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In Print: Sep 14, 2010


Microarray Papers of Note Published August 2010

Journal: American Journal of Respiratory and Critical Care Medicine. 2010 Aug 27. [Epub ahead of print]

Title: Genome-wide association study identifies BICD1 as a susceptibility gene for emphysema.

Authors: Kong X, et al.

The authors of this study sought to identify genetic determinants of emphysema assessed through high-resolution chest computed tomography in individuals with chronic obstructive pulmonary disease. To do this, they performed a genome-wide association study of emphysema determined from chest CT scans with a total of 2,380 individuals with COPD in three independent Caucasian cohorts. Using microarrays, they tested SNP associations with the presence or absence of emphysema determined by radiologist assessment in two of the three cohorts and a quantitative emphysema trait in all three cohorts. The authors identified association of a SNP in BICD1 with the presence or absence of emphysema.

Journal: BMC Research Notes. 2010 Aug 8;3:223.

Title: Evaluation of high-resolution microarray platforms for genomic profiling of bone tumors.

Authors: Kresse S, et al.

As part of the EuroBoNeT network of excellence for research on bone tumors, the authors of this study evaluated four different commercial high-resolution microarray platforms in order to identify the most appropriate technology for mapping DNA copy number aberrations in such tumors. Specifically, DNA from two different cytogenetically well-characterized bone sarcoma cell lines, representing a simple and a complex karyotype, respectively, was tested in duplicate on four high-resolution microarray platforms: Affymetrix's Genome-Wide Human SNP Array 6.0, Agilent's Human Genome CGH 244A, Illumina's HumanExon510s-Duo, and NimbleGen's HG18 CGH 385K WG Tiling v1.0. The authors found that all platforms performed reasonably well, but stated in the study that Agilent microarrays showed better dynamic range, and that Agilent and Affymetrix microarrays performed well with platform-independent analysis software, implying more robust data.

BioArray News interviewed co-author Leonardo Meza-Zepeda about the study last month (BAN 8/17/2010).

Journal: Carcinogenesis. 2010 Aug;31(8):1354-9.

Title: Functional screening using a microRNA virus library and microarrays: a new high-throughput assay to identify tumor-suppressive microRNAs.

Authors: Izumiya M, et al.

The authors of this paper developed a functional screening assay that supports the high-throughput identification of microRNAs that have a role in cancer phenotypes of interest, via the combination of pooled lentivirus vectors expressing several hundred miRNA precursors and a custom-made microarray. Self versus self-hybridization analysis using pooled PCR products generated highly linear and reproducible results, according to the authors. To test the feasibility of the assay, the authors focused on miRNAs that control proliferation of pancreatic cancer cells and successfully identified five miRNAs that negatively control cell proliferation, including miRNA-34a, which was previously identified as a representative tumor-suppressive miRNA, the authors stated in the paper. The results were further validated using lentivirus vectors expressing each of the five miRNAs or synthetic miRNAs.

Journal: Clinical Chemistry. 2010 Aug 20. [Epub ahead of print]

Title: Identification of pregnancy-associated microRNAs in maternal plasma.

Authors: Miura K, et al.

The aim of this study was to isolate and characterize pregnancy-associated microRNAs in maternal plasma. Based on a microarray screen of 723 human miRNAs, the authors selected miRNAs that exhibited signal intensities more than 100 times higher in placental tissues than in the corresponding whole blood samples. Subsequent quantitative real-time, reverse-transcription PCR revealed miRNAs produced predominantly in the placenta that showed significantly decreased concentrations in maternal plasma after delivery. These miRNAs were identified as pregnancy-associated miRNAs. Most of the genes encoding the identified miRNAs were clustered on chromosomes 19q13.42 or 14q32, which are critical regions for placental and embryonic development, the authors stated. They believe the new pregnancy-associated miRNAs may be useful molecular markers for monitoring pregnancy-associated diseases.

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Journal: Clinical Chemistry. 2010 Aug;56(8):1297-306.

Title: Evaluation of oligonucleotide sequence capture arrays and comparison of next-generation sequencing platforms for use in molecular diagnostics.

Authors: Hoppman-Chaney N, et al.

The authors evaluated the NimbleGen Sequence Capture 385K Human Custom Arrays for enrichment of 22 genes. They sequenced each sample on both the Roche 454 Genome Sequencer FLX and the Illumina Genome Analyzer II to compare platform performance. While the sequence capture method allowed the authors to rapidly develop a large number of sequencing assays, they encountered difficulty enriching G+C-rich regions. They also observed discrepancies among sequence variants identified by the different sequencing platforms. According to the authors, neither sequencing technology was able to detect every variant identified by Sanger sequencing because of "well-known drawbacks of the NGS technologies."

