title: Genome-wide identification of conserved regulatory function in diverged sequences.
abstract: Plasticity of gene regulatory encryption can permit DNA sequence divergence without loss of function. Functional information is preserved through conservation of the composition of transcription factor binding sites (TFBS) in a regulatory element. We have developed a method that can accurately identify pairs of functional noncoding orthologs at evolutionarily diverged loci by searching for conserved TFBS arrangements. With an estimated 5% false-positive rate (FPR) in approximately 3000 human and zebrafish syntenic loci, we detected approximately 300 pairs of diverged elements that are likely to share common ancestry and have similar regulatory activity. By analyzing a pool of experimentally validated human enhancers, we demonstrated that 7/8 (88%) of their predicted functional orthologs retained in vivo regulatory control. Moreover, in 5/7 (71%) of assayed enhancer pairs, we observed concordant expression patterns. We argue that TFBS composition is often necessary to retain and sufficient to predict regulatory function in the absence of overt sequence conservation, revealing an entire class of functionally conserved, evolutionarily diverged regulatory elements that we term "covert."
authors.affiliation: Computational Biology Branch, National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA.
authors.forename: Leila
authors.initials: L
authors.lastname: Taher
authors.forename: David M
authors.initials: DM
authors.lastname: McGaughey
authors.forename: Samantha
authors.initials: S
authors.lastname: Maragh
authors.forename: Ivy
authors.initials: I
authors.lastname: Aneas
authors.forename: Seneca L
authors.initials: SL
authors.lastname: Bessling
authors.forename: Webb
authors.initials: W
authors.lastname: Miller
authors.forename: Marcelo A
authors.initials: MA
authors.lastname: Nobrega
authors.forename: Andrew S
authors.initials: AS
authors.lastname: McCallion
authors.forename: Ivan
authors.initials: I
authors.lastname: Ovcharenko
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified / Q000235:genetics; D019295:Computational Biology / Q000379:methods; D017124:Conserved Sequence; D004742:Enhancer Elements, Genetic; D019143:Evolution, Molecular; D018507:Gene Expression Regulation, Developmental; D056426:Genetic Loci; D015894:Genome, Human; D006801:Humans; D008957:Models, Genetic; D020411:Oligonucleotide Array Sequence Analysis; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA / Q000379:methods*; D026801:Synteny; D014157:Transcription Factors / Q000235:genetics; D015027:Zebrafish / Q000235:genetics
chemical_list: D014157:Transcription Factors