Large-scale genotyping of complex DNA

Kennedy, Giulia C.; Matsuzaki, Hajime; Dong, Shoulian; Liu, Weimin; Huang, Jing; Li, Guoying; Su, Xing; Cao, Manqiu; Chen, Wenwei; Zhang, Jingyan; Liu, Weiwei; Yang, Guang; Di, Xiaojun; Ryder, Thomas B.; Zhang, He; Surti, Urvashi; Phillips, Michael; Boyce-Jacino, Michael T.; Fodor, Stephen P. A.; Jones, Keith

doi:10.1038/nbt869

Cited by 502 publications

(364 citation statements)

References 27 publications

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“…With the recent development of high throughput, array-based technology, it is now affordable to genotype 10,000 -100,000 SNPs simultaneously (Kennedy et al 2003). Systematically genotyping various indigenous populations using this or other similar platforms has at least two advantages: first, population-specific allele frequencies obtained from these studies enable all future association studies to genotype only the admixed individuals, which thereby facilitates the control for IA variation.…”

Section: Discussionmentioning

confidence: 99%

Estimation of individual admixture: Analytical and study design considerations

Tang

Peng

Wang

et al. 2005

Genetic Epidemiology

630

642

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The genome of an admixed individual represents a mixture of alleles from different ancestries.In the United States, the two largest minority groups, African Americans and Hispanics, are both admixed. An understanding of the admixture proportion at an individual level (individual admixture, or IA) is valuable for both population geneticists and epidemiologists who conduct case-control association studies in these groups. Here we present an extension of a previously described frequentist (maximum likelihood or ML) approach to estimate individual admixture that allows for uncertainty in ancestral allele frequencies. We compare this approach both to prior partial likelihood based methods as well as more recently described Bayesian MCMC methods.Our full ML method demonstrates increased robustness when compared to an existing partial ML approach. Simulations also suggest that this frequentist estimator achieves similar efficiency, measured by the mean squared error criterion, as Bayesian methods but requires just a tiny fraction of the computational time to produce point estimates, allowing for extensive analysis (e.g. simulations) not possible by Bayesian methods. Our simulation results demonstrate that inclusion of ancestral populations or their surrogates in the analysis is required by any method of IA estimation to obtain reasonable results.keywords: admixture, EM algorithm, maximum likelihood estimate.

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Section: Discussionmentioning

confidence: 99%

Estimation of individual admixture: Analytical and study design considerations

Tang

Peng

Wang

et al. 2005

Genetic Epidemiology

630

642

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“…Amplified products were fragmented, labeled by biotinylation and hybridized to the microarrays. Hybridization was detected by incubation with streptavidin-phycoerythrin conjugates, followed by scanning of the array, and analysis was carried out as described earlier (Kennedy et al, 2003). Copy number changes were calculated using the Copy Number Analyzer for Affymetrix GeneChip Mapping Arrays (CNAG; http://www.genome.umin.jp; Nannya et al, 2005).…”

Section: Array Analysismentioning

confidence: 99%

Defective expression of polarity protein PAR-3 gene (PARD3) in esophageal squamous cell carcinoma

et al. 2009

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The partition-defective 3 (PAR-3) protein is implicated in the formation of tight junctions at epithelial cell-cell contacts. We investigated DNA copy number aberrations in human esophageal squamous cell carcinoma (ESCC) cell lines using a high-density oligonucleotide microarray and found a homozygous deletion of PARD3 (the gene encoding PAR-3). Exogenous expression of PARD3 in ESCC cells lacking this gene enhanced the recruitment of zonula occludens 1 (ZO-1), a marker of tight junctions, to sites of cell-cell contact. Conversely, knockdown of PARD3 in ESCC cells expressing this gene caused a disruption of ZO-1 localization at cell-cell borders. A copy number loss of PARD3 was observed in 15% of primary ESCC cells. Expression of PARD3 was significantly reduced in primary ESCC tumors compared with their nontumorous counterparts, and this reduced expression was associated with positive lymph node metastasis and poor differentiation. Our results suggest that deletion and reduced expression of PARD3 may be a novel mechanism that drives the progression of ESCC.

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“…Genotyping was carried out using Affymetrix GeneChip 10K Human Mapping Arrays [Kennedy et al, 2003;Matsuzaki et al, 2004]. Briefly, the method consisted of a one-primer amplification assay performed on genomic DNA in which sequence complexity had been reduced by restriction enzyme digestion with XbaI.…”

Section: Genotypingmentioning

confidence: 99%

“…The markers in the Affymetrix panel were selected from SNPs previously validated by the SNP Consortium and for their genome-wide coverage [Kennedy et al, 2003;Matsuzaki et al, 2004]. Each SNP had a relatively high heterozygosity (40.25) in three population groups, and the SNPs were selected without consideration for proximity to genes.…”

Section: Snp Selectionmentioning

confidence: 99%

Localization of breast cancer susceptibility loci by genome‐wide SNP linkage disequilibrium mapping

Ellis

Kirchhoff

Mitra

et al. 2005

Genetic Epidemiology

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We studied the feasibility of a novel approach to localize breast cancer susceptibility genes, using a low-density genomewide panel of single-nucleotide polymorphisms and taking advantage of large regions of linkage disequilibrium (LD) flanking Jewish disease genes in high-risk cases. With Affymetrix GeneChip arrays, we genotyped 8,576 polymorphisms in three sets of Ashkenazi Jewish breast cancer cases: a ''validation'' set of 27 breast cancer cases, all of whom carried the BRCA2*6174delT founder mutation; a ''field'' set of 19 breast cancer cases from male breast cancer kindreds, which simulated conditions for finding new genes; and a ''test'' set of 57 probands from breast cancer kindreds (4 or more cases/ kindred), in which mutations in BRCA1 and BRCA2 had been excluded. To identify associations, we compared the frequency of genotypes and haplotypes in cases vs. controls by the Fisher's exact test and a maximum likelihood ratio test. In the ''validation'' set, we demonstrated the presence of a region of linkage disequilibrium on BRCA2*6174delT chromosomes that spanned over 5 million bases. In the ''field'' set, we showed that this large region of linkage disequilibrium flanking BRCA2 was detectable despite the presence of heterogeneity in the sample set. Finally, in the ''test'' set, at least three regions of interest emerged that could contain novel breast cancer genes, one of which had been identified previously by linkage analysis. While these results demonstrate the feasibility of genome-wide association strategies, further application of this approach will critically depend on optimizing the density and distribution of SNPs and the size and type of study design. Genet. Epidemiol. 30:48-61, 2006. r 2005 Wiley-Liss, Inc.

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Large-scale genotyping of complex DNA

Cited by 502 publications

References 27 publications

Estimation of individual admixture: Analytical and study design considerations

Estimation of individual admixture: Analytical and study design considerations

Defective expression of polarity protein PAR-3 gene (PARD3) in esophageal squamous cell carcinoma

Localization of breast cancer susceptibility loci by genome‐wide SNP linkage disequilibrium mapping

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