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Vivian G Cheung

Publications and source records attributed to Vivian G Cheung.

16 recordsLinked to original sources
PubMed2007

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

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.

Ethnicity↗
PubMed2006

In silico method for inferring genotypes in pedigrees.

Our genotype inference method combines sparse marker data from a linkage scan and high-resolution SNP genotypes for several individuals to infer genotypes for related individuals. We illustrate the method's utility by inferring over 53 million SNP genotypes for 78 children in the Centre d'Etude du Polymorphisme Humain families. The method can be used to obtain high-density genotypes in different family structures, including nuclear families commonly used in complex disease gene mapping studies.

Chi-Square Distribution↗
PubMed2006

Heterozygous carriers of Nijmegen Breakage Syndrome have a distinct gene expression phenotype.

Autosomal recessive diseases are those that require mutations in both alleles to exhibit the disorder. Although most recessive conditions are rare, heterozygous carriers of recessive mutations are quite common. In this study, we show that carriers of Nijmegen Breakage Syndrome (NBS) have a distinct gene expression phenotype that differs from that of noncarriers and also from that of carriers of a similar syndrome, Ataxia Telangiectasia (AT). We found 520 genes whose expression levels differ significantly (P < or = 0.001) between NBS carriers and controls. By linear discriminant analysis, we found a combination of 16 genes that allows 100% correct classification of individuals as either NBS carriers or noncarriers in a training set with 25 individuals, and in a test set with 52 individuals. When applied to AT carriers, the discriminant function misclassified only one out of 18 AT carriers as an NBS carrier. Our result shows that NBS carriers have a specific gene expression phenotype. It suggests that heterozygous mutations can contribute significantly to natural variation in gene expression. This has implications for the role that heterozygosity for recessive diseases plays in the overall genetic architecture of complex human traits and diseases.

Case-Control Studies↗
PubMed2005

DNA reassociation using oscillating phenol emulsions.

Reassociating double-stranded DNA from single-stranded components is necessary for many molecular genetics experiments. The choice of a DNA reassociation method is dictated by the complexity of the starting material. Reassociation of simple oligomers needs only slow cooling in an aqueous environment, whereas reannealing the many single-stranded DNAs of complex genomic mixtures requires both a phenol emulsion to accelerate DNA reassociation and dedicated equipment to maintain the emulsion. We present a method that is equally suitable for reassociating either simple or complex DNA mixtures. The Oscillating Phenol Emulsion Reassociation Technique (OsPERT) was primarily developed to prepare heteroduplex DNA from alkali-denatured high molecular weight human genomic DNA samples in which hundreds of thousands of fragments need to be reannealed, but the simplicity of the technique makes it practical for less demanding DNA reassociation applications.

DNA↗
PubMed2005

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

To study the genetic basis of natural variation in gene expression, we previously carried out genome-wide linkage analysis and mapped the determinants of approximately 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.

Alleles↗
PubMed2005

Identification of novel p53 target genes in ionizing radiation response.

The tumor suppressor p53 plays an essential role in cellular adaptation to stress. In response to ionizing radiation, p53 regulates the transcription of genes in a diverse set of pathways including DNA repair, cell cycle arrest, and apoptosis. Previously, we identified by microarray analysis a set of genes that are transcriptionally activated or repressed in response to radiation exposure. In this study, we use computational methods and molecular techniques, including location analysis (ChIP-on-chip assay), to identify ionizing radiation-responsive genes that are directly regulated by p53. Among the 489 ionizing radiation-responsive genes examined, 38 genes were found to be p53 targets. Some of these genes are previously known to be directly regulated by p53 whereas others are novel p53 targets. We further showed that the novel p53 target genes are transcriptionally regulated by p53. The binding of p53 to promoters of target genes correlated with increased transcript levels of these genes in cells with functional p53. However, p53 binding and subsequent transcriptional activation of these target genes were significantly diminished in cells with mutant p53 and in cells from patients with ataxia telangiectasia, which have impaired p53 activation following ionizing radiation exposure. Identification and characterization of ionizing radiation-responsive p53 target genes extend our knowledge of the diverse role that p53 plays in the DNA damage response.

Ataxia Telangiectasia↗
PubMed2004

Genetic variation in radiation-induced expression phenotypes.

Studies have demonstrated that natural variation in the expression level of genes at baseline is extensive, and the determinants of this variation can be mapped by a genetic-linkage approach. In this study, we used lymphoblastoid cells to explore the variation in radiation-induced transcriptional changes. We found that, among normal individuals, there is extensive variation in transcriptional response to radiation exposure. By studying monozygotic twins, we demonstrated that there is evidence of a heritable component to this variation. The postradiation variation in the expression level of several genes, including the ferredoxin reductase gene (FDXR) and the cyclin-dependent kinase inhibitor 1A gene (CDKN1A), is significantly greater (P<.001) among twin pairs than within twin pairs. The induction of FDXR by radiation showed a bimodal distribution. Our findings have important implications for understanding the genetic basis of radiation response, which has remained largely unknown due to the lack of family material needed for genetic studies. Our approach, which uses expression phenotypes in cell lines, allows us to expose cells from family members to radiation. Similar study design can be applied to dissect the genetic basis of other complex human traits.

