title: De novo search for non-coding RNA genes in the AT-rich genome of Dictyostelium discoideum: performance of Markov-dependent genome feature scoring.
abstract: Genome data are increasingly important in the computational identification of novel regulatory non-coding RNAs (ncRNAs). However, most ncRNA gene-finders are either specialized to well-characterized ncRNA gene families or require comparisons of closely related genomes. We developed a method for de novo screening for ncRNA genes with a nucleotide composition that stands out against the background genome based on a partial sum process. We compared the performance when assuming independent and first-order Markov-dependent nucleotides, respectively, and used Karlin-Altschul and Karlin-Dembo statistics to evaluate the significance of hits. We hypothesized that a first-order Markov-dependent process might have better power to detect ncRNA genes since nearest-neighbor models have been shown to be successful in predicting RNA structures. A model based on a first-order partial sum process (analyzing overlapping dinucleotides) had better sensitivity and specificity than a zeroth-order model when applied to the AT-rich genome of the amoeba Dictyostelium discoideum. In this genome, we detected 94% of previously known ncRNA genes (at this sensitivity, the false positive rate was estimated to be 25% in a simulated background). The predictions were further refined by clustering candidate genes according to sequence similarity and/or searching for an ncRNA-associated upstream element. We experimentally verified six out of 10 tested ncRNA gene predictions. We conclude that higher-order models, in combination with other information, are useful for identification of novel ncRNA gene families in single-genome analysis of D. discoideum. Our generalizable approach extends the range of genomic data that can be searched for novel ncRNA genes using well-grounded statistical methods.
authors.affiliation: Department of Cell and Molecular Biology, Biomedical Center, Uppsala University, SE-75124 Uppsala, Sweden.
authors.forename: Pontus
authors.initials: P
authors.lastname: Larsson
authors.forename: Andrea
authors.initials: A
authors.lastname: Hinas
authors.forename: David H
authors.initials: DH
authors.lastname: Ardell
authors.forename: Leif A
authors.initials: LA
authors.lastname: Kirsebom
authors.forename: Anders
authors.initials: A
authors.lastname: Virtanen
authors.forename: Fredrik
authors.initials: F
authors.lastname: Söderbom
mesh_terms: D000225:Adenine / Q000032:analysis; D000818:Animals; D001482:Base Composition; D001483:Base Sequence; D017124:Conserved Sequence; D004023:Dictyostelium / Q000235:genetics*; D017125:Genes, Protozoan; D018503:Genome, Protozoan; D023281:Genomics / Q000379:methods*; D008390:Markov Chains; D008969:Molecular Sequence Data; D005810:Multigene Family; D009711:Nucleotides / Q000032:analysis; D022661:RNA, Untranslated / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D013941:Thymine / Q000032:analysis
chemical_list: D009711:Nucleotides; D022661:RNA, Untranslated; D000225:Adenine; D013941:Thymine