title: Long non-coding RNAs display higher natural expression variation than protein-coding genes in healthy humans.
abstract: BACKGROUND
  Long non-coding RNAs (lncRNAs) are increasingly implicated as gene regulators and may ultimately be more numerous than protein-coding genes in the human genome. Despite large numbers of reported lncRNAs, reference annotations are likely incomplete due to their lower and tighter tissue-specific expression compared to mRNAs. An unexplored factor potentially confounding lncRNA identification is inter-individual expression variability. Here, we characterize lncRNA natural expression variability in human primary granulocytes.
  
  
  RESULTS
  We annotate granulocyte lncRNAs and mRNAs in RNA-seq data from 10 healthy individuals, identifying multiple lncRNAs absent from reference annotations, and use this to investigate three known features (higher tissue-specificity, lower expression, and reduced splicing efficiency) of lncRNAs relative to mRNAs. Expression variability was examined in seven individuals sampled three times at 1- or more than 1-month intervals. We show that lncRNAs display significantly more inter-individual expression variability compared to mRNAs. We confirm this finding in two independent human datasets by analyzing multiple tissues from the GTEx project and lymphoblastoid cell lines from the GEUVADIS project. Using the latter dataset we also show that including more human donors into the transcriptome annotation pipeline allows identification of an increasing number of lncRNAs, but minimally affects mRNA gene number.
  
  
  CONCLUSIONS
  A comprehensive annotation of lncRNAs is known to require an approach that is sensitive to low and tight tissue-specific expression. Here we show that increased inter-individual expression variability is an additional general lncRNA feature to consider when creating a comprehensive annotation of human lncRNAs or proposing their use as prognostic or disease markers.
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, AKH BT 25.3, 1090, Vienna, Austria. akornienko@cemm.oeaw.ac.at.
authors.forename: Aleksandra E
authors.initials: AE
authors.lastname: Kornienko
authors.affiliation: Present Address: Institute of Science and Technology Austria, Lab Building East, Am Campus 1, A-3400, Klosterneuburg, Austria. christoph.dotter@ist.ac.at.
authors.forename: Christoph P
authors.initials: CP
authors.lastname: Dotter
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, AKH BT 25.3, 1090, Vienna, Austria. philipp.guenzl@gmx.at.
authors.forename: Philipp M
authors.initials: PM
authors.lastname: Guenzl
authors.affiliation: Department of Internal Medicine I, Division of Hematology and Blood Coagulation, Medical University of Vienna, Vienna, Austria. heinz.gisslinger@meduniwien.ac.at.
authors.forename: Heinz
authors.initials: H
authors.lastname: Gisslinger
authors.affiliation: Department of Internal Medicine I, Division of Hematology and Blood Coagulation, Medical University of Vienna, Vienna, Austria. bettina.gisslinger@meduniwien.ac.at.
authors.forename: Bettina
authors.initials: B
authors.lastname: Gisslinger
authors.affiliation: , Present Address: Piso 23, Av. Santa Fe No 481, Lomas de Santa Fe, 05349, D.F., Mexico. ciaracleary10@gmail.com.
authors.forename: Ciara
authors.initials: C
authors.lastname: Cleary
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, AKH BT 25.3, 1090, Vienna, Austria. rkralovics@cemm.oeaw.ac.at.
authors.forename: Robert
authors.initials: R
authors.lastname: Kralovics
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, AKH BT 25.3, 1090, Vienna, Austria. fpauler@cemm.oeaw.ac.at.
authors.forename: Florian M
authors.initials: FM
authors.lastname: Pauler
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, AKH BT 25.3, 1090, Vienna, Austria. dbarlow@cemm.oeaw.ac.at.
authors.forename: Denise P
authors.initials: DP
authors.lastname: Barlow
mesh_terms: D015870:Gene Expression / Q000235:genetics; D014644:Genetic Variation; D015894:Genome, Human; D006801:Humans; D058977:Molecular Sequence Annotation; D016366:Open Reading Frames / Q000235:genetics*; D062085:RNA, Long Noncoding / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D059467:Transcriptome / Q000235:genetics*
chemical_list: D062085:RNA, Long Noncoding; D012333:RNA, Messenger
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