title: Features of 5'-splice-site efficiency derived from disease-causing mutations and comparative genomics.
abstract: Many human diseases, including Fanconi anemia, hemophilia B, neurofibromatosis, and phenylketonuria, can be caused by 5'-splice-site (5'ss) mutations that are not predicted to disrupt splicing, according to position weight matrices. By using comparative genomics, we identify pairwise dependencies between 5'ss nucleotides as a conserved feature of the entire set of 5'ss. These dependencies are also conserved in human-mouse pairs of orthologous 5'ss. Many disease-associated 5'ss mutations disrupt these dependencies, as can some human SNPs that appear to alter splicing. The consistency of the evidence signifies the relevance of this approach and suggests that 5'ss SNPs play a role in complex diseases.
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
authors.forename: Xavier
authors.initials: X
authors.lastname: Roca
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Olson
authors.forename: Atmakuri R
authors.initials: AR
authors.lastname: Rao
authors.forename: Espen
authors.initials: E
authors.lastname: Enerly
authors.forename: Vessela N
authors.initials: VN
authors.lastname: Kristensen
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Børresen-Dale
authors.forename: Brage S
authors.initials: BS
authors.lastname: Andresen
authors.forename: Adrian R
authors.initials: AR
authors.lastname: Krainer
authors.forename: Ravi
authors.initials: R
authors.lastname: Sachidanandam
mesh_terms: D000818:Animals; D030561:Databases, Nucleic Acid; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D051379:Mice; D020641:Polymorphism, Single Nucleotide; D022821:RNA Splice Sites / Q000235:genetics*; D012326:RNA Splicing / Q000235:genetics*
chemical_list: D022821:RNA Splice Sites