title: Correlated Evolution of Nucleotide Positions within Splice Sites in Mammals.
abstract: Splice sites (SSs)--short nucleotide sequences flanking introns--are under selection for spliceosome binding, and adhere to consensus sequences. However, non-consensus nucleotides, many of which probably reduce SS performance, are frequent. Little is known about the mechanisms maintaining such apparently suboptimal SSs. Here, we study the correlations between strengths of nucleotides occupying different positions of the same SS. Such correlations may arise due to epistatic interactions between positions (i.e., a situation when the fitness effect of a nucleotide in one position depends on the nucleotide in another position), their evolutionary history, or to other reasons. Within both the intronic and the exonic parts of donor SSs, nucleotides that increase (decrease) SS strength tend to co-occur with other nucleotides increasing (respectively, decreasing) it, consistent with positive epistasis. Between the intronic and exonic parts of donor SSs, the correlations of nucleotide strengths tend to be negative, consistent with negative epistasis. In the course of evolution, substitutions at a donor SS tend to decrease the strength of its exonic part, and either increase or do not change the strength of its intronic part. In acceptor SSs, the situation is more complicated; the correlations between adjacent positions appear to be driven mainly by avoidance of the AG dinucleotide which may cause aberrant splicing. In summary, both the content and the evolution of SSs is shaped by a complex network of interdependences between adjacent nucleotides that respond to a range of sometimes conflicting selective constraints.
authors.affiliation: A. A. Kharkevich Insitute for Information Transmission Problems RAS, Moscow, Russia.
authors.forename: Stepan
authors.initials: S
authors.lastname: Denisov
authors.affiliation: A. A. Kharkevich Insitute for Information Transmission Problems RAS, Moscow, Russia.|Faculty of Bioengineering and Bioinformatics, M. V. Lomonosov Moscow State University, Moscow, Russia.
authors.forename: Georgii
authors.initials: G
authors.lastname: Bazykin
authors.affiliation: Division of Oncology Biostatistics, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, United States of America.|Laboratory of System Biology and Computational Genetics, Department of Computational System Biology, N. I. Vavilov Institute of General Genetics, Moscow, Russia.|Laboratory of Bioinformatics, State Research Institute of Genetics and Selection of Industrial Microorganism (GosNIIGenetika), Moscow, Russia.
authors.forename: Alexander
authors.initials: A
authors.lastname: Favorov
authors.affiliation: A. A. Kharkevich Insitute for Information Transmission Problems RAS, Moscow, Russia.|Faculty of Bioengineering and Bioinformatics, M. V. Lomonosov Moscow State University, Moscow, Russia.
authors.forename: Andrey
authors.initials: A
authors.lastname: Mironov
authors.affiliation: A. A. Kharkevich Insitute for Information Transmission Problems RAS, Moscow, Russia.|Faculty of Bioengineering and Bioinformatics, M. V. Lomonosov Moscow State University, Moscow, Russia.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Gelfand
mesh_terms: D000465:Algorithms; D000818:Animals; D001483:Base Sequence; D005075:Biological Evolution; D016384:Consensus Sequence / Q000235:genetics*; D030561:Databases, Nucleic Acid; D004285:Dogs; D019143:Evolution, Molecular; D005091:Exons / Q000235:genetics*; D016678:Genome / Q000235:genetics; D006801:Humans; D007438:Introns / Q000235:genetics*; D051379:Mice; D009711:Nucleotides / Q000235:genetics; D022821:RNA Splice Sites / Q000235:genetics*; D012326:RNA Splicing / Q000235:genetics; D017381:Spliceosomes / Q000235:genetics*
chemical_list: D009711:Nucleotides; D022821:RNA Splice Sites