title: Constant splice-isoform ratios in human lymphoblastoid cells support the concept of a splico-stat.
abstract: Splicing generates mature transcripts from genes in pieces in eukaryotic cells. Overwhelming evidence has accumulated that alternative routes in splicing are possible for most human and mammalian genes, thereby allowing formation of different transcripts from one gene. No function has been assigned to the majority of identified alternative splice forms, and it has been assumed that they compose inert or tolerated waste from aberrant or noisy splicing. Here we demonstrate that five human transcription units (WT1, NOD2, GNAS, RABL2A, RABL2B) have constant splice-isoform ratios in genetically diverse lymphoblastoid cell lines independent of the type of alternative splicing (exon skipping, alternative donor/acceptor, tandem splice sites) and gene expression level. Even splice events that create premature stop codons and potentially trigger nonsense-mediated mRNA decay are found at constant fractions. The analyzed alternative splicing events were qualitatively but not quantitatively conserved in corresponding chimpanzee cell lines. Additionally, subtle splicing at tandem acceptor splice sites (GNAS, RABL2A/B) was highly constrained and strongly depends on the upstream donor sequence content. These results also demonstrate that unusual and unproductive splice variants are produced in a regulated manner.
authors.affiliation: Leibniz Institute for Age Research–Fritz Lipmann Institute, 07745 Jena, Germany. mkramer@fli-leibniz.de
authors.forename: Marcel
authors.initials: M
authors.lastname: Kramer
authors.forename: Klaus
authors.initials: K
authors.lastname: Huse
authors.forename: Uwe
authors.initials: U
authors.lastname: Menzel
authors.forename: Oliver
authors.initials: O
authors.lastname: Backhaus
authors.forename: Philip
authors.initials: P
authors.lastname: Rosenstiel
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.forename: Jochen
authors.initials: J
authors.lastname: Hampe
authors.forename: Matthias
authors.initials: M
authors.lastname: Platzer
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D002460:Cell Line; D002864:Chromogranins; D018389:Codon, Nonsense; D005091:Exons; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics; D002679:Pan troglodytes / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics; D022821:RNA Splice Sites / Q000235:genetics; D025721:WT1 Proteins / Q000235:genetics; D020691:rab GTP-Binding Proteins / Q000235:genetics
chemical_list: D002864:Chromogranins; D018389:Codon, Nonsense; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D020033:Protein Isoforms; D022821:RNA Splice Sites; D025721:WT1 Proteins; C406732:GNAS protein, human; C513285:RABL2A protein, human; C513286:RABL2B protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs; D020691:rab GTP-Binding Proteins