CpG islands, clusters of CpG dinucleotides in GC-rich regions, are often located in the 5'end of genes and are considered gene markers in mammalian genomes. Experiments have shown that methylation of promoter CpG islands plays an important role in gene silencing, genomic imprinting, X-chromosome inactivation, and carcinogenesis. Although many studies have been performed to identify CpG islands, to estimate the CpG mutation rates, and to examine the methylation modulation on disease genes, little is known about the distribution of CpG islands in the specific genomic regions across mammalian genomes or the pattern of genetic variation in CpG islands or in promoter-associated CpG islands. In addition, how CpG islands in mammalian genomes evolved and which kind of genes tend to gain or lose CpG islands remains largely unknown to us. The recent releases of several mammalian genomes, the discovery of millions of single nucleotide polymorphisms (SNPs) in these genomes, and large-scale methylation status data in the human genome provide us with an unprecedented opportunity to examine these issues in details. In this project, we will first perform a comprehensive survey of the distribution of CpG islands in five mammalian genomes (human, chimpanzee, mouse, rat, and dog) and their genomic regions. We will compare the features of CpG islands in the housekeeping genes with those in tissue-specific genes and compare the distribution and features of CpG islands in different categories of Gene Ontology (GO). Second, we will examine mutation patterns in CpG islands in four genomes (human, chimpanzee, mouse, and dog), each of which has more than 1 million SNPs. Third, we will investigate the mechanisms of CpG island evolution in mammalian genomes and to infer its effect on gene function. One approach is to examine the mutation pattern (e.g., CpG??TpG/CpA) and sequence features in each segment of CpG islands. Using the HapMap SNPs with their allele frequencies, we will test the possible natural selection in CpG islands. Finally, we will test the hypothesis that there is a relationship between CpG island loss and methylation status in CpG islands. Our comparative genomics and biomedical informatics analyses will provide a detailed view of the CpG island distribution in mammalian genomes, the mechanisms of CpG island evolution, and the relationship of the mutation pattern in CpG islands with functional categories of genes, especially cancer-related genes.

Agency
National Institute of Health (NIH)
Institute
National Library of Medicine (NLM)
Type
Small Research Grants (R03)
Project #
7R03LM009598-02
Application #
7679715
Study Section
Biomedical Library and Informatics Review Committee (BLR)
Program Officer
Ye, Jane
Project Start
2008-09-01
Project End
2011-08-31
Budget Start
2009-09-01
Budget End
2011-08-31
Support Year
2
Fiscal Year
2009
Total Cost
$77,500
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Zheng, Siyuan; Zhao, Zhongming (2012) DNA methylation profiling distinguishes three clusters of breast cancer cell lines. Chem Biodivers 9:848-56
Xia, Junfeng; Sun, Jingchun; Jia, Peilin et al. (2011) Do cancer proteins really interact strongly in the human protein-protein interaction network? Comput Biol Chem 35:121-5
Su, Zhixi; Xia, Junfeng; Zhao, Zhongming (2011) Functional complementation between transcriptional methylation regulation and post-transcriptional microRNA regulation in the human genome. BMC Genomics 12 Suppl 5:S15
Su, Zhixi; Han, Leng; Zhao, Zhongming (2011) Conservation and divergence of DNA methylation in eukaryotes: new insights from single base-resolution DNA methylomes. Epigenetics 6:134-40
Sun, Jingchun; Han, Leng; Zhao, Zhongming (2010) Gene- and evidence-based candidate gene selection for schizophrenia and gene feature analysis. Artif Intell Med 48:99-106
Guo, An-Yuan; Sun, Jingchun; Jia, Peilin et al. (2010) Network analysis of EtOH-related candidate genes. Chem Biodivers 7:1142-52
Jia, P; Sun, J; Guo, A Y et al. (2010) SZGR: a comprehensive schizophrenia gene resource. Mol Psychiatry 15:453-62
Zhao, Zhongming; Jiang, Cizhong (2010) Features of recent codon evolution: a comparative polymorphism-fixation study. J Biomed Biotechnol 2010:202918
Sun, Jingchun; Zhao, Zhongming (2010) Functional features, biological pathways, and protein interaction networks of addiction-related genes. Chem Biodivers 7:1153-62
Sun, Jingchun; Zhao, Zhongming (2010) A comparative study of cancer proteins in the human protein-protein interaction network. BMC Genomics 11 Suppl 3:S5

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