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Dive into the research topics where Vivian G. Cheung is active.

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Featured researches published by Vivian G. Cheung.


Nature | 2004

Genetic analysis of genome-wide variation in human gene expression

Michael Morley; Cliona M. Molony; Teresa M. Weber; James L. Devlin; Kathryn G. Ewens; Richard S. Spielman; Vivian G. Cheung

Natural variation in gene expression is extensive in humans and other organisms, and variation in the baseline expression level of many genes has a heritable component. To localize the genetic determinants of these quantitative traits (expression phenotypes) in humans, we used microarrays to measure gene expression levels and performed genome-wide linkage analysis for expression levels of 3,554 genes in 14 large families. For approximately 1,000 expression phenotypes, there was significant evidence of linkage to specific chromosomal regions. Both cis- and trans-acting loci regulate variation in the expression levels of genes, although most act in trans. Many gene expression phenotypes are influenced by several genetic determinants. Furthermore, we found hotspots of transcriptional regulation where significant evidence of linkage for several expression phenotypes (up to 31) coincides, and expression levels of many genes that share the same regulatory region are significantly correlated. The combination of microarray techniques for phenotyping and linkage analysis for quantitative traits allows the genetic mapping of determinants that contribute to variation in human gene expression.


Journal of Toxicology and Environmental Health-part B-critical Reviews | 2010

TOXICITY TESTING IN THE 21ST CENTURY: A VISION AND A STRATEGY

Daniel Krewski; Daniel Acosta; Melvin E. Andersen; Henry A. Anderson; John C. Bailar; Kim Boekelheide; Robert L. Brent; Gail Charnley; Vivian G. Cheung; Sidney Green; Karl T. Kelsey; Nancy I. Kerkvliet; Abby A. Li; Lawrence McCray; Otto Meyer; Reid D. Patterson; William Pennie; Robert A. Scala; Gina Solomon; Martin L. Stephens; James D. Yager; Lauren Zeise

With the release of the landmark report Toxicity Testing in the 21st Century: A Vision and a Strategy, the U.S. National Academy of Sciences, in 2007, precipitated a major change in the way toxicity testing is conducted. It envisions increased efficiency in toxicity testing and decreased animal usage by transitioning from current expensive and lengthy in vivo testing with qualitative endpoints to in vitro toxicity pathway assays on human cells or cell lines using robotic high-throughput screening with mechanistic quantitative parameters. Risk assessment in the exposed human population would focus on avoiding significant perturbations in these toxicity pathways. Computational systems biology models would be implemented to determine the dose-response models of perturbations of pathway function. Extrapolation of in vitro results to in vivo human blood and tissue concentrations would be based on pharmacokinetic models for the given exposure condition. This practice would enhance human relevance of test results, and would cover several test agents, compared to traditional toxicological testing strategies. As all the tools that are necessary to implement the vision are currently available or in an advanced stage of development, the key prerequisites to achieving this paradigm shift are a commitment to change in the scientific community, which could be facilitated by a broad discussion of the vision, and obtaining necessary resources to enhance current knowledge of pathway perturbations and pathway assays in humans and to implement computational systems biology models. Implementation of these strategies would result in a new toxicity testing paradigm firmly based on human biology.


Nature Genetics | 1999

Making and reading microarrays

Vivian G. Cheung; Michael Morley; Francisco Aguilar; Aldo Massimi; Raju Kucherlapati; Geoffrey Childs

There are a variety of options for making microarrays and obtaining microarray data. Here, we describe the building and use of two microarray facilities in academic settings. In addition to specifying technical detail, we comment on the advantages and disadvantages of components and approaches, and provide a protocol for hybridization. The fact that we are now making and using microarrays to answer biological questions demonstrates that the technology can be implemented in a university environment.


Nature Genetics | 2003

Natural variation in human gene expression assessed in lymphoblastoid cells

Vivian G. Cheung; Laura K. Conlin; Teresa M. Weber; Melissa Arcaro; Kuang-Yu Jen; Michael Morley; Richard S. Spielman

The sequencing of the human genome has resulted in greater attention to genetic variation among individuals, and variation at the DNA sequence level is now being extensively studied. At the same time, it has become possible to study variation at the level of gene expression by various methods. At present, it is largely unknown how widespread this variation in transcript levels is over the entire genome and to what extent individual differences in expression level are genetically determined. In the present study, we used lymphoblastoid cells to examine variation in gene expression and identified genes whose transcript levels differed greatly among unrelated individuals. We also found evidence for familial aggregation of expression phenotype by comparing variation among unrelated individuals, among siblings within families and between monozygotic twins. These observations suggest that there is a genetic contribution to polymorphic variation in the level of gene expression.


Nature | 2005

Mapping determinants of human gene expression by regional and genome-wide association

Vivian G. Cheung; Richard S. Spielman; Kathryn G. Ewens; Teresa M. Weber; Michael Morley; Joshua T. Burdick

To study the genetic basis of natural variation in gene expression, we previously carried out genome-wide linkage analysis and mapped the determinants of ∼1,000 expression phenotypes. In the present study, we carried out association analysis with dense sets of single-nucleotide polymorphism (SNP) markers from the International HapMap Project. For 374 phenotypes, the association study was performed with markers only from regions with strong linkage evidence; these regions all mapped close to the expressed gene. For a subset of 27 phenotypes, analysis of genome-wide association was performed with >770,000 markers. The association analysis with markers under the linkage peaks confirmed the linkage results and narrowed the candidate regulatory regions for many phenotypes with strong linkage evidence. The genome-wide association analysis yielded highly significant results that point to the same locations as the genome scans for about 50% of the phenotypes. For one candidate determinant, we carried out functional analyses and confirmed the variation in cis-acting regulatory activity. Our findings suggest that association studies with dense SNP maps will identify susceptibility loci or other determinants for some complex traits or diseases.


