PUBLICATION
Genome-wide identification of conserved regulatory function in diverged sequences
- Authors
- Taher, L., McGaughey, D.M., Maragh, S., Aneas, I., Bessling, S.L., Miller, W., Nobrega, M.A., McCallion, A.S., and Ovcharenko, I.
- ID
- ZDB-PUB-110609-41
- Date
- 2011
- Source
- Genome research 21(7): 1139-49 (Journal)
- Registered Authors
- McCallion, Andy
- Keywords
- none
- MeSH Terms
-
- Animals
- Animals, Genetically Modified/genetics
- Computational Biology/methods
- Conserved Sequence*
- Enhancer Elements, Genetic*
- Evolution, Molecular
- Gene Expression Regulation, Developmental*
- Genetic Loci
- Genome, Human
- Humans
- Models, Genetic
- Oligonucleotide Array Sequence Analysis
- Sequence Alignment
- Sequence Analysis, DNA/methods*
- Synteny
- Transcription Factors/genetics
- Zebrafish/genetics
- PubMed
- 21628450 Full text @ Genome Res.
Citation
Taher, L., McGaughey, D.M., Maragh, S., Aneas, I., Bessling, S.L., Miller, W., Nobrega, M.A., McCallion, A.S., and Ovcharenko, I. (2011) Genome-wide identification of conserved regulatory function in diverged sequences. Genome research. 21(7):1139-49.
Abstract
Genome-wide identification of conserved regulatory function in diverged sequences
Leila Taher1,
David M. McGaughey2,
Samantha Maragh2,3,
Ivy Aneas4,
Seneca L. Bessling2,
Webb Miller5,
Marcelo A. Nobrega4,
Andrew S. McCallion2,6 and
Ivan Ovcharenko1,6
+ Author Affiliations
1Computational Biology Branch, National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland 20894, USA;
2McKusick–Nathans Institute of Genetic Medicine, Department of Molecular and Comparative Pathobiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;
3Biochemical Science Division, National Institute of Standards and Technology, Gaithersburg, Maryland 20899, USA;
4Department of Human Genetics, University of Chicago, Chicago, Illinois 60637, USA;
5Center for Comparative Genomics and Bioinformatics, Pennsylvania State University, University Park, Pennsylvania 16802, USA
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.”
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping