Abstract

Disorders of the cardiovascular (CV) system are frequently due to temporal or quantitative changes in the expression of a large, but finite set of genes. Noncoding cis regulatory sequences play a central role in controlling gene expression and inter-species (i.e., human/mouse) genomic sequence comparisons serve as a rapid and accurate means for identifying such noncoding regulatory elements. The central goal of this PGA will be to use a comparative genomic approach first to identify, and them to determine the function of elements regulating the expression of genes affecting the CV system. The activities of this PGA are not centered on the discovery of new genes, but rather upon using comparative genomics to understand the role of cis regulating elements in the expression of genes already being studied by CV researchers. In this integrated program to """"""""genomically"""""""" explore the regulation of CV genes, 200 human genomic intervals (=~200 BACs), each containing a CV gene(s), will be comparatively characterized. The components of this program will include: (1) The acquisition of orthologous human/mouse and other mammalian genomic sequence for a set of prioritized CV genes. Sequences will either be accessed from publicly funded databases or generated by the sequencing component of this PGA. (2) The creation of a cardiovascular comparative genomic database that will contain extensively annotated human and mouse sequences including the localization of conserved noncoding elements in proximity to well studied CV genes. (3) Genome-wide expression profiling to discover genes co-regulated with CV genes and identify shared noncoding regulatory elements, through intra-species analysis. (4) The identification of SNPs within conserved non- coding sequences, and analysis of their effect on CV gene expression in humans. (5) Analysis in genetically engineered mice of a prioritized set of the conserved noncoding elements for their role in CV gene expression. (6) The establishment of an educational program for cardiovascular researchers in the use of genomic databases and tools.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01HL066728-03
Application #
6527838
Study Section
Special Emphasis Panel (ZHL1-CSR-L (S2))
Program Officer
Applebaum-Bowden, Deborah
Project Start
2000-09-30
Project End
2004-07-31
Budget Start
2002-08-01
Budget End
2003-07-31
Support Year
3
Fiscal Year
2002
Total Cost
$940,397
Indirect Cost

  Institution

Name
Lawrence Berkeley National Laboratory
Department
Type
Organized Research Units
DUNS #
078576738
City
Berkeley
State
CA
Country
United States
Zip Code
94720

  Publications

Saha, Nil Ratan; Ota, Tatsuya; Litman, Gary W et al. (2014) Genome complexity in the coelacanth is reflected in its adaptive immune system. J Exp Zool B Mol Dev Evol 322:438-63
Crow, Karen D; Smith, Christopher D; Cheng, Jan-Fang et al. (2012) An independent genome duplication inferred from Hox paralogs in the American paddlefish--a representative basal ray-finned fish and important comparative reference. Genome Biol Evol 4:937-53
Raphael, Benjamin J; Volik, Stanislav; Yu, Peng et al. (2008) A sequence-based survey of the complex structural organization of tumor genomes. Genome Biol 9:R59
Crawford, Dana C; Nord, Alex S; Badzioch, Michael D et al. (2008) A common VLDLR polymorphism interacts with APOE genotype in the prediction of carotid artery disease risk. J Lipid Res 49:588-96
Crawford, Dana C; Zimmer, Shanta M; Morin, Craig A et al. (2008) Integrating host genomics with surveillance for invasive bacterial diseases. Emerg Infect Dis 14:1138-40
Crawford, Dana C; Peng, Ze; Cheng, Jan-Fang et al. (2008) LPA and PLG sequence variation and kringle IV-2 copy number in two populations. Hum Hered 66:199-209
Volik, Stanislav; Raphael, Benjamin J; Huang, Guiqing et al. (2006) Decoding the fine-scale structure of a breast cancer genome and transcriptome. Genome Res 16:394-404
Margulies, Elliott H; NISC Comparative Sequencing Program; Maduro, Valerie V B et al. (2005) Comparative sequencing provides insights about the structure and conservation of marsupial and monotreme genomes. Proc Natl Acad Sci U S A 102:3354-9
Hughes, Jim R; Cheng, Jan-Fang; Ventress, Nicki et al. (2005) Annotation of cis-regulatory elements by identification, subclassification, and functional assessment of multispecies conserved sequences. Proc Natl Acad Sci U S A 102:9830-5
Krauss, Ronald M (2005) Dietary and genetic probes of atherogenic dyslipidemia. Arterioscler Thromb Vasc Biol 25:2265-72

Showing the most recent 10 out of 17 publications