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In Print: Nov 16, 2010


Microarray Papers of Note Published October 2010

Journal: Analytical Chemistry. 2010 Oct 14. [Epub ahead of print]

Title: In-plane parallel scanning: a microarray technology for point-of-care testing.

Authors: Duer R, et al.

In this study, the authors describe a new microarray platform for multiplex diagnostics assays. Called in-plane parallel scanning, or IPPS, the authors believe the technology could replace expensive laser scanning. The new arrays contain grids of 100-μm-wide waveguides embedded in the chip's substrate, enabling real-time quantification of molecular complex formation on the chip's surface. Two different chip formats are described. One is a low-density microarray with 10 sensing wells, and the other is a medium-density one with 100 sensing wells. Performance was evaluated in two different proof-of-principle immunoassays to detect interleukin-1β and Clostridium difficile toxin A. The multiplexing capabilities of the IPPS technology were also demonstrated in a multiplex assay for both analytes on the IPPS-10 chip. Based on these results, the authors contend that the IPPS platform "holds promise for translating diagnostic microarrays into near-patient environments."

Journal: Analytical Chemistry. 2010 Oct 15. [Epub ahead of print]

Title: A sol-gel-derived acetylcholinesterase microarray for nanovolume small-molecule screening.

Authors: Monton M, et al.

A fluorimetric acetylcholinesterase, or AChE, assay was developed and migrated to microarrays using contact pin-printing of sol-gel-derived silica. A total of 392 sol-gel formulations were screened for gelation times and 192 of these were further evaluated for array fabrication on four different surfaces using a factor analysis approach. Of these, 66 sol-gel/surface combinations produced "robust" microarrays, while 26 sol-gel/surface combinations were identified that could produce "highly active" AChE microarrays, the authors found. Using specific dyes, the microarrays could be used to screen two libraries of small molecules, one composed of newly synthesized alkaloids and another consisting of bioactive compounds for activity against AChE. Values were obtained on microarrays for compounds showing "significant inhibitory activity," and "demonstrating the utility of arrays for quantitative inhibition assays."

Journal: Analytical & Bioanalytical Chemistry. 2010 Oct;398(4):1723-33.

Title: Allergen microarrays on high-sensitivity silicon slides.

Authors: Cretich M, et al.

In this study, the authors introduce a silicon substrate for high-sensitivity microarrays, coated with a functional polymer named copoly (DMA-NAS-MAPS). The authors used the new silicon microarray substrate for allergy diagnosis, in the detection of specific IgE in serum samples of subjects with sensitizations to inhalant allergens. They compared the performance of silicon versus glass substrates and measured reproducibility data. Receiver-operating characteristic curves were plotted to discriminate between the allergy and no-allergy status in 30 well-characterized serum samples. The authors found that reproducibility of the microarray on glass supports was not different from available data on allergen arrays, while the reproducibility on the silicon substrate was "consistently better" than on glass. Additionally, they noted that the silicon "significantly enhanced" the performance of the allergen microarray as compared to glass in accurately identifying allergic patients spanning a wide range of specific IgE titers to the considered allergens.

Journal: Biomaterials. 2010 Oct 19. [Epub ahead of print]

Title: A sandwiched microarray platform for benchtop cell-based high throughput screening.

Authors: Wu J, et al.

The authors present a microarray sandwich system suitable for screening chemical libraries in cell-based assays. The platform delivers chemical compounds to isolated cell cultures by 'sandwiching' chemical-laden arrayed posts with cell-seeded microwells. In this way, an array of sealed cell-based assays was generated without cross-contamination between neighboring assays, the authors reported. After chemical exposure, cell viability was analyzed by fluorescence detection of cell viability assays on a per-microwell basis using a standard microarray scanner. The authors demonstrated the efficacy of the system by generating four hits from toxicology screens toward MCF-7 human breast cancer cells. Three of the hits were identified in a combinatorial screen of a library of natural compounds in combination with verapamil, a P-glycoprotein inhibitor. A fourth hit, 9-methoxy-camptothecin, was identified by screening the natural compound library in the absence of verapamil, according to the authors. They claim that their method is amenable to combinatorial drug screening.

Journal: BMC Genomics. 2010 Oct 21;11:592.

Title: Development and validation of a flax (Linum usitatissimum L.) gene expression oligo microarray.

Authors: Fenart S, et al.

In this paper, the authors report the development and validation of a high-density oligo microarray dedicated to gene expression analyses in flax. To create the platform, nine different RNA samples obtained from flax inner- and outer-stems, seeds, leaves, and roots were used to generate a collection of 1,066,481 expressed sequence tags by massive parallel pyrosequencing. Sequences were assembled into 59,626 unigenes and 48,021 sequences were selected for oligo design and high-density microarray fabrication by Roche NimbleGen with eight, non-overlapping 25-mers oligos per unigene. Following experiments and cross-validation with quantitative PCR, the authors suggested that their flax array could be used for analyzing gene expression in a large variety of tissues as well as in different cultivars.

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Journal: European Urology. 2010 Oct 15. [Epub ahead of print]

Title: Diagnostic, staging, and grading of urothelial carcinomas from urine: performance of BCA-1, a mini-array comparative genomic hybridization-based test.

Authors: Larré S, et al.

The authors assessed the performance of an array-based test based to diagnose, stage, and grade bladder urothelial carcinomas from urine. They used a 341 bacterial artificial chromosome comparative genomic hybridization array, designed to include loci affected in BUC. The chip was first used on 32 frozen BUC biopsies to design staging and grading prediction models based on Bayesian network analysis. The models were then validated on external data obtained from 98 tumor samples using a 2,464 BAC CGH chip. The performance of the test was finally assessed on 44 urine pellets collected, including 22 patients who had BUC and 22 controls. The authors found that their array detected BUC in urine with a "high diagnostic performance." They also report the chip could "accurately discriminate low-grade from high-grade tumors and, to a lesser extent, lamina propria-invasive tumors from pTa tumors."

Journal: Expert Reviews in Molecular Diagnostics. 2010 Oct;10(7):875-82.

Title: Is there a niche for DNA microarrays in molecular diagnostics?

Authors: Jordan B, et al.

In this article, the author evaluates the strengths and weaknesses of different microarray-based approaches to diagnostics, and highlights the fields in which it is most likely to achieve a durable presence. The author notes that several tests have been introduced and have obtained regulatory approval, "mostly in the fields of bacterial identification, mutation detection and the global assessment of genome alterations," with a "particularly successful case being the whole-genome assay of copy-number variations." At the same time, the author argues that gene-expression applications have been "less successful because of technical issues," such as reproducibility, platform-to-platform consistency, statistical issues in data analysis, and "difficulties in demonstrating the clinical utility of expression signatures." The author also notes that arrays have faced competition from PCR-based assays, and now next-generation sequencing.

Journal: Fertility & Sterility. 2010 Oct 23. [Epub ahead of print]

Title: Validation of microarray comparative genomic hybridization for comprehensive chromosome analysis of embryos.

Authors: Gutiérrez-Mateo C, et al.

The authors of this study sought to validate the best array-comparative genomic hybridization protocols for preimplantation genetic screening. In the study, embryos had one cell removed as a biopsy specimen and analyzed by one of two array-CGH protocols. Abnormal embryos were reanalyzed by fluorescence in situ hybridization. Method one produced 11.2 percent of embryos with no results and a 9.1 percent error rate compared with 3 percent and 1.9 percent for method two, respectively. Afterwards, only method two was used clinically. The aneuploidy rate for cleavage-stage embryos was 63.2 percent, significantly increasing with maternal age. The chromosomes most involved in aneuploidy were 16, 22, 21, and 15. In the paper, the authors also claim to report the first live births after array-CGH combined with single blastomere biopsy.

Journal: Genome Research. 2010 Oct;20(10):1420-31. Epub 2010 Sep 1.

Title: Systematic comparison of three genomic enrichment methods for massively parallel DNA sequencing.

Authors: Teer J, et al.

