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In Print: Dec 7, 2010


Microarray Papers of Note Published November 2010

Journal: Animal Genetics. 2010 Nov 11. [Epub ahead of print]

Title: Assessment of the functionality of genome-wide canine SNP arrays and implications for canine disease association studies.

Authors: Ke X, et al.

This study is a dedicated large-scale assessment of the linkage disequilibrium and SNP tagging performance of canine genome-wide SNP arrays in multiple domestic dog breeds. The authors used genotype data from 18 breeds as well as wolves and coyotes genotyped by the Illumina 22K canine SNP array and Affymetrix 50K canine SNP array. High tagging performance was observed with most of the breeds using both Illumina and Affymetrix arrays when multi-marker tagging was applied. In contrast, however, large differences in population structure, LD coverage, and pairwise tagging performance were found between breeds, suggesting that study designs should be carefully assessed for individual breeds before undertaking genome-wide association studies.

Journal: Biochemical and Biophysical Research Communications. 2010 Nov 13. [Epub ahead of print]

Title: Differential expression of cellular microRNAs in HPV-11 transfected cells. An analysis by three different array platforms and qRT-PCR.

Authors: Dreher A, et al.

Human papillomavirus type 11 infects the genitals and the respiratory tract leading to condylomas and respiratory papillomatosis. HPV infections are restricted to epithelial tissue and the progression through the virus lifecycle is tightly coordinated with the differentiation of the host cell. The authors of this study investigated the changes of cellular microRNAs by HPV-11 gene expression in a cell culture model of HaCaT cells transfected with HPV-11, with the goal of understanding which cellular processes were affected by the virus. Human microRNA profiling was conducted on three different array platform systems. A few microRNAs — miR-663, -638, -149∗ and -92b∗ — were consistently found in all three array data sets. The authors also performed statistical analyses of the array data and the qRT-PCR validation.

Journal: BMC Genomics. 2010 Nov 9;11:623.

Title: Use of a bovine genome array to identify new biological pathways for beef marbling in Hanwoo (Korean Cattle).

Authors: Lee SH, et al.

Marbling, or intramuscular fat, is a valuable trait that impacts meat quality and is an important factor in determining the price of beef in the Korean beef market, according to the authors of this study. Using microarrays, they aimed to identify candidate genes and pathways associated with intramuscular fat deposition on highly divergent marbling phenotypes in adult Hanwoo cattle. Bovine genome array analysis was conducted to detect differentially expressed genes in M. longissimus with divergent marbling phenotypes. Statistical analysis identified 21 significant transcripts from at least two data-processing methods. All 21 differentially expressed genes were validated by real-time PCR. Results showed a high concordance in the gene expression fold change between the microarrays and the RT- PCR data. The authors concluded that marbling differences are possibly a function of complex signaling pathway interactions between muscle and fat.

Journal: BMC Genomics. 2010 Nov 29;11(1):673.

Title: Analysis of copy loss and gain variations in Holstein cattle autosomes using BeadChip SNPs.

Authors: Seroussi E, et al.

The authors of this study used the Illumina BovineSNP50 BeadChip to analyze copy number variation in cattle. The BovineSNP50 contains 54,001 SNPs, some of which fall within CNV regions. The authors used BeadChip data obtained for 912 Israeli bulls to investigate the effects of CNV on SNP calls. For each of the SNPs, they estimated the frequencies of occurrence of loss of heterozygosity and of gain based either on deviation from the expected Hardy-Weinberg equilibrium or on signal intensity using the PennCNV detect option. Altogether, 418 locations displayed "significantly high frequencies" of LOH/CNV. The authors noted that enrichment of transporters in CNV loci suggested their potential effect on milk-production traits. At the same time, they warned that the method has "severe limitations," and that the CNVs reported in the paper for the Holstein breed may represent as little as one-tenth of inherited common structural variation.

Journal: Breast Cancer Research and Treatment. 2010 Nov 30. [Epub ahead of print]

Title: Prediction of lymph node involvement in breast cancer from primary tumor tissue using gene expression profiling and miRNAs.

Authors: Smeets A, et al.

The aim of this study was to investigate whether lymph node involvement in breast cancer is influenced by gene or microRNA expression of the primary tumor. To do this, the authors compared gene expression profiles of primary tumor tissue from a group of 96 breast cancer patients balanced for lymph node involvement using Affymetrix Human U133 Plus 2.0 microarrays. Next, miRNA profiling was performed on a subset of 82 tumors using Illumina human miRNA microarrays. Finally, for each miRNA the number of significant inverse correlated targets was determined and compared with 1,000 sets of randomly chosen targets. A model based on 241 genes was built. The model includes multiple kinases, apoptosis-related, and zinc ion-binding genes. Integration of the microarray and miRNA data revealed 10 miRNAs suppressing lymph node invasion and one miRNA promoting lymph node invasion. The authors contend the results provide evidence that measurable differences in gene and miRNA expression exist between node-negative and node-positive patients and that lymph node involvement is not a genetically random process.

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Journal: Clinical Genetics. 2010 Nov;78(5):478-83.

Title: Mapping of three novel loci for non-syndromic autosomal recessive mental retardation (NS-ARMR) in consanguineous families from Pakistan.

Authors: Rafiq M, et al.

The authors of this study opted to study non-syndromic autosomal recessive mental retardation, or NS-ARMR, among the Pakistani population, where "people are traditionally bound to marry within the family or the wider clan." For their research purposes, they have identified more than 50 consanguineous families exhibiting clinical symptoms of NS-ARMR. In the first step of the study, nine families with multiple affected individuals were selected for molecular genetic studies. Two of these families showed linkage to previously identified NS-ARMR loci. Fifteen affected and 10 unaffected individuals from six families were genotyped by using Affymetrix 5.0 or 6.0 SNP microarrays. SNP microarray data was visually inspected by dChip and genome-wide homozygosity analysis was performed by HomozygosityMapper. Additional mapping was performed on all available affected and unaffected members in seven NS-ARMR families, using microsatellite markers. Using this methodology, the authors report that they were ultimately able to map three novel loci in seven different families originating from different areas of Pakistan.

Journal: European Journal of Human Genetics. 2010 Nov 24. [Epub ahead of print]

Title: Experiences with array-based sequence capture; toward clinical applications.

Authors: Almomani R, et al.

The authors performed array-based sequence capture using 385K Roche NimbleGen arrays to zoom in on the protein-coding and immediate intron-flanking sequences of 112 genes that are potentially involved in mental retardation and congenital malformation. Captured material was sequenced using an Illumina sequencer. The researchers also built a data analysis pipeline to detect sequence variants, position them in relation to the gene, check for their presence in databases, and predict the potential consequences at the level of RNA splicing and protein translation. In the samples analyzed, the authors found that all known variants were reliably detected, including pathogenic variants from control cases and SNPs derived from array experiments. Still, the authors argue that for ultimate diagnostic application, overall results need to be improved. For example, they wrote in the paper, future arrays should contain probes from both DNA strands, and to obtain more even coverage, one could add fewer probes from densely covered regions and more probes from sparsely covered regions.

Journal: Genes, Chromosomes and Cancer. 2010 Nov;49(11):1046-53.

Title: Array-CGH analysis of microdissected chromosome 19 markers in ovarian carcinoma identifies candidate target genes.

Authors: Micci F, et al.

The authors of this study used high-resolution array comparative genomic hybridization to investigate 29 different chromosome 19 markers after previous microdissection of ovarian carcinoma metaphases. Along the entire chromosome 19, a total of nine regions were found gained in 10 or more carcinomas, while 15 regions were gained in six to 10 markers. The most commonly gained region was observed in 19p13. According to the authors, a total of 43 genes reside in the most commonly gained regions. Most of them code for zinc finger proteins. None of these genes is known to be involved in human neoplasia, the authors noted, but their frequent gain in the examined tumors makes all of them candidates for a pathogenetic role in ovarian carcinogenesis.

Journal: Genes, Chromosomes and Cancer. 2010 Nov 22. [Epub ahead of print]

Title: Common pathogenetic mechanism involving human chromosome 18 in familial and sporadic ileal carcinoid tumors.

Authors: Cunningham J, et al.

The authors of this study investigated 55 sporadic and familial patients diagnosed with ileal carcinoid tumors. Molecular analyses of 61 tumors from 45 individuals, including eight familial and 37 sporadic patients, was conducted to determine global copy number aberrations using BAC and Illumina SNP arrays and Affymetrix gene expression profiling chips. The clinical and molecular similarities identified between sporadic and familial cases suggested a common pathogenetic mechanism involved in tumor initiation, the authors concluded. They also argued that the familial variant of ileal carcinoid represents a previously unrecognized autosomal dominant inherited tumor disease, which they propose to call familial ileal endocrine carcinoma.

Journal: Genomics. 2010 Nov 6. [Epub ahead of print]

Title: Genome-wide association study of copy number variations associated with pulmonary function measures in Korea Associated Resource (KARE) cohorts.

Authors: Lee B, et al.