Journal: Clinical Chemistry and Laboratory Medicine. 2010 Aug 13. [Epub ahead of print]

Title: ThalassoChip, an array mutation and single nucleotide polymorphism detection tool for the diagnosis of beta-thalassemia.

Authors: Shammas C, et al.

The authors of this study describe the ThalassoChip, a beta-thalassemia genetic diagnostic tool that is based on arrayed primer extension technology. Using a redesigned chip, 666 DNA samples collected from eight Mediterranean countries were used for standardization, optimization, and validation of the array. The beta-globin gene region was amplified by PCR, the products were hybridized to the probes after fragmentation, and the APEX reaction followed. According to the authors, the ThalassoChip can now detect 57 beta-globin gene mutations and three SNPs in a single test.

Journal: Environmental Microbiology. 2010 Aug 1. [Epub ahead of print]

Title: Time-series analyses of Monterey Bay coastal microbial picoplankton using a 'genome proxy' microarray.

Authors: Rich V, et al.

To investigate the temporal, spatial and phylogenetic resolution of marine microbial community structure and variability, the authors of this study designed a "genome proxy array," an oligonucleotide microarray targeting marine microbial genome fragments and genomes, evaluated it against metagenomic sequencing, and applied it to time-series samples from Monterey Bay in California. The expanded array targeted 268 microbial genotypes across much of the known diversity of cultured and uncultured marine microbes, according to the authors. Fifty-seven samples from Monterey Bay were examined with the array, spanning the photic zone, the base of the surface mixed layer, and the subphotic zone. Ninety-five out of 268 targets present showed signal. The genome-proxy array's ability to track populations of closely related genotypes indicated population shifts within several abundant target taxa, with specific populations in some cases clustering by depth or oceanographic season. Although 51 cultivated organisms were targeted on the chip, the majority of targets detected and of total target signal were from uncultivated genotypes. The authors believe the $15 array provided a relatively cost-effective approach for surveying the natural history of uncultivated lineages.

Journal: Epigenetics. 2010 Aug 27;5(6). [Epub ahead of print]

Title: Genome-wide DNA methylation profiling of chronic lymphocytic leukemia allows identification of epigenetically repressed molecular pathways with clinical impact.

Authors: Tong W, et al.

The authors of this study performed a genome-wide analysis of aberrant DNA methylation in chronic lymphocytic leukemia using methylated CpG island amplification coupled with a promoter microarray. They identified 280 potential targets of aberrant DNA methylation in CLL. These genes were located more frequently in chromosomes 19, 16, 17, and 11 and could be grouped in several functional networks. Methylation status was confirmed for 22 of these genes in 78 CLL patients by pyrosequencing. The authors also analyzed the expression of two genes, PRIMA1 and APP, in primary cells and of GALGT2, TFAP2C, and PRIMA1 in leukemia cells and found there was an inverse association between methylation and gene expression.

Journal: Genomics. 2010 Aug 3. [Epub ahead of print]

Title: Development of a versatile, target-oriented tiling microarray assay for measuring allele-specific gene expression.

Authors: He H, et al.

The authors of this study designed an oligonucleotide tiling microarray to specifically target 518 SNPs between the two sequenced rice Oryza sativa subspecies, indica and japonica. The tiling array included all 25-mer probes interrogating each SNP by placing the polymorphic site at all 25 possible positions within the probe. Through hybridization to a titration series in which the japonica- and indica-derived cDNA templates were mixed with altering proportions, a regression model was used to screen for diagnostic probe sets for each SNP. The study's results indicate that 55 percent of SNPs have at least one diagnostic probe pair suitable for distinguishing and quantifying the relative abundance of allele-specific transcripts. The authors also analyzed allele-specific expression in reciprocal indicaxjaponica F(1) hybrids and detected imbalanced expression at approximately one-third of the SNPs. These results were validated by RNA-sequencing and allele-specific real-time PCR experiments.

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Journal: Hepatology. 2010 Aug;52(2):443-53.

Title: Transcriptome sequencing, microarray, and proteomic analyses reveal cellular and metabolic impact of hepatitis C virus infection in vitro.

Authors: Woodhouse S, et al.

