Person: Lee, Charles
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Lee, Charles
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Publication 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, CharlesCopy 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.Publication 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, DavidHuman 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.Publication EGFRMutation Is a Better Predictor of Response to Tyrosine Kinase Inhibitors in Non–Small Cell Lung Carcinoma Than FISH, CISH, and Immunohistochemistry(Oxford University Press (OUP), 2010) Sholl, Lynette; Xiao, Yun; Joshi, Victoria; Yeap, Beow; Cioffredi, Leigh-Anne; Jackman, David M; Lee, Charles; Janne, Pasi; Lindeman, NealAbout 10% of patients with non–small cell lung carcinoma (NSCLC) respond to epidermal growth factor receptor (EGFR)-targeted tyrosine kinase inhibitors (TKIs). More than 75% of “responders” have activating mutations in EGFR. However, mutation analysis is not widely available, and proposed alternatives (in situ hybridization and immunohistochemical analysis) have shown inconsistent associations with outcome. Fluorescence in situ hybridization (FISH), chromogenic in situ hybridization (CISH), immunohistochemical analysis, and DNA sequencing were compared in this study of 40 NSCLC samples from TKI-treated patients. Response rates were 12 of 19 in EGFR-mutant vs 1 of 20 EGFR wild-type tumors (P = .0001), 7 of 19 FISH+ vs 4 of 17 FISH– tumors (not significant [NS]), 5 of 16 CISH+ vs 6 of 21 CISH– tumors (NS), and 3 of 9 immunohistochemically positive vs 7 of 22 immunohistochemically negative tumors (NS). EGFR mutation was associated with improved progression-free survival (P = .0004). Increased copy number (FISH or CISH) and protein expression (immunohistochemical) did not independently predict outcome. Thus, EGFR sequence analysis was the only method useful for predicting response and progression-free survival following TKI therapy in NSCLC.Publication Investor Sentiment and the Closed-End Fund Puzzle(Wiley, 1991) Lee, Charles; Shleifer, Andrei; Thaler, Richard H.This paper examines the proposition that fluctuations in discounts on closed end funds are driven by changes in individual investor sentiment toward closed end funds and other securities. The theory implies that discounts on various funds must move together, that new funds get started when seasoned funds sell at a premium or a small discount, and that discounts on the funds fluctuate together with prices of securities affected by the same investor sentiment. The evidence supports these predictions. In particular, we find that discounts on closed end funds narrow when small stocks do well, as would be expected if closed end funds were subject to the same sentiment as small stocks, whim tern. also to be held by individual investors. The evidence thus suggests that investor sentiment affects security returns.Publication ROS1 Immunohistochemistry for Detection of ROS1-Rearranged Lung Adenocarcinomas(Ovid Technologies (Wolters Kluwer Health), 2013) Sholl, Lynette; Sun, Heather; Butaney, Mohit; Zhang, Chengsheng; Lee, Charles; Janne, Pasi; Rodig, ScottROS1 gene rearrangements are reported in 1–2% of lung adenocarcinomas (ACA) and are associated with response to the multitargeted tyrosine kinase inhibitor, crizotinib. ROS1 rearrangements can be detected using fluorescence in situ hybridization (FISH) however immunohistochemistry (IHC) for ROS1 protein is a promising alternate screening modality. In this study we examine the correlation between ROS1 IHC and FISH and describe the clinicopathologic characteristics of ROS1-rearranged lung tumors. ROS1 IHC was performed using clone D4D6 (Cell Signaling Technology, Danvers, MA) on whole tissue sections. In a validation cohort, IHC was compared to ROS1 break-apart FISH in 53 cases of lung ACA enriched for an absence of known genetic alterations and never-smoking status. In a screening cohort, we performed ROS1 IHC on 167 consecutive cases of lung ACA from a routine molecular diagnostics practice and confirmed positive results by FISH. In