The authors performed a copy number variant-based genome-wide association study of pulmonary function measures in Korea Associated Resource cohorts. The Affymetrix Genome-wide Human SNP Array 5.0 was used to measure genome-wide variation and CNV segmentation was performed using Golden Helix's SVS 7.0 software platform. The authors identified significantly associated 1,260 CNVs with pulmonary function measures. Functional gene classification and annotation analysis found five highly enriched clusters: the BPI/LBP/Plunc superfamily; myosin; serpin peptidase inhibitor; protein tyrosine phosphatase; and olfactory receptors. According to the authors, gene-based CNVs are likely to be involved in the pathogenesis and inflammatory responsiveness of pulmonary diseases.

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Journal: Lab on a Chip. 2010 Nov 7;10(21):2917-24.

Title: Micromolded arrays for separation of adherent cells.

Authors: Wang Y, et al.

The authors present an approach for isolating viable single cells or colonies from a mixed population using a cell microarray platform. The platform includes arrays of microwells with bases composed of detachable concave elements, termed microrafts. The arrays were fabricated by a dip-coating process using a polydimethylsiloxane mold as the template and the array substrate. This manufacturing approach enabled the use of materials other than photoresists to create the array elements, according to the authors. Microrafts possessing low autofluorescence could be fabricated for fluorescence-based identification of cells. Cells plated on the microarray settled and attached at the center of the wells due to the microrafts' concavity. Individual microrafts were readily dislodged by the action of a needle inserted through the compliant polymer substrate. For cell analysis and isolation, cells of interest were identified using a standard inverted microscope and microrafts carrying target cells were dislodged with the needle. The released cells/microrafts could be collected, cultured, and clonally expanded, the authors demonstrated.

Journal: Lab on a Chip. 2010 Nov 21;10(22):3084-93.

Title: Multiplexed protein detection using antibody-conjugated microbead arrays in a microfabricated electrophoretic device.

Authors: Barbee K, et al.

This paper highlights the development of a microfabricated electrophoretic device for assembling high-density arrays of antibody-conjugated microbeads for chip-based protein detection. The device consists of a flow cell formed between a gold-coated silicon chip with an array of microwells etched in a silicon dioxide film and a glass coverslip with a series of thin gold counter electrode lines. In this study, the authors demonstrated that 0.4 and 1 micrometer beads conjugated with antibodies could be assembled into the microwells by applying a pulsed electric field across the chamber. They also showed that these antibody-conjugated microbead arrays could be used to perform on-chip sandwich immunoassays. The authors argue that their device will be useful for assembling high-density, encoded antibody arrays for multiplexed detection of proteins and other types of protein-conjugated microbeads for applications such as the analysis of protein-protein interactions.

Journal: Molecular Biotechnology. 2010 Nov;46(3):234-42.

Title: High resolution array-CGH characterization of human stem cells using a stem cell focused microarray.

Authors: Elliott A, et al.

This paper discusses a stem cell focused array-comparative genomic hybridization microarray that covers the entire genome at high resolution with increased probe coverage in more than 60 stem cell associated genes and more than 195 cancer-related genes. Several induced pluripotent stem cells lines were analyzed using the focused microarray and compared with either karyotyping or a standard Agilent 44K microarray. In addition to the abnormalities detected by these platforms, the custom microarray identified several small duplications spanning stem cell or cancer-related genes. The authors conclude that scientists using a stem cell focused microarray to characterize their stem cells will be aware of the structural variants present in their cells and be more confident in their experimental results.

Journal: Molecular Cytogenetics. 2010 Nov 9;3:22.

Title: The use of array-CGH in a cohort of Greek children with developmental delay.

Authors: Manolakos E, et al.

The authors report the use of array comparative genomic hybridization to study mental retardation in a Greek cohort. In total, 82 children of Greek origin were analyzed using arrays. Fourteen CNVs were detected in the studied patients. In nine patients, the chromosomal aberrations were inherited from one of the parents. Furthermore, three de novo clinically significant CNVs were detected. All CNVs were confirmed by fluorescence in situ hybridization. The authors note that their 11 percent diagnostic yield of clinically significant CNVs matches yields in studies conducted outside of Greece.

Journal: Molecular Cytogenetics. 2010 Nov 26;3(1):24. [Epub ahead of print]

Title: Clinical application of whole genome array CGH during prenatal diagnosis: Study of 25 selected pregnancies with abnormal ultrasound findings or apparently balanced structural aberrations.

Authors: Evangelidou P, et al.