The authors of this study conducted a full-genome RNA-seq analysis of hepatitis C virus in a host cell to analyze infected and non-infected cells, and compared this to microarray and proteomic analyses. The combined power of the triple approach revealed that HCV infection affects a number of previously unreported canonical pathways and biological functions, including pregnane X receptor/retinoic acid receptor activation as a potential host antiviral response, and integrin-linked kinase signaling as an entry factor, the authors found. This approach also identified several mechanisms implicated in HCV pathogenesis, including an increase in reactive oxygen species. HCV infection had a broad effect on cellular metabolism, leading to increases in cellular cholesterol and free fatty acid levels, associated with a profound and specific decrease in cellular glucose levels.

Journal: Molecular Human Reproduction. 2010 Aug;16(8):583-9.

Title: SNP microarray-based 24 chromosome aneuploidy screening is significantly more consistent than FISH.

Authors: Treff N, et al.

This study investigated the prevalence of chromosomal abnormality and mosaicism found with two different single-cell aneuploidy screening techniques. Thirteen arrested cleavage-stage embryos were studied. Each was biopsied into 160 individual cells. The cells from each embryo were randomized into two groups. Those destined for fluorescent in situ hybridization-based aneuploidy screening were fixed, one cell per slide. Cells for SNP microarray-based aneuploidy screening were put into individual tubes. The authors determined that the microarray provided an interpretable result in 96 percent of cases, while FISH provided an interpretable result in 83 percent of cases. Mosaicism was significantly less commonly observed by microarray than by FISH. The authors suggest that FISH technology may overestimate the contribution of mitotic error to the origin of aneuploidy at the cleavage stage of human embryogenesis.

Journal: Nature. 2010 Aug 5;466(7307):707-13.

Title: Biological, clinical and population relevance of 95 loci for blood lipids.

Author: Teslovich T, et al.

In this study, researchers from 17 countries used a meta-analysis of dozens of genome-wide association studies on more than 100,000 individuals to pin down 95 variants linked to blood lipid levels in European and other populations, with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include SNPs near known lipid regulators as well as in scores of loci not previously implicated in lipoprotein metabolism, the authors reported. Additionally, they found that the 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations — East Asians, South Asians, and African Americans.

Journal: Nature. 2010 Aug 19;466(7309):973-7.

Title: An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis.

Author: Berry M, et al.

In this paper, the authors used arrays to identify a gene transcript pattern in the blood of individuals with active TB infections that is not detected in healthy individuals. According to the authors, a fraction of individuals with a latent or dormant form of infection with TB-causing bacteria have the same signature, and they speculated that the signature may eventually help find those at risk of developing active TB. The researchers used Illumina HumanHT-12 v3 BeadChip arrays in the study to assess gene transcript patterns in blood samples from 42 individuals recruited in London, including 13 participants with active TB, 17 with latent TB, and a dozen healthy controls. Based on the results, the team found a 393-gene signature linked to active TB infection that was independent of factors such as age, sex, or ethnicity. They subsequently verified their findings by looking at 21 active and 21 latent TB cases and a dozen controls from the UK and a second validation set from South Africa that included 20 individuals with active TB and 31 individuals with latent TB.

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Journal: Nature Genetics. Epub 2010 Aug 8.

Title: Genome-wide association analyses identifies a susceptibility locus for tuberculosis on chromosome 18q11.2.

Authors: Thye T, et al.

The authors of this study combined data on more than 11,000 individuals from two genome-wide association studies done in Ghana and The Gambia to identify genetic loci linked to tuberculosis. Individuals in Ghana were genotyped at more than 740,000 autosomal SNPs using the Affymetrix SNP 6.0 array, while genotype data at more than 350,000 autosomal SNPs had been generated with the Affy GeneChip 500K for individuals in The Gambia. Results from these studies, as well as replication testing involving individuals from Ghana and Malawi, identified a chromosome 18 locus distinct from TB susceptibility variants in the major histocompatibility locus, which contributes to immune system function.

Journal: Nucleic Acids Research. 2010 Aug 6. [Epub ahead of print]

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

Authors: Borovkov A, et al.

The authors of this study developed a protocol for gene assembly directly from microarray-synthesized oligonucleotides. The protocol was tested on mixtures of up to 2,000 oligonucleotides eluted directly from microarrays obtained from three different chip manufacturers. These mixtures contained less than 5 percent perfect oligos, and 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. Genes assembled from the microarray-eluted material using the new protocol matched the quality of the genes assembled from greater than 95 percent pure column-synthesized oligonucleotides by the standard protocol, according to the authors. The overall cost of assembly by the authors' method approached $0.05 per base, a price point they note could make gene synthesis more affordable than traditional cloning.

