title: Chimeras taking shape: potential functions of proteins encoded by chimeric RNA transcripts.
abstract: Chimeric RNAs comprise exons from two or more different genes and have the potential to encode novel proteins that alter cellular phenotypes. To date, numerous putative chimeric transcripts have been identified among the ESTs isolated from several organisms and using high throughput RNA sequencing. The few corresponding protein products that have been characterized mostly result from chromosomal translocations and are associated with cancer. Here, we systematically establish that some of the putative chimeric transcripts are genuinely expressed in human cells. Using high throughput RNA sequencing, mass spectrometry experimental data, and functional annotation, we studied 7424 putative human chimeric RNAs. We confirmed the expression of 175 chimeric RNAs in 16 human tissues, with an abundance varying from 0.06 to 17 RPKM (Reads Per Kilobase per Million mapped reads). We show that these chimeric RNAs are significantly more tissue-specific than non-chimeric transcripts. Moreover, we present evidence that chimeras tend to incorporate highly expressed genes. Despite the low expression level of most chimeric RNAs, we show that 12 novel chimeras are translated into proteins detectable in multiple shotgun mass spectrometry experiments. Furthermore, we confirm the expression of three novel chimeric proteins using targeted mass spectrometry. Finally, based on our functional annotation of exon organization and preserved domains, we discuss the potential features of chimeric proteins with illustrative examples and suggest that chimeras significantly exploit signal peptides and transmembrane domains, which can alter the cellular localization of cognate proteins. Taken together, these findings establish that some chimeric RNAs are translated into potentially functional proteins in humans.
authors.affiliation: Structural Biology and BioComputing Program, Spanish National Cancer Research Centre, Madrid, Spain;
authors.forename: Milana
authors.initials: M
authors.lastname: Frenkel-Morgenstern
authors.forename: Vincent
authors.initials: V
authors.lastname: Lacroix
authors.forename: Iakes
authors.initials: I
authors.lastname: Ezkurdia
authors.forename: Yishai
authors.initials: Y
authors.lastname: Levin
authors.forename: Alexandra
authors.initials: A
authors.lastname: Gabashvili
authors.forename: Jaime
authors.initials: J
authors.lastname: Prilusky
authors.forename: Angela
authors.initials: A
authors.lastname: Del Pozo
authors.forename: Michael
authors.initials: M
authors.lastname: Tress
authors.forename: Rory
authors.initials: R
authors.lastname: Johnson
authors.forename: Roderic
authors.initials: R
authors.lastname: Guigo
authors.forename: Alfonso
authors.initials: A
authors.lastname: Valencia
mesh_terms: D000595:Amino Acid Sequence; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D030561:Databases, Nucleic Acid; D005091:Exons; D005786:Gene Expression Regulation; D015894:Genome, Human; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D013058:Mass Spectrometry / Q000379:methods; D058977:Molecular Sequence Annotation; D008969:Molecular Sequence Data; D050506:Mutant Chimeric Proteins / Q000235:genetics* / Q000378:metabolism; D009928:Organ Specificity; D014176:Protein Biosynthesis; D021382:Protein Sorting Signals; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D040901:Proteomics / Q000379:methods; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017423:Sequence Analysis, RNA / Q000379:methods; D013329:Structure-Activity Relationship
chemical_list: D050506:Mutant Chimeric Proteins; D021382:Protein Sorting Signals; D012333:RNA, Messenger