The authors of this study applied array comparative genomic hybridization in selected cases during prenatal diagnosis. Specifically, array CGH was applied in 25 fetal samples out of which 15 had normal karyotypes and abnormal ultrasound findings and 10 had apparently balanced structural aberrations with or without abnormal ultrasound findings. DNA was extracted from peripheral blood, chorionic villi samples and amniotic fluid. A BlueGnome bacterial artificial chromosome array was applied and results were confirmed with fluorescence in situ hybridization, multiplex ligation-dependant probe amplification, or real-time PCR. The authors found that three out of 25 samples referred for prenatal array CGH were found to carry copy number alterations. There were two cases with clinically significant alterations, while one was of uncertain clinical significance. They determined that array CGH is capable of identifying chromosomal abnormalities that cannot be detected during routine prenatal cytogenetic analysis.

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Journal: Molecular Psychiatry. 2010 Nov 16. [Epub ahead of print]

Title: A genome-wide association study on common SNPs and rare CNVs in anorexia nervosa.

Authors: Wang K, et al.

The authors carried out a genome-wide association study on 1,033 anorexia nervosa cases and 3,733 pediatric control subjects, all of whom were of European ancestry and were genotyped on the Illumina HumanHap610 platform. They confirmed that common SNPs within OPRD1 confer risk for AN, and obtained suggestive evidence that common SNPs near HTR1D confer risk for restricting-type AN specifically. However, no SNPs reached genome-wide significance in the study's data, while top association signals were detected near ZNF804B, CSRP2BP, NTNG1, AKAP6, and CDH9. In parallel, the authors also performed genome-wide analysis on copy number variations using the signal intensity data from the SNP arrays. They did not find evidence that AN cases have more CNVs than control subjects, nor do they have over-representation of rare or large CNVs. However, the authors did identify several regions with rare CNVs that were only observed in AN cases. The authors suggested that both common SNPs and rare CNVs may confer genetic risk to AN.

Journal: Nature Biotechnology. 2010 Nov 28. [Epub ahead of print]

Title: High-fidelity gene synthesis by retrieval of sequence-verified DNA identified using high-throughput pyrosequencing.

Authors: Matzas M, et al.

The authors of this paper describe a highly parallel and miniaturized method, called megacloning, for obtaining high-quality DNA by using next-generation sequencing technology as a preparative tool. The authors carried out the method by processing both chemically synthesized and microarray-derived DNA oligonucleotides with a robotic system for imaging and picking beads directly off of a high-throughput pyrosequencing platform. They claim that their method can reduce error rates by a factor of 500 compared to the starting oligonucleotide pool generated by microarray. They used the DNA obtained by megacloning to assemble synthetic genes. The authors argued that millions of DNA fragments could in principle be sequenced, characterized, and sorted in a single megacloner run, enabling constructive biology up to the megabase scale.

Journal: PLoS One. 2010 Nov 8;5(11):e15476.

Title: DNA suspension arrays: silencing discrete artifacts for high-sensitivity applications.

Authors: Lalonde M, et al.

The authors of this paper demonstrated a model assay for HIV-1 drug resistance mutations, where ligase discrimination products were collected on a suspension array. In developing the system, the authors discovered that signal from multiple polymorphisms was obscured by two discrete hybridization artifacts. Specifically, they noted that tethering of unligated probes on the template DNA elicited false signal, and unpredictable probe secondary structures impaired probe capture and suppressed legitimate signal from the array. Two sets of oligonucleotides were used to disrupt these structures; one to displace unligated reporter labels from the bead-bound species and another to occupy sequences that interfered with array hybridization. The resulting artifact silencing system resulted in a mean 21-fold increase in sensitivity for 29 minority variants of 17 codons in a model assay for mutations most commonly associated with HIV-1 drug resistance. According to the authors, since the artifacts characterized are not unique to their system, their specific inhibition might improve the quality of data from solid-state microarrays as well as from the growing number of multiple analyte suspension arrays relying on sequence-specific nucleic acid target capture.

Journal: PLoS One. 2010 Nov 15;5(11):e15393.

Title: Genome-wide analysis of copy number variation in type 1 diabetes.

Authors: Grayson B, et al.

The authors performed a genome-wide copy number variant analysis on a cohort of 20 unrelated adults with type 1 diabetes and a control cohort of 20 subjects using the Affymetrix SNP Array 6.0 in combination with the Birdsuite copy number calling software. They identified 39 CNVs as enriched or depleted in T1D cases versus controls. Additionally, they performed CNV analysis in a group of 10 monozygotic twin pairs discordant for T1D. Eleven of these 39 CNVs were also respectively enriched or depleted in the twin cohort, suggesting that these variants may be involved in the development of islet autoimmunity, as the presently unaffected twin is at high risk for developing islet autoimmunity and T1D in his or her lifetime, the authors noted.

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