Journal: The Pharmacogenomics Journal. 2010 Aug;10(4):247-57.

Title: Consistency of predictive signature genes and classifiers generated using different microarray platforms.

Authors: Fan X, et al.

As part of the MicroArray Quality Control Phase II project, the authors of this study showed between 80 percent and 90 percent cross-platform prediction consistency using a large toxicogenomics data set by demonstrating that the signature genes of a classifier generated from one platform can be directly applied to another platform to develop a predictive classifier, and that a classifier developed using data generated from one platform can accurately predict samples that were profiled using a different platform. According to the authors, the results suggest the potential of using published signature genes in cross-platform applications and the possible adoption of the published classifiers for a variety of applications.

Journal: The Pharmacogenomics Journal. 2010 Aug;10(4):278-91.

Title: A comparison of batch effect removal methods for enhancement of prediction performance using MAQC-II microarray gene expression data.

Authors: Luo J, et al.

This paper uses a broad selection of data sets from the Microarray Quality Control Phase II effort, generated on three microarray platforms with different causes of batch effects, to assess the efficacy of their removal. Two data sets from cross-tissue and cross-platform experiments are also included. Of the 120 cases studied using support vector machines and K nearest neighbors as classifiers and Matthews correlation coefficient as a performance metric, the authors found that ratio-G, ratio-A, EJLR, mean-centering, and standardization methods perform better or equivalent to no batch effect removal in 89, 85, 83, 79, and 75 percent of the cases, respectively. The authors suggest these results reveal that the application of these methods is generally advisable and ratio-based methods are preferred.

Journal: The Pharmacogenomics Journal. 2010 Aug;10(4):324-35.

Title: Variability in GWAS analysis: the impact of genotype calling algorithm inconsistencies.

Authors: Miclaus K, et al.

In this paper, the Genome-Wide Association Working Group of the MAQC-II project assessed the variability of genotype calls within and between different genotype-calling algorithms using data for coronary artery disease from the Wellcome Trust Case Control Consortium and the University of Ottawa Heart Institute. Their results show that the choice of genotyping algorithm, for example, the Bayesian robust linear model with Mahalanobis distance classifier (BRLMM) or the corrected robust linear model with maximum-likelihood-based distances (CRLMM), can introduce marked variability in the results of downstream case-control association analysis for the Affymetrix 500K array. According to the authors, the amount of discordance between results is influenced by how samples are combined and processed through the respective genotype-calling algorithm. Further work using HapMap samples shows that inconsistencies between Affy arrays and calling algorithms can lead to genotyping errors that influence downstream analysis.

Journal: PLoS Biology. 2010 Aug 10;8(8):e1000451.

Title: A simple genetic architecture underlies morphological variation in dogs.

Authors: Boyko A, et al.

In this study, the authors generated a high-density map of canine genetic variation by genotyping 915 dogs from 80 domestic dog breeds, 83 wild canids, and 10 outbred African shelter dogs across 60,968 SNPs using the Affymetrix version 2 Canine GeneChip array. Coupling this genomic resource with external measurements from breed standards and individuals as well as skeletal measurements from museum specimens, they identified 51 regions of the dog genome associated with phenotypic variation among breeds in 57 traits. Additionally, the authors determined that across dog breeds, a small number of quantitative trait loci explain the majority of phenotypic variation for most of the traits studied.

Journal: PLoS One. 2010 Aug 11;5(8):e12132.

Title: MicroRNAs miR-17 and miR-20a inhibit T cell activation genes and are under-expressed in MS whole blood.

Authors: Cox, et al.

The authors of this study investigated the transcriptome of currently known microRNAs using Illumina miRNA microarray analysis in peripheral blood samples of 59 treatment-naïve multiple sclerosis patients and 37 controls. Of these 59, the authors found that 18 had a primary progressive, 17 a secondary progressive and 24 a relapsing remitting disease course. In all MS subtypes, they determined that miR-17 and miR-20a were significantly under-expressed in MS, and confirmed this finding by RT-PCR. Additionally, the authors demonstrated that these miRNAs modulate T cell activation genes in a knock-in and knock-down T cell model, and found that the same T cell activation genes are also up-regulated in MS whole-blood mRNA, suggesting these miRNAs or their analogs could provide useful targets for new therapeutic approaches in the future.

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