Ivan Ovcharenko 's Research Group

	Computational Biology Branch

	Ivan Ovcharenko's Research Group

Research Projects

Group Members

Collaborations

Resources

Publications

Ivan Ovcharenko, Ph.D.
Investigator
Computational Biology Branch
National Center for Biotechnology Information (NCBI)
NLM, NIH, Building 38A, Room 6S602
8600 Rockville Pike, Bethesda, MD 20894
Phone: (301) 435-8944
Fax: (301) 480-2290
Email: ovcharei_AT_ncbi.nlm.nih.gov

Visitor information

Research Interests:

Comparative genomics and genome evolution
Semantics of the gene regulatory code
Disease associated noncoding mutations
Heart and brain gene regulatory networks

Open postdoctoral position.

Gene Regulation: From Sequence to Function, to Disease.

The research of the Ovcharenko group focuses on deciphering semantics and studying evolution of the gene regulatory code in eukaryotes.

With less than 2% of the human genome sequence being coding, the search for noncoding functional DNA is a guileless treasure hunt. We currently lack fundamental understanding of the genomic language that governs the temporal and spatial dynamics of gene expression regulation, native to every cell of a living creature. In an effort to breach the gap between the modern success in genome sequencing and sequencing data interpretation, we are developing pattern recognition methods to functionally characterize noncoding DNA. Our ultimate goal is to be able to use these methods in translating noncoding genome sequence into function.

Understanding the gene regulatory landscape of the human genome will open doors for studies of population variation in noncoding functional elements, thus promoting identification of disease-causing mutations residing outside of genes. Although one of the common hypotheses speculates that mutations in gene regulatory regions might be mainly linked to an increased susceptibility to disease, not necessarily resulting in disease, our research has a potential for mapping key regulatory elements in the vicinity of disease-linked genes. Availability of computationally defined datasets of human regulatory elements tailored to specific common diseases (including heart disease, obesity, diabetes, and cancer, for example) will permit designing novel disease susceptibility measurement methods, expressly targeting selected elements.

We utilize comparative genomics, Bayesian statistics, multiple sequence alignments, libraries of transcription factor binding sites, microarray gene expression data, sequence pattern recognition techniques, dynamic programming, population genetics, and transgenic animals experimentation (the latter through collaborations); all to infer the noncoding genome function through the analysis of sequence data and evolutionary trends. As part of our trust in interdisciplinary research, we heavily rely on our collaborative studies with several research and clinical groups within the NIH and from other research Universities and Institutions.

Group Members:
	Leelavati Narlikar	Computational modeling of enhancers. I am interested in understanding how far away regulatory regions--enhancers---control the tissue-specific activity of vertebrate genes. While it is known that enhancers harbor binding sites of transcription factors which drive the expression of specific genes, the identity and functionality of few enhancers are completely understood. By exploiting information from large-scale data such as sequence conservation and gene-expression, as well as data arising from small-scale experiments such as enhancer-reporter constructs, I am working towards modeling the architecture of tissue-specific enhancers. My goal is to accurately predict novel enhancers in the human genome using these models.
	Leila Taher	Alphabet of gene regulation. The main goal of my project is to design an alphabet for transcriptional regulation. Transcription factor binding sites can be modeled as combinations of letters representing binding specificities. Then, enhancers common to several sequences can be identified by looking for good alignments between these letters. Such a simple representation of the regulatory code will provide an original means to indirectly compare sequences of multiple species or co-expressed genes for which traditional methods are unable to detect any sequence homology.
	Valer Gotea	Primeval Gene Regulation in Vertebrates The clustering of transcription factor binding sites (TFBS), which provides a simple mechanism for transcriptional cis-regulation, is known to exist in organisms such as yeast and Drosophila. It is well known that vertebrate cis-regulatory modules (CRMs) also consist of TFBS clusters. I am interested in finding the extent and nuances of how vertebrates use the modularity of CRMs to establish the mechanisms of gene regulation. The redundancy offered by TFBS clusters can provide a robust regulatory mechanism for basic functional genes or transcription factors, but can also be used for regulating gene dosage or tissue specificity. Detailed knowledge of the use of this mechanism could ultimately reveal a basic regulatory network, conserved among vertebrates, on top of which specific complexity evolved.