the validation cohort, 6 cases (11%) were both FISH and IHC positive. One FISH-negative case was strongly ROS1 IHC positive. All IHC negative cases were FISH negative. In the screening cohort, 2 of 167 (1.2%) had strong, diffuse ROS1 protein expression; a rearrangement was confirmed by FISH in both. ROS1-translocated tumors were wild type for EGFR, KRAS, and ALK and commonly had solid growth with mucinous/cribriform features and psammomatous calcification. ROS1 protein expression in tumor cells is 100% sensitive and 92% specific for ROS1 rearrangements by FISH. ROS1 IHC is an effective screening tool for this rare but clinically important subset of lung ACA.Publication Anomalies: Closed-End Mutual Funds(American Economic Association, 1990) Lee, Charles; Shleifer, Andrei; Thaler, Richard HPublication Comprehensive genomic analyses associate UGT8 variants with musical ability in a Mongolian population(BMJ Publishing Group, 2012) Park, Hansoo; Lee, Seungbok; Kim, Hyun-Jin; Ju, Young Seok; Shin, Jong-Yeon; Hong, Dongwan; von Grotthuss, Marcin; Lee, Dong-Sung; Park, Changho; Kim, Jennifer; Kim, Boram; Yoo, Yun Joo; Cho, Sung-Il; Sung, Joohon; Lee, Charles; Kim, Jong-Il; Seo, Jeong-SunBackground: Musical abilities such as recognising music and singing performance serve as means for communication and are instruments in sexual selection. Specific regions of the brain have been found to be activated by musical stimuli, but these have rarely been extended to the discovery of genes and molecules associated with musical ability. Methods: A total of 1008 individuals from 73 families were enrolled and a pitch-production accuracy test was applied to determine musical ability. To identify genetic loci and variants that contribute to musical ability, we conducted family-based linkage and association analyses, and incorporated the results with data from exome sequencing and array comparative genomic hybridisation analyses. Results: We found significant evidence of linkage at 4q23 with the nearest marker D4S2986 (LOD=3.1), whose supporting interval overlaps a previous study in Finnish families, and identified an intergenic single nucleotide polymorphism (SNP) \((rs1251078, p=8.4×10^{−17})\) near UGT8, a gene highly expressed in the central nervous system and known to act in brain organisation. In addition, a non-synonymous SNP in UGT8 was revealed to be highly associated with musical ability \((rs4148254, p=8.0×10^{−17})\), and a 6.2 kb copy number loss near UGT8 showed a plausible association with musical ability \((p=2.9×10^{−6})\). Conclusions: This study provides new insight into the genetics of musical ability, exemplifying a methodology to assign functional significance to synonymous and non-coding alleles by integrating multiple experimental methods.Publication Complex Reorganization and Predominant Non-Homologous Repair Following Chromosomal Breakage in Karyotypically Balanced Germline Rearrangements and Transgenic Integration(Nature Publishing Group, 2012) Chiang, Colby; Jacobsen, Jessie C.; Ernst, Carl; Hanscom, Carrie; Heilbut, Adrian; Blumenthal, Ian; Mills, Ryan E.; Kirby, Andrew; Rudiger, Skye R.; McLaughlan, Clive J.; Bawden, C. Simon; Reid, Suzanne J.; Faull, Richard L. M.; Snell, Russell G.; Hall, Ira M.; Ohsumi, Toshiro K.; Shen, Yiping; Borowsky, Mark L; Daly, Mark; Lee, Charles; Morton, Cynthia; MacDonald, Marcy; Gusella, James; Talkowski, Michael; Lindgren, Amelia M.We defined the genetic landscape of balanced chromosomal rearrangements at nucleotide resolution by sequencing 141 breakpoints from cytogenetically-interpreted translocations and inversions. We confirm that the recently described phenomenon of “chromothripsis” (massive chromosomal shattering and reorganization) is not unique to cancer cells but also occurs in the germline where it can resolve to a karyotypically balanced state with frequent inversions. We detected a high incidence of complex rearrangements (19.2%) and substantially less reliance on microhomology (31%) than previously observed in benign CNVs. We compared these results to experimentally-generated DNA breakage-repair by sequencing