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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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      Most cited references 44

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      Mapping and quantifying mammalian transcriptomes by RNA-Seq.

      We have mapped and quantified mouse transcriptomes by deeply sequencing them and recording how frequently each gene is represented in the sequence sample (RNA-Seq). This provides a digital measure of the presence and prevalence of transcripts from known and previously unknown genes. We report reference measurements composed of 41-52 million mapped 25-base-pair reads for poly(A)-selected RNA from adult mouse brain, liver and skeletal muscle tissues. We used RNA standards to quantify transcript prevalence and to test the linear range of transcript detection, which spanned five orders of magnitude. Although >90% of uniquely mapped reads fell within known exons, the remaining data suggest new and revised gene models, including changed or additional promoters, exons and 3' untranscribed regions, as well as new candidate microRNA precursors. RNA splice events, which are not readily measured by standard gene expression microarray or serial analysis of gene expression methods, were detected directly by mapping splice-crossing sequence reads. We observed 1.45 x 10(5) distinct splices, and alternative splices were prominent, with 3,500 different genes expressing one or more alternate internal splices.
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         James Galagan (2001)
        The human genome holds an extraordinary trove of information about human development, physiology, medicine and evolution. Here we report the results of an international collaboration to produce and make freely available a draft sequence of the human genome. We also present an initial analysis of the data, describing some of the insights that can be gleaned from the sequence.
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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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            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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