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Brown, Kim H.

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Brown

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Kim H.

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Brown, Kim H.

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2012 - 20132

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Author's Publications: search.filters.isAuthorOfPublication.38244dba-3fc2-45b6-97d1-c92615923522

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    Extensive Genetic Diversity and Substructuring Among Zebrafish Strains Revealed through Copy Number Variant Analysis
    (Proceedings of the National Academy of Sciences, 2012) Brown, Kim H.; Dobrinski, Kimberly P.; Lee, Arthur S.; Gokcumen, Omer; Mills, Ryan Edward; Shi, Xinghua; Chong, Wilson W. S.; Chen, Jin Yun Helen; Yoo, Paulo; David, Sthuthi; Peterson, Samuel M.; Raj, Towfique; Choy, Kwong Wai; Stranger, Barbara Elaine; Williamson, Robin E.; Zon, Leonard; Freeman, Jennifer L.; Lee, Charles
    Copy number variants (CNVs) represent a substantial source of genomic variation in vertebrates and have been associated with numerous human diseases. Despite this, the extent of CNVs in the zebrafish, an important model for human disease, remains unknown. Using 80 zebrafish genomes, representing three commonly used laboratory strains and one native population, we constructed a genome-wide, high-resolution CNV map for the zebrafish comprising 6,080 CNV elements and encompassing 14.6% of the zebrafish reference genome. This amount of copy number variation is four times that previously observed in other vertebrates, including humans. Moreover, 69% of the CNV elements exhibited strain specificity, with the highest number observed for Tubingen. This variation likely arose, in part, from Tubingen's large founding size and composite population origin. Additional population genetic studies also provided important insight into the origins and substructure of these commonly used laboratory strains. This extensive variation among and within zebrafish strains may have functional effects that impact phenotype and, if not properly addressed, such extensive levels of germ-line variation and population substructure in this commonly used model organism can potentially confound studies intended for translation to human diseases.
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    Cross-Species Array Comparative Genomic Hybridization Identifies Novel Oncogenic Events in Zebrafish and Human Embryonal Rhabdomyosarcoma
    (Public Library of Science, 2013) Chen, Eleanor Y.; Dobrinski, Kimberly P.; Brown, Kim H.; Clagg, Ryan; Edelman, Elena; Ignatius, Myron S.; Chen, Jin Yun Helen; Brockmann, Jillian; Nielsen, G. Petur; Ramaswamy, Sridhar; Keller, Charles; Lee, Charles; Langenau, David
    Human cancer genomes are highly complex, making it challenging to identify specific drivers of cancer growth, progression, and tumor maintenance. To bypass this obstacle, we have applied array comparative genomic hybridization (array CGH) to zebrafish embryonal rhabdomyosaroma (ERMS) and utilized cross-species comparison to rapidly identify genomic copy number aberrations and novel candidate oncogenes in human disease. Zebrafish ERMS contain small, focal regions of low-copy amplification. These same regions were commonly amplified in human disease. For example, 16 of 19 chromosomal gains identified in zebrafish ERMS also exhibited focal, low-copy gains in human disease. Genes found in amplified genomic regions were assessed for functional roles in promoting continued tumor growth in human and zebrafish ERMS – identifying critical genes associated with tumor maintenance. Knockdown studies identified important roles for Cyclin D2 (CCND2), Homeobox Protein C6 (HOXC6) and PlexinA1 (PLXNA1) in human ERMS cell proliferation. PLXNA1 knockdown also enhanced differentiation, reduced migration, and altered anchorage-independent growth. By contrast, chemical inhibition of vascular endothelial growth factor (VEGF) signaling reduced angiogenesis and tumor size in ERMS-bearing zebrafish. Importantly, VEGFA expression correlated with poor clinical outcome in patients with ERMS, implicating inhibitors of the VEGF pathway as a promising therapy for improving patient survival. Our results demonstrate the utility of array CGH and cross-species comparisons to identify candidate oncogenes essential for the pathogenesis of human cancer.