The authors compared three methods for enriching genomic regions of interest for targeted sequencing: molecular inversion probes, solution hybrid selection, and microarray-based genomic selection. Using HapMap DNA samples, they assessed the ability of each of these methods to capture an identical set of exons and evolutionarily conserved regions associated with 528 genes. The authors determined that all three capture methods were effective, but found that the percentage of targeted bases associated with high-quality genotypes varied for an equivalent amount of pass-filtered sequence. All methods yielded similar accuracies when compared to Infinium 1M SNP BeadChip-derived genotypes and when compared to 30-fold coverage whole-genome shotgun sequencing data. The authors ultimately concluded that all three methods "are highly accurate and practical, with sensitivities comparable to that of 30-fold coverage whole-genome shotgun data."

Journal: Genome Research. 2010 Oct 29. [Epub ahead of print]

Title: Pervasive gene content variation and copy number variation in maize and its undomesticated progenitor.

Authors: Swanson-Wagner R, et al.

Array comparative genomic hybridization was used to compare gene content and copy number variation among 19 diverse maize inbreds and 14 genotypes of the wild ancestor of maize, teosinte. The authors identified 479 genes exhibiting higher copy number in some genotypes and 3,410 genes that have either fewer copies or are missing in the genome of at least one genotype relative to maize B73. The authors determined that many of the genes affected by CNVs are either maize specific or members of large gene families, suggesting that the gene loss can be tolerated through buffering by redundant functions encoded elsewhere in the genome. "While this structural variation may not result in major qualitative variation due to genetic buffering, it may significantly contribute to quantitative variation," the authors noted.

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Journal: Human Molecular Genetics. 2010 Oct 11. [Epub ahead of print]

Title: A genome-wide association study reveals susceptibility variants for non-small cell lung cancer in the Korean population.

Authors: Yoon K, et al.

To identify genetic risk factors for non-small cell lung cancer, the authors conducted a genome-wide association study and a replication study in 1,425 patients with NSCLC and 3,011 controls from Korea. From the data for 2,162 participants analyzed using the Affymetrix GeneChip Mapping 500K Array Set, 168 SNPs were selected for validation. In the second stage, the authors were able to genotype 168 SNPs in 804 patients and 1,470 controls to confirm the results of the study. In the meta-analysis, rs2131877 at the chromosome 3q29 region was the most significant biomarker of lung cancer susceptibility in Koreans. Four markers that were located within the chromosome 3q29 region were also associated with lung cancer susceptibility, along with markers on 5p15 that were previously reported in populations of European descent.

Journal: Journal of Human Genetics. 2010 Oct 28 [Epub ahead of print]

Title: Clinical application of array-based comparative genomic hybridization by two-stage screening for 536 patients with mental retardation and multiple congenital anomalies

Authors: Hayashi S, et al.

The authors of this paper applied array comparative genomic hybridization to investigate multiple congenital anomalies and mental retardation. To do this, they constructed a consortium with 23 medical institutes and hospitals in Japan, and recruited 536 patients with clinically uncharacterized MCA/MR, whose karyotypes were normal according to conventional cytogenetics, for two-stage screening using two types of bacterial artificial chromosome-based microarrays. The first screening using a targeted array detected pathogenic CNVs in 54 of 536 cases, while the second screening of the 349 cases negative in the first screening used a genome-wide high-density array to detect pathogenic CNVs in 48 cases, including CNVs relevant to recently established microdeletion or microduplication syndromes, CNVs containing pathogenic genes, and recurrent CNVs containing the same region among different patients.

Journal: Langmuir. 2010 Oct 18. [Epub ahead of print]

Title: Surface characterization of carbohydrate microarrays.

Authors: Scurr D, et al.

