title: The "alternative" choice of constitutive exons throughout evolution.
abstract: Alternative cassette exons are known to originate from two processes-exonization of intronic sequences and exon shuffling. Herein, we suggest an additional mechanism by which constitutively spliced exons become alternative cassette exons during evolution. We compiled a dataset of orthologous exons from human and mouse that are constitutively spliced in one species but alternatively spliced in the other. Examination of these exons suggests that the common ancestors were constitutively spliced. We show that relaxation of the 5' splice site during evolution is one of the molecular mechanisms by which exons shift from constitutive to alternative splicing. This shift is associated with the fixation of exonic splicing regulatory sequences (ESRs) that are essential for exon definition and control the inclusion level only after the transition to alternative splicing. The effect of each ESR on splicing and the combinatorial effects between two ESRs are conserved from fish to human. Our results uncover an evolutionary pathway that increases transcriptome diversity by shifting exons from constitutive to alternative splicing.
authors.affiliation: Department of Human Molecular Genetics, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Galit
authors.initials: G
authors.lastname: Lev-Maor
authors.forename: Amir
authors.initials: A
authors.lastname: Goren
authors.forename: Noa
authors.initials: N
authors.lastname: Sela
authors.forename: Eddo
authors.initials: E
authors.lastname: Kim
authors.forename: Hadas
authors.initials: H
authors.lastname: Keren
authors.forename: Adi
authors.initials: A
authors.lastname: Doron-Faigenboim
authors.forename: Shelly
authors.initials: S
authors.lastname: Leibman-Barak
authors.forename: Tal
authors.initials: T
authors.lastname: Pupko
authors.forename: Gil
authors.initials: G
authors.lastname: Ast
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D005075:Biological Evolution; D002460:Cell Line; D017124:Conserved Sequence; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005091:Exons / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D022821:RNA Splice Sites / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D037941:Silencer Elements, Transcriptional / Q000235:genetics; D013045:Species Specificity
chemical_list: D022821:RNA Splice Sites