title: A novel splicing outcome reveals more than 2000 new mammalian protein isoforms.
abstract: BACKGROUND
  We have recently characterized an instance of alternative splicing that differs from the canonical gene transcript by deletion of a length of sequence not divisible by three, but where translation can be rescued by an alternative start codon. This results in a predicted protein in which the amino terminus differs markedly in sequence from the known protein product(s), as it is translated from an alternative reading frame. Automated pipelines have annotated thousands of splice variants but have overlooked these protein isoforms, leading to them being underrepresented in current databases.
  
  
  RESULTS
  Here we describe 1849 human and 733 mouse transcripts that can be transcribed from an alternate ATG. Of these, >80% have not been annotated previously. Those conserved between human and mouse genomes (and hence under likely evolutionary selection) are identified. We provide mass spectroscopy evidence for translation of selected transcripts. Of the described splice variants, only one has previously been studied in detail and converted the encoded protein from an activator of cell-function to a suppressor, demonstrating that these splice variants can result in profound functional change. We investigate the potential functional effects of this splicing using a variety of bioinformatic tools. The 2582 variants we describe are involved in a wide variety of biological processes, and therefore open many new avenues of research.
authors.affiliation: Research School of Biology, Australian National University, Canberra, ACT 0200 and CSIRO Plant Industry, Black Mountain Laboratories, Canberra, ACT 2601, Australia.
authors.forename: Laurence O W
authors.initials: LO
authors.lastname: Wilson
authors.forename: Andrew
authors.initials: A
authors.lastname: Spriggs
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Taylor
authors.forename: Aude M
authors.initials: AM
authors.lastname: Fahrer
mesh_terms: D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D019295:Computational Biology; D005786:Gene Expression Regulation; D016678:Genome; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D022821:RNA Splice Sites / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; C572282:Ncaph2 protein, mouse; D009687:Nuclear Proteins; D020033:Protein Isoforms; D011506:Proteins; D022821:RNA Splice Sites