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In Print: Mar 3, 2009


Journal: Analytical Biochemistry. 2009 Feb 15;385(2):203-7.
Title: Correlation analysis of external RNA controls reveals its utility for assessment of microarray assay.
Authors: X Fan; H Fang; H Hong; R Perkins; L Shi; W Tong.

Abstract: The US Food and Drug Administration-led community-wide Microarray Quality Control study generated a large amount of microarray data with the implementation of External RNA controls across several commercial microarray platforms. In this paper, an ERC-based correlation analysis was conducted to assess the quality of a microarray experiment. The authors found that the "pairwise correlations of tERCs are sample independent, indicating that the array data obtained from different biological samples can be treated as technical replicates in analysis of tERCs." Consequently, the commonly used quality control method of applying correlation analysis on technical replicates can be adopted for assessing array performance based on different biological samples using tERCs, the authors state. They also claim the proposed approach is "sensitive to identifying outlying assays and is not dependent on the choice of normalization method."

Journal: Bioinformatics. 2009 Feb 1;25(3):315-21
Title: Reference alignment of SNP microarray signals for copy number analysis of tumors.
Authors: S Pounds; C Cheng; C Mullighan; S Raimondi; S Shurtleff; J Downing

Abstract: The paper describes a procedure to align single nucleotide polymorphism microarray signals for copy number analysis. For each individual array, this reference alignment procedure uses a set of selected markers as internal references to direct the signal alignment. RAP aligns the signals so that each array has a similar signal distribution among its reference markers. An accompanying reference selection algorithm, or RSA, uses genotype calls and initial signal intensities to choose two-copy markers as the internal references for each array. After RSA and RAP are applied, each array has a "similar distribution of signals of two-copy markers so that across-array signal comparisons are biologically meaningful," the authors write. An upper bound for a statistical metric of signal misalignment is derived and provides a theoretical basis to choose RSA-RAP over other alignment procedures for copy number analysis of cancers. In a study of acute lymphoblastic leukemia described in the paper, RSA-RAP gives copy number analysis results that show "substantially better concordance with cytogenetics than do two other alignment procedures."

Journal: Bioinformatics. 2009 Feb 18. [Epub ahead of print]
Title: gcExplorer: interactive exploration of gene clusters.
Authors: T Scharl; F Leisch

Abstract: Cluster analysis plays an important role in the analysis of gene expression data and is routinely used to find groups of genes with common expression pattern. Visualization of cluster solutions is particularly important. This paper presents the new R package gcExplorer for the interactive exploration of gene clusters. Specifically, the authors state that gcExplorer facilitates the interpretation of cluster results and allows investigation of extensive information about clusters.

Journal: Biosensors and Bioelectronics. 2009 Feb 15;24(6):1706-11.
Title: SNPs detection by a single-strand specific nuclease on a PNA zip-code microarray.
Authors: H Mun; A Girigoswami; C Jung; D Cho; H Park

Abstract: This paper discusses a peptide nucleic acid microarray-based method for SNP detection in human genes. The technique relies on the mismatched cleavage activity of a single-strand specific nuclease. PCR amplification is performed to prepare gene fragments containing the mutation sites. The amplified fragments are then employed as templates for the SSS nuclease reaction using chimeric probes, modified with biotin at the 5' end and extended with a unique anchoring zip-code complement sequence at the 3' end. The SSS nuclease promotes cleavage of heteroduplex DNAs at base mismatched positions to produce crumbled chimeric probes in the presence of imperfectly matching template strands. In contrast, the probes remain intact when they interact with perfectly matched template strands. Only the non-fragmented probes generate fluorescence signals after treatment with streptavidin-Cy3 on the PNA zip-code array, the authors write. The authors claim the methodology was used to "successfully genotype selected Korean-specific BRCA mutation sites with wild type and mutant samples."

Journal: BMC Bioinformatics. 2009 Feb 4;10:49.
Title: "GenotypeColour": colour visualisation of SNPs and CNVs.
Authors: S Barlati; S Chiesa; C Magri

Abstract: The authors present GenotypeColour, a "rapid user-friendly tool able to upload, visualize and compare the huge amounts of data produced by Affymetrix Human Mapping GeneChips without losing the overall view of the data." Some features of GenotypeColour include: a) visualizing the entire genome variability in a single screenshot for one or more samples; b) the simultaneous display of the genotype and copy number state for thousands of SNPs; and the comparison of large amounts of samples by producing consensus images displaying regions of complete or partial identity. The software is also useful for genotype analysis of trios and to show regions of potential uniparental disomy, according to the authors. All information can then be exported in a tabular format for analysis with dedicated software. At present, the software can handle data from 10 K, 100 K, 250 K, 5.0 and 6.0 Affymetrix chips.

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Journal: BMC Bioinformatics. 2009 Feb 6;10:50.
Title: EMMA 2 — a MAGE-compliant system for the collaborative analysis and integration of microarray data.
Authors: M Dondrup; S Albaum; T Griebel; K Henckel; S Jünemann; T Kahlke; C Kleindt; H Küster; B Linke; D Mertens; V Mittard-Runte; H Neuweger; K Runte; A Tauch; F Tille; A Pühler; A Goesmann

Abstract: The authors present EMMA 2, a software package designed to "resolve shortcomings with respect to full MAGE-ML and ontology support and makes use of modern data integration techniques." The system features comprehensive data analysis functions for spotted arrays, and for the most common synthesized oligo arrays such as Agilent, Affymetrix, and NimbleGen, based on a full MAGE object model. Analysis functionality is based on R and Bioconductor packages and can make use of a compute cluster for distributed services.