Cell Cycle Proteins↗
PubMed2004

Genetic analysis of genome-wide variation in human gene expression.

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.

Alleles↗
PubMed2004

Method for manufacturing whole-genome microarrays by rolling circle amplification.

Comparative genomic hybridization (CGH) to metaphase chromosomes is a method for genome-wide detection of chromosomal aberrations in DNA samples. Recent advances in microarray technology have improved CGH by replacing metaphase chromosomes with a collection of mapped genomic clones placed on glass slides. However, it is quite expensive and labor-intensive to prepare DNA from the genomic clones for use in constructing genomic microarrays. Here we used strand-displacement rolling circle amplification (RCA) to manufacture whole-genome microarrays by using a collection of about 4,500 mapped RPCI-11 BAC clones that cover the human genome at approximately a 1-Mb resolution. These genomic microarrays detected all major chromosomal aberrations in cancer cells lines and in cell lines with aneuploidy. In this article, we discuss the advantages of using RCA for the manufacturing of large genomic microarrays.

Cell Line, Tumor↗
PubMed2004

Direct IBD mapping: identical-by-descent mapping without genotyping.

Direct identical-by-descent (IBD) mapping is a technique, that combines genomic mismatch scanning (GMS) and DNA microarray technology, for mapping regions shared IBD between two individuals without locus-by-locus genotyping or sequencing. The lack of reagents has limited its widespread application. In particular, two key reagents have been limiting, 1). mismatch repair proteins MutS, L and H, and 2). genomic microarrays for identifying the genomic locations of the GMS-selected IBD fragments. Here, we describe steps that optimized the procedure and resources that will facilitate the development of direct IBD mapping.

Base Pair Mismatch↗
PubMed2003

Transcriptional response of lymphoblastoid cells to ionizing radiation.

The effects of ionizing radiation (IR) on the temporal transcriptional response of lymphoblastoid cells were investigated in this study. We used oligonucleotide microarrays to assess mRNA levels of genes in lymphoblastoid cells at various time points within 24 h following gamma-irradiation. We identified 319 and 816 IR-responsive genes following 3 Gy and 10 Gy of IR exposure, respectively, with 126 genes in common between the two doses. A high percentage of IR-responsive genes are involved in the control of cell cycle, cell death, DNA repair, DNA metabolism, and RNA processing. We determined the temporal expression profiles of the IR-responsive genes and assessed effects of IR dose on this temporal pattern of expression. By combining dose-response data with temporal profiles of expression, we have identified sets of coordinately responding genes. Through a genomic approach, we characterized a set of genes that are implicated in cellular adaptation to IR stress. These findings will allow a better understanding of complex processes such as radiation-induced carcinogenesis and the development of biomarkers for radiation exposure.

Cell Line, Transformed↗
PubMed2003

Natural variation in human gene expression assessed in lymphoblastoid cells.

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.

Female↗
PubMed2002

Gene expression phenotype in heterozygous carriers of ataxia telangiectasia.

The defining characteristic of recessive diseases is the absence of a phenotype in the heterozygous carriers. Nonetheless, subtle manifestations may be detectable by new methods, such as expression profiling. Ataxia telangiectasia (AT) is a typical recessive disease, and individual carriers cannot be reliably identified. As a group, however, carriers of an AT disease allele have been reported to have a phenotype that distinguishes them from normal control individuals: increased radiosensitivity and risk of cancer. We show here that the phenotype is also detectable, in lymphoblastoid cells from AT carriers, as changes in expression level of many genes. The differences are manifested both in baseline expression levels and in response to ionizing radiation. Our findings show that carriers of a recessive disease may have an "expression phenotype." In the particular case of AT, this suggests a new approach to the identification of carriers and enhances understanding of their increased cancer risk. More generally, we demonstrate that genomic technologies offer the opportunity to identify and study unaffected carriers, who are hundreds of times more common than affected patients.

Ataxia Telangiectasia↗
PubMed2002

Bridging genetics and genomics in neurology.

The Human Genome Project has stimulated a change in the ways human diseases are studied genetically. The field is moving towards a genome-wide approach to identifying susceptibility genes and to understanding the molecular basis of diseases. In this article, we review the emerging technologies and discuss results from studies that have used genomic approaches.

Cytogenetic Analysis↗
PubMed2002

The genetics of variation in gene expression.

The genetic basis of variation in gene expression lends itself to investigation by microarrays. For genetic analysis, we view the expression level of a gene as a quantitative or 'complex' trait, analogous to an individual's height or cholesterol level, and, therefore, as an inherited phenotype. Several genetic analyses of 'gene expression phenotypes' have been carried out in experimental organisms, and initial steps have been taken toward similar studies in humans--although these present challenging technical and statistical problems. Further advances in the genetic analysis of variation in gene expression will contribute to our understanding of transcriptional regulation and will provide models for studying other quantitative and complex traits.

Animals↗