General Medical Sciences : NIGMS
            Award ID: R01 GM085319-01 ||GM
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