Collaborative Projects:
	Dr. Len Pennacchio Lawrence Berkeley National Laboratory	Forebrain gene regulation. Computational analysis of sequence motifs specific to forebrain enhancers. Transgenic mouse experimentation.
	Dr. Gabriela Loots Lawrence Livermore National Laboratory	Bone development. Identification of bone development genes and gene regulatory elements. Characterization of limb, cartilage, and bone enhancer elements in transgenic frog, Xenopus tropicalis.
	Prof. John Rubenstein University of California, San Francisco	Forebrain development. Reconstruction of forebrain gene regulatory networks. Identification of upstream regulators responsible for the initiation of regulatory cascades in different sub-domains of the forebrain.
	Dr. David Klein NICHD, NIH	Pineal gland development. Using microarray data to identify enhancer elements and key transcription factors playing role in the pineal gland development.
	Prof. Marcelo Nobrega University of Chicago	Heart regulatory code. Coupled computational identification and experimental validation of gene regulatory elements partaking in the heart development. Transgenic zebrafish experimentation.
	Dr. Laura Elnitski NHGRI, NIH	Gene expression repressors. Identification of regulatory elements with repressor function in the human genome. Experimental validation of predicted liver repressors in Hep G2 cell lines.
	Prof. Webb Miller Penn State University	Genome evolution. Development of software resources for evolutionary studies. Comparative genomics analysis of variable gene desert evolution in eukaryotic genomes.
	Dr. John Spouge NCBI, NIH	Sequence pattern analysis. Development of computational methods to identify specific sequence patterns in gene regulatory elements with shared biological functions.

NCBI Dcode.org Comparative Genomics Developments

	DCODE.org	Dcode.org Comparative Genomics Center
	ECR Browser	Interactive browser of genome conservation and evolution
	SynoR	Genome scanner for gene regulatory elements with synonymous function
	Mulan	Multiple sequence alignment tool (TBA-based)
	zPicture	Pairwise sequence alignment tool (blastz-based)
	eShadow	Phylogenetic shadowing
	MultiTF	Identification of transcription factor binding sites (TFBS) conserved in multiple alignments
	rVista 2.0	Identification of TFBS conserved in pairwise alignments
	Creme 2.0	Cis-REgulatory Module Explorer
	Array2BIO	Integrative platform for the analysis of microarray data
	ECRbase	Database of evolutionary conserved regions (ECRs), promoters, and TFBS in vertebrate genomes

Selected Publications:

I. Ovcharenko, Widespread ultraconservation divergence in primates, Molecular Biology and Evolution, 25(8), 1668-1676 (2008) [PDF].

L.A. Pennacchio, G.G. Loots, M.A. Nobrega, and I. Ovcharenko, Predicting tissue-specific enhancers in the human genome, Genome Research, 17(2), 201-11 (2007) [PDF].

G.G. Loots and I. Ovcharenko, Dcode.org anthology of comparative genomic tools, Nucleic Acids Research, 33, W56-64, (2005) [PDF].

I. Ovcharenko, G.G. Loots, M.A. Nobrega, R.C. Hardison, W. Miller, and L. Stubbs, Evolution and functional classification of vertebrate gene deserts, Genome Research, 15, 137-145 (2005) [PDF]

I. Ovcharenko, L. Stubbs, and G.G. Loots, Interpreting mammalian evolution using Fugu genome comparisons, Genomics, 84(5), 890-895 (2004) [PDF]

M. Nobrega*, I. Ovcharenko*, V. Afzal, E. Rubin, Scanning Human Gene Deserts for Long-Range Enhancers, Science 302(5644), 413 (2003) [PDF]

D. Boffelli, J. MacAuliffe, D. Ovcharenko, K. Lewis, I. Ovcharenko, L. Pachter, E. Rubin, Phylogenetic analysis of primate sequences reveals functional regions of the human genome, Science, 299(5611), 1391-4, (2003) [PDF]

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Last modified: January 31, 2008