Nature Genetics | 2007

Common genetic variants account for differences in gene expression among ethnic groups

Richard S. Spielman; Laurel A Bastone; Joshua T. Burdick; Michael Morley; Warren J. Ewens; Vivian G. Cheung

Variation in DNA sequence contributes to individual differences in quantitative traits, but in humans the specific sequence variants are known for very few traits. We characterized variation in gene expression in cells from individuals belonging to three major population groups. This quantitative phenotype differs significantly between European-derived and Asian-derived populations for 1,097 of 4,197 genes tested. For the phenotypes with the strongest evidence of cis determinants, most of the variation is due to allele frequency differences at cis-linked regulators. The results show that specific genetic variation among populations contributes appreciably to differences in gene expression phenotypes. Populations differ in prevalence of many complex genetic diseases, such as diabetes and cardiovascular disease. As some of these are probably influenced by the level of gene expression, our results suggest that allele frequency differences at regulatory polymorphisms also account for some population differences in prevalence of complex diseases.


Science | 2011

Widespread RNA and DNA Sequence Differences in the Human Transcriptome

Mingyao Li; Isabel X. Wang; Yun Li; Alan Bruzel; Allison L. Richards; Jonathan M. Toung; Vivian G. Cheung

All 12 categories of discordances can be observed where the RNA sequence does not match that of the DNA. The transmission of information from DNA to RNA is a critical process. We compared RNA sequences from human B cells of 27 individuals to the corresponding DNA sequences from the same individuals and uncovered more than 10,000 exonic sites where the RNA sequences do not match that of the DNA. All 12 possible categories of discordances were observed. These differences were nonrandom as many sites were found in multiple individuals and in different cell types, including primary skin cells and brain tissues. Using mass spectrometry, we detected peptides that are translated from the discordant RNA sequences and thus do not correspond exactly to the DNA sequences. These widespread RNA-DNA differences in the human transcriptome provide a yet unexplored aspect of genome variation.


Nature | 2001

Integration of cytogenetic landmarks into the draft sequence of the human genome

Vivian G. Cheung; N. Nowak; W. Jang; Irving Kirsch; S. Zhao; X. N. Chen; Terrence S. Furey; U. J. Kim; W. L. Kuo; M. Olvier; J. Conroy; A. Kasprzyk; Hillary Massa; R. Yonescu; S.S.J. Sait; C. Thoreen; A. Snijders; E. Lemyre; J. A. Bailey; A. Bruzel; W. D. Burrill; S. M. Clegg; Steven J. Collins; P. Dhami; Cynthia Friedman; C. S. Han; S. Herrick; Joyce Lee; Azra H. Ligon; S. Lowry

We have placed 7,600 cytogenetically defined landmarks on the draft sequence of the human genome to help with the characterization of genes altered by gross chromosomal aberrations that cause human disease. The landmarks are large-insert clones mapped to chromosome bands by fluorescence in situ hybridization. Each clone contains a sequence tag that is positioned on the genomic sequence. This genome-wide set of sequence-anchored clones allows structural and functional analyses of the genome. This resource represents the first comprehensive integration of cytogenetic, radiation hybrid, linkage and sequence maps of the human genome; provides an independent validation of the sequence map and framework for contig order and orientation; surveys the genome for large-scale duplications, which are likely to require special attention during sequence assembly; and allows a stringent assessment of sequence differences between the dark and light bands of chromosomes. It also provides insight into large-scale chromatin structure and the evolution of chromosomes and gene families and will accelerate our understanding of the molecular bases of human disease and cancer.


Nature Reviews Genetics | 2009

Genetics of human gene expression: mapping DNA variants that influence gene expression

Vivian G. Cheung; Richard S. Spielman

There is extensive natural variation in human gene expression. As quantitative phenotypes, expression levels of genes are heritable. Genetic linkage and association mapping have identified cis- and trans-acting DNA variants that influence expression levels of human genes. New insights into human gene regulation are emerging from genetic analyses of gene expression in cells at rest and following exposure to stimuli. The integration of these genetic mapping results with data from co-expression networks is leading to a better understanding of how expression levels of individual genes are regulated and how genes interact with each other. These findings are important for basic understanding of gene regulation and of diseases that result from disruption of normal gene regulation.


Nature | 2009

Genetic analysis of radiation-induced changes in human gene expression

Denis A. Smirnov; Michael Morley; Eunice Shin; Richard S. Spielman; Vivian G. Cheung

Humans are exposed to radiation through the environment and in medical settings. To deal with radiation-induced damage, cells mount complex responses that rely on changes in gene expression. These gene expression responses differ greatly between individuals and contribute to individual differences in response to radiation. Here we identify regulators that influence expression levels of radiation-responsive genes. We treated radiation-induced changes in gene expression as quantitative phenotypes, and conducted genetic linkage and association studies to map their regulators. For more than 1,200 of these phenotypes there was significant evidence of linkage to specific chromosomal regions. Nearly all of the regulators act in trans to influence the expression of their target genes; there are very few cis-acting regulators. Some of the trans-acting regulators are transcription factors, but others are genes that were not known to have a regulatory function in radiation response. These results have implications for our basic and clinical understanding of how human cells respond to radiation.

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Michael Morley

University of Pennsylvania

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Joshua T. Burdick

University of Pennsylvania

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Denis A. Smirnov

University of Pennsylvania

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Alan Bruzel

Howard Hughes Medical Institute

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Warren J. Ewens

University of Pennsylvania

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