The authors of this study analyzed a glycan array by time-of-flight secondary ion mass spectrometry to study the physicochemical properties of array spots and to improve carbohydrate microarray quality. Their carbohydrate microarray was prepared by piezo printing of thiol-terminated sugars onto a maleimide functionalized glass slide. The hyperspectral ToF-SIMS imaging data were then analyzed by multivariate curve resolution to discern secondary ions from regions of the array containing saccharide, linker, salts from the printing buffer, and the background linker chemistry. Analysis of secondary ions from the linker common to all of the sugar molecules employed revealed a relatively uniform distribution of the sugars within the spots formed from solutions. A detailed analysis of individual spots revealed, though, that in the larger spots the phosphate-buffered saline salts were heterogeneously distributed, apparently resulting in saccharide concentrated at the rim of the spots. Finally, the multivariate analytical partial least squares technique identified ions from the sugars that in the complex ToF-SIMS spectra correlate with the binding of galectin proteins.

Journal: Nucleic Acids Research. 2010 Oct 1;38(19):e180.

Title: High-quality gene assembly directly from unpurified mixtures of microarray-synthesized oligonucleotides

Authors: Borovkov A, et al.

The authors present a protocol for high-quality gene assembly from low-cost marginal-quality microarray-synthesized oligonucleotides. They report that by using hybridization-based selection embedded in the assembly process, they were able to eliminate the time- and money-consuming oligonucleotide purification steps. The protocol was tested on mixtures of up to 2,000 oligonucleotides eluted directly from microarrays obtained from three different chip manufacturers. These mixtures were used directly for the assembly of 27 test genes of different sizes. Gene quality was assessed by sequencing, and their activity was tested in coupled in vitro transcription/translation reactions. According to the authors, genes assembled from the microarray-eluted material using the new protocol matched the quality of the genes assembled from pure, column-synthesized oligonucleotides by the standard protocol.

Journal: Nucleic Acids Research. 2010 Oct 14. [Epub ahead of print]

Title: A comparison of RNA-seq and high-density exon array for detecting differential gene expression between closely related species.

Authors: Liu S, et al.

The authors of this paper compared RNA-seq and high-density exon arrays for detecting differential gene expression between closely related species. On a panel of human/chimpanzee/rhesus cerebellum RNA samples previously examined by a high-density human exon junction array and real-time quantitative PCR, they generated 48.7 million RNA-seq reads. Based on these results, the authors argue that RNA-seq "significantly improved gene coverage and increased sensitivity for differentially expressed genes" compared with the high-density array. At the same time, the authors observed a systematic increase in the RNA-seq error rate for lowly expressed genes. Specific between-species differentially expressed genes detected by array and qPCR but missed by RNA-seq were characterized by relatively low expression levels, as indicated by lower RNA-seq read counts, lower array expression indices, and higher qPCR raw cycle threshold values. The authors argue that their findings have "important implications for the design and data interpretation of RNA-seq studies on gene expression differences between and within species."

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Journal: Oncogene. 2010 Oct 4. [Epub ahead of print]

Title: Integration of cap analysis of gene expression and chromatin immunoprecipitation analysis on array reveals genome-wide androgen receptor signaling in prostate cancer cells.

Authors: Takayama K, et al.

In this study, the authors performed 5'-cap analysis of gene expression, or CAGE, to determine androgen-regulated transcription start sites, and chromatin immunoprecipitation on array, or ChIP-on-chip, to identify androgen receptor binding sites and histone H3 acetylated sites in the prostate cancer cells. CAGE determined 13,110 distinct, androgen-regulated transcription start sites; and ChIP-on-chip analysis identified 2,872 androgen-dependent androgen receptor binding sites and 25,945 AcH3 sites. Both androgen-regulated coding genes and noncoding RNAs, including microRNAs, were determined as androgen target genes. Additionally, by integrating CAGE and ChIP-on-chip the authors identified a cluster of androgen-inducible miRNAs, as exemplified by the miR-125b-2 cluster on chromosome 21.

Journal: PLoS One. 2010 Oct 13;5(10):e13422.

Title: New copy number variations in schizophrenia.

Authors: Magri C, et al.

