title: The complete local genotype-phenotype landscape for the alternative splicing of a human exon.
abstract: The properties of genotype-phenotype landscapes are crucial for understanding evolution but are not characterized for most traits. Here, we present a >95% complete local landscape for a defined molecular function-the alternative splicing of a human exon (FAS/CD95 exon 6, involved in the control of apoptosis). The landscape provides important mechanistic insights, revealing that regulatory information is dispersed throughout nearly every nucleotide in an exon, that the exon is more robust to the effects of mutations than its immediate neighbours in genotype space, and that high mutation sensitivity (evolvability) will drive the rapid divergence of alternative splicing between species unless it is constrained by selection. Moreover, the extensive epistasis in the landscape predicts that exonic regulatory sequences may diverge between species even when exon inclusion levels are functionally important and conserved by selection.
authors.affiliation: EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr Aiguader 88, Barcelona 08003, Spain.|Universitat Pompeu Fabra (UPF), Barcelona 08003, Spain.
authors.forename: Philippe
authors.initials: P
authors.lastname: Julien
authors.affiliation: Universitat Pompeu Fabra (UPF), Barcelona 08003, Spain.|Gene Regulation, Stem Cells and Cancer Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr Aiguader 88, Barcelona 08003, Spain.
authors.forename: Belén
authors.initials: B
authors.lastname: Miñana
authors.affiliation: EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr Aiguader 88, Barcelona 08003, Spain.|Universitat Pompeu Fabra (UPF), Barcelona 08003, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Baeza-Centurion
authors.affiliation: Universitat Pompeu Fabra (UPF), Barcelona 08003, Spain.|Gene Regulation, Stem Cells and Cancer Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr Aiguader 88, Barcelona 08003, Spain.|Institució Catalana de Recerca i Estudis Avançats (ICREA), Pg. Lluís Companys 23, 08010 Barcelona, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Valcárcel
authors.affiliation: EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr Aiguader 88, Barcelona 08003, Spain.|Universitat Pompeu Fabra (UPF), Barcelona 08003, Spain.|Institució Catalana de Recerca i Estudis Avançats (ICREA), Pg. Lluís Companys 23, 08010 Barcelona, Spain.
authors.forename: Ben
authors.initials: B
authors.lastname: Lehner
mesh_terms: D017398:Alternative Splicing; D001483:Base Sequence; D004843:Epistasis, Genetic; D019143:Evolution, Molecular; D005091:Exons; D056726:Genetic Association Studies; D057809:HEK293 Cells; D006801:Humans; D008957:Models, Genetic; D009154:Mutation; D012641:Selection, Genetic; D019014:fas Receptor / Q000235:genetics*
chemical_list: C491901:FAS protein, human; D019014:fas Receptor