title: Distinguishing regulatory DNA from neutral sites.
abstract: We explore several computational approaches to analyzing interspecies genomic sequence alignments, aiming to distinguish regulatory regions from neutrally evolving DNA. Human-mouse genomic alignments were collected for three sets of human regions: (1) experimentally defined gene regulatory regions, (2) well-characterized exons (coding sequences, as a positive control), and (3) interspersed repeats thought to have inserted before the human-mouse split (a good model for neutrally evolving DNA). Models that potentially could distinguish functional noncoding sequences from neutral DNA were evaluated on these three data sets, as well as bulk genome alignments. Our analyses show that discrimination based on frequencies of individual nucleotide pairs or gaps (i.e., of possible alignment columns) is only partially successful. In contrast, scoring procedures that include the alignment context, based on frequencies of short runs of alignment columns, dramatically improve separation between regulatory and neutral features. Such scoring functions should aid in the identification of putative regulatory regions throughout the human genome.
authors.affiliation: Departments of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Elnitski
authors.forename: Ross C
authors.initials: RC
authors.lastname: Hardison
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.forename: Shan
authors.initials: S
authors.lastname: Yang
authors.forename: Diana
authors.initials: D
authors.lastname: Kolbe
authors.forename: Pallavi
authors.initials: P
authors.lastname: Eswara
authors.forename: Michael J
authors.initials: MJ
authors.lastname: O'Connor
authors.forename: Scott
authors.initials: S
authors.lastname: Schwartz
authors.forename: Webb
authors.initials: W
authors.lastname: Miller
authors.forename: Francesca
authors.initials: F
authors.lastname: Chiaromonte
mesh_terms: D000818:Animals; D001482:Base Composition / Q000235:genetics; D020029:Base Pairing / Q000235:genetics; D019295:Computational Biology / Q000379:methods; D004247:DNA / Q000235:genetics*; D019143:Evolution, Molecular; D005091:Exons / Q000235:genetics; D006801:Humans; D020071:Interspersed Repetitive Sequences / Q000235:genetics; D051379:Mice; D008957:Models, Genetic; D009711:Nucleotides / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D016415:Sequence Alignment / Q000379:methods
chemical_list: D009711:Nucleotides; D004247:DNA