title: Locating protein-coding sequences under selection for additional, overlapping functions in 29 mammalian genomes.
abstract: The degeneracy of the genetic code allows protein-coding DNA and RNA sequences to simultaneously encode additional, overlapping functional elements. A sequence in which both protein-coding and additional overlapping functions have evolved under purifying selection should show increased evolutionary conservation compared to typical protein-coding genes--especially at synonymous sites. In this study, we use genome alignments of 29 placental mammals to systematically locate short regions within human ORFs that show conspicuously low estimated rates of synonymous substitution across these species. The 29-species alignment provides statistical power to locate more than 10,000 such regions with resolution down to nine-codon windows, which are found within more than a quarter of all human protein-coding genes and contain ∼2% of their synonymous sites. We collect numerous lines of evidence that the observed synonymous constraint in these regions reflects selection on overlapping functional elements including splicing regulatory elements, dual-coding genes, RNA secondary structures, microRNA target sites, and developmental enhancers. Our results show that overlapping functional elements are common in mammalian genes, despite the vast genomic landscape.
authors: Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors: Michael F
authors: MF
authors: Lin
authors: Pouya
authors: P
authors: Kheradpour
authors: Stefan
authors: S
authors: Washietl
authors: Brian J
authors: BJ
authors: Parker
authors: Jakob S
authors: JS
authors: Pedersen
authors: Manolis
authors: M
authors: Kellis
mesh_terms: D000818:Animals; D001482:Base Composition; D001483:Base Sequence; D003062:Codon; D018387:Codon, Initiator; D019295:Computational Biology; D017124:Conserved Sequence; D004742:Enhancer Elements, Genetic; D005091:Exons; D023061:Gene Order; D019398:Genes, BRCA1; D016678:Genome; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008322:Mammals / Q000235:genetics*; D035683:MicroRNAs / Q000378:metabolism; D008969:Molecular Sequence Data; D059645:Mutation Rate; D009690:Nucleic Acid Conformation; D009707:Nucleosomes / Q000378:metabolism; D016366:Open Reading Frames / Q000235:genetics*; D010442:Peptide Chain Initiation, Translational; D012326:RNA Splicing; D012641:Selection, Genetic; D016415:Sequence Alignment; D014158:Transcription, Genetic
chemical_list: D003062:Codon; D018387:Codon, Initiator; D018398:Homeodomain Proteins; D035683:MicroRNAs; D009707:Nucleosomes