Using Affymetrix 6.0 arrays, the authors searched for CNVs in 172 patients with schizophrenia and 160 healthy controls, all of Italian origin, with the aim of confirming previously identified loci and identifying new schizophrenia susceptibility genes. They found five patients with a CNV occurring in regions implicated as risk factors for schizophrenia: the NRXN1 and the 16p13.1 regions were found to be deleted in individual patients and 15q11.2 in two patients, while the 15q13.3 region was duplicated in one patient. The authors also found three distinct patients with CNVs in 2q12.2, 3q29 and 17p12 loci, respectively. These loci were previously reported to be deleted or duplicated in patients with schizophrenia but were never formally associated with the disease. Finally, the authors found five large CNVs in 4q32, 5q14.3, 8q23.3, 11q25 and 17q12 in five different patients that could include some new candidate schizophrenia susceptibility genes.

Journal: PLoS One. 2010 Oct 27;5(10):e13661.

Title: Genome wide association studies for milk production traits in Chinese Holstein population.

Authors: Jiang L, et al.

The authors conducted a genome-wide association study to identify genes affecting milk production traits using the Illumina BovineSNP50 BeadChip. The analysis concerned the five most commonly evaluated milk production traits, including milk yield, milk fat yield, milk protein yield, milk fat percentage, and milk protein percentage. Association tests between each trait and the 54K SNPs on the chip were achieved via two different analysis approaches, a paternal transmission disequilibrium test, or TDT, approach, and a mixed model-based regression analysis, or MMRA, approach. In total, 105 SNPs were detected to be significantly associated genome-wide with one or multiple milk production traits. Of the 105 SNPs, 38 were commonly detected by both methods, while four and 63 were solely detected by TDT and MMRA, respectively. The authors also reported that 86 out of 105 of the significant SNPs detected are located within the previously reported regions and some are within or close to the reported candidate genes.

Journal: PLoS Genetics. 2010 Oct 28;6(10):e1001183.

Title: Common genetic variants and modification of penetrance of BRCA2-associated breast cancer.

Authors: Gaudet M, et al.

To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, these researchers undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In the first stage, using the Affymetrix 6.0 platform, 592,163 filtered SNP genotypes were available on 899 young affected and 804 unaffected carriers of European ancestry. The stage 1 association analysis revealed multiple variants associated with breast cancer risk. These variants included several previously associated with sporadic breast cancer risk and two novel loci on chromosome 20 and chromosome 10. In stage 2, the top 85 loci from stage 1 were genotyped in 1,264 cases and 1,222 controls. According to the authors, the results of the second stage indicate that SNPs that modify BRCA2 penetrance are limited to variants that also modify risk of sporadic BRCA2 wild-type breast cancer.

Journal: Prenatal Diagnostics. 2010 Oct 14. [Epub ahead of print]

Title: Molecular diagnosis of Down syndrome using quantitative APEX-2 microarrays.

Authors: Oitmaa E, et al.

The authors of this paper aimed to develop a high-throughput microarray-based prenatal diagnostic test for the detection of trisomy 21. The T21 arrayed primer extension-2, or APEX-2, assay they developed discriminates between trisomy and euploid DNA samples by comparing the signal intensities of allelic fractions of heterozygous SNPs after APEX reaction. After preliminary validation using DNA samples from Down syndrome patients, the authors analyzed DNA samples from cultured and uncultured amniocytes and chorionic villus for 90 SNPs with high heterozygosity from the 21(q21.1q22.2) region in 134 clinical samples. Differences in allelic ratios of heterozygous SNPs in normal and T21 individuals were verified by t-test.

Journal: Science. 2010 Oct 22;330(6003):514-7.

Title: SNP genotyping defines complex gene-flow boundaries among African malaria vector mosquitoes.

Authors: Neafsey D, et al.

Mosquitoes in the Anopheles gambiae complex show rapid ecological and behavioral diversification, traits that promote malaria transmission and complicate vector control efforts, according to the authors of this study. They used an Affymetrix-manufactured, high-density, custom genome-wide mosquito SNP-genotyping array to map genomic differentiation between populations and species that exhibit varying levels of reproductive isolation. Based on the array results, they authors found that regions near centromeres or within polymorphic inversions exhibited the greatest genetic divergence, but divergence was also observed elsewhere in the genomes. Additionally, signals of natural selection within populations were overrepresented among genomic regions that are differentiated between populations, implying that differentiation is often driven by population-specific selective events.

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