seven transgenic animals, and revealed extensive rearrangement of the transgene and host genome with similar complexity to human germline alterations. Inversion is the most common rearrangement, suggesting that a combined mechanism involving template switching and non-homologous repair mediates the formation of balanced complex rearrangements that are viable, stably replicated and transmitted unaltered to subsequent generations.Publication Balancing Selection on a Regulatory Region Exhibiting Ancient Variation That Predates Human–Neandertal Divergence(Public Library of Science, 2013) Gokcumen, Omer; Zhu, Qihui; Mulder, Lubbertus C. F.; Iskow, Rebecca C.; Austermann, Christian; Scharer, Christopher D.; Raj, Towfique; Boss, Jeremy M.; Sunyaev, Shamil; Price, Alkes; Stranger, Barbara; Simon, Viviana; Lee, CharlesAncient population structure shaping contemporary genetic variation has been recently appreciated and has important implications regarding our understanding of the structure of modern human genomes. We identified a ∼36-kb DNA segment in the human genome that displays an ancient substructure. The variation at this locus exists primarily as two highly divergent haplogroups. One of these haplogroups (the NE1 haplogroup) aligns with the Neandertal haplotype and contains a 4.6-kb deletion polymorphism in perfect linkage disequilibrium with 12 single nucleotide polymorphisms (SNPs) across diverse populations. The other haplogroup, which does not contain the 4.6-kb deletion, aligns with the chimpanzee haplotype and is likely ancestral. Africans have higher overall pairwise differences with the Neandertal haplotype than Eurasians do for this NE1 locus (p<10−15). Moreover, the nucleotide diversity at this locus is higher in Eurasians than in Africans. These results mimic signatures of recent Neandertal admixture contributing to this locus. However, an in-depth assessment of the variation in this region across multiple populations reveals that African NE1 haplotypes, albeit rare, harbor more sequence variation than NE1 haplotypes found in Europeans, indicating an ancient African origin of this haplogroup and refuting recent Neandertal admixture. Population genetic analyses of the SNPs within each of these haplogroups, along with genome-wide comparisons revealed significant FST (p = 0.00003) and positive Tajima's D (p = 0.00285) statistics, pointing to non-neutral evolution of this locus. The NE1 locus harbors no protein-coding genes, but contains transcribed sequences as well as sequences with putative regulatory function based on bioinformatic predictions and in vitro experiments. We postulate that the variation observed at this locus predates Human–Neandertal divergence and is evolving under balancing selection, especially among European populations.Publication Refinement of Primate Copy Number Variation Hotspots Identifies Candidate Genomic Regions Evolving Under Positive Selection(BioMed Central, 2011) Babb, Paul L; Iskow, Rebecca C; Mills, Ryan E; Ionita-Laza, Iuliana; Gokcumen, Omer; Zhu, Qihui; Shi, Xinghua; Vallender, Eric; Clark, Andrew G.; Johnson, Welkin Eric; Lee, CharlesBackground: Copy number variants (CNVs), defined as losses and gains of segments of genomic DNA, are a major source of genomic variation. Results: In this study, we identified over 2,000 human CNVs that overlap with orthologous chimpanzee or orthologous macaque CNVs. Of these, 170 CNVs overlap with both chimpanzee and macaque CNVs, and these were collapsed into 34 hotspot regions of CNV formation. Many of these hotspot regions of CNV formation are functionally relevant, with a bias toward genes involved in immune function, some of which were previously shown to evolve under balancing selection in humans. The genes in these primate CNV formation hotspots have significant differential expression levels between species and show evidence for positive selection, indicating that they have evolved under species-specific, directional selection. Conclusions: These hotspots of primate CNV formation provide a novel perspective on divergence and selective pressures acting on these genomic regions.