Journal: BMC Bioinformatics. 2009 Feb 20;10(1):64.
Title: Inverse Langmuir method for oligonucleotide microarray analysis.
Authors: G Mulders; G Barkema; E Carlon

Abstract: This paper presents an algorithm for the analysis of Affymetrix arrays. The algorithm, referred to as the Inverse Langmuir Method, estimates the binding of transcripts to complementary probes using DNA/RNA hybridization free energies, and the hybridization between partially complementary transcripts in solution using RNA/RNA free energies. The balance between these two competing reactions allows for the translation of background-subtracted intensities into transcript concentrations. To validate the ILM, the authors applied the algorithm to publicly available microarray data from a multi-lab comparison study. The microarray experiments were performed on samples which deviated only in few genes. The log2 fold change between these two samples, as obtained from RT-PCR experiments, agreed well with the log2 fold change as obtained with the ILM, indicating that the ILM determines changes in the expression level accurately, the authors state. The paper also shows that the ILM allows for the identification of outlying probes, as it yields independent concentration estimates per probe.

Journal: BMC Genomics. 2009 Feb 20;10(1):85. [Epub ahead of print]
Title: Ultraspecific probes for high throughput HLA typing.
Authors: C Feng; C Putonti; M Zhang; R Eggers; R Mitra; M Hogan; K Jayaraman; Y Fofanov

Abstract: This paper presents a three-step approach for the design of high-throughput microarray assays for human leukocyte antigen typing. According to the authors, the approach first selects sequences containing the SNPs present in all alleles of the locus of interest and next calculates the number of base changes necessary to convert a candidate probe sequence to the closest subsequence within the set of sequences that are likely to be present in the sample, including the remainder of the human genome, in order to identify those candidate probes which are "ultraspecific" for the allele of interest. Due to the high specificity of these sequences, it is possible that preliminary steps such as PCR amplification are no longer necessary. Lastly, the minimum number of these ultraspecific probes is selected such that the highest resolution typing can be achieved for the minimal cost of production. As an example, an array was designed and in silico results were obtained for typing of the HLA-B locus. The authors conclude that the assay presented "provides a higher resolution than has previously been developed and includes more alleles than previously considered."

Journal: Chembiochem. 2009 Feb 26. [Epub ahead of print]
Title: Bacterial glycoprofiling by using random sequence peptide microarrays.
Authors: C Morales Betanzos; M Gonzalez-Moa; K Boltz; B Vander Werf; S Johnston; S Svarovsky

Abstract: The paper presents a high-throughput screening platform for identification of surface-immobilized peptides that specifically bind O-antigenic glycans of bacterial lipopolysaccharides. The method involves the screening of random sequence peptide libraries in addressable high-density microarray format using luminescent LPS-quantum dot micelles. While the main value of this approach lies in the "ability to rapidly differentiate bacterial and possibly other complex glycans," the peptides discovered in this study can "potentially be used off-array as antiendotoxic and antimicrobial lead compounds, and on-array/on-bead as diagnostic and affinity reagents," the authors find.

Journal: Human Molecular Genetics. 2009 Feb 15;18(4):767-78.
Title: Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis.
Authors: S Baranzini; J Wang; R Gibson; N Galwey; Y Naegelin; F Barkhof; E Radue; R Lindberg; B Uitdehaag; M Johnson; A Angelakopoulou; L Hall; J Richardson; R Prinjha; A Gass; J Geurts; J Kragt; M Sombekke; H Vrenken; P Qualley; R Lincoln; R Gomez; S Caillier; M George; H Mousavi; R Guerrero; D Okuda; B Cree; A Green; E Waubant; D Goodin; D Pelletier; P Matthews; S Hauser; L Kappos; C Polman; J Oksenberg

Abstract: This paper reports the results of a genome-wide association study performed in a 1,000 prospective case series of well-characterized individuals with multiple sclerosis and group-matched controls using the Illumina Sentrix HumanHap550 BeadChip platform. After quality control data filtering, the authors compared allele frequencies for 551 642 SNPs in 978 cases, and 883 controls, and assessed genotypic influences on susceptibility, age of onset, disease severity, as well as brain lesion load and normalized brain volume from magnetic resonance imaging exams. A multi-analytical strategy identified 242 susceptibility SNPs exceeding established thresholds of significance, including 65 within the MHC locus in chromosome 6p21.3. Independent replication confirms a role for GPC5, a heparan sulfate proteoglycan, in disease risk. Gene ontology-based analysis shows a functional dichotomy between genes involved in the susceptibility pathway and those affecting the clinical phenotype, the authors state.

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Journal: IEEE Transitions in Medical Imaging. 2009 Feb;28(2):194-201.
Title: Lossless compression of microarray images using image-dependent finite-context models.
Authors: A Neves; A Pinho

Abstract: The widespread adoption of microarray technology, coupled with the significant volume of data generated per experiment, in the form of images, has led to "significant challenges in storage and query retrieval," according to the authors. In this paper, a lossless bitplane-based method for efficient compression of microarray images is presented. The method is based on arithmetic coding driven by image-dependent multibitplane finite-context models. It produces an embedded bitstream that allows progressive, lossy-to-lossless decoding. The authors compare the compression efficiency of the proposed method with three image compression standards — JPEG2000, JPEG-LS, and JBIG — and also with the two most recent specialized methods for microarray image coding. The proposed method "gives better results for all images of the test sets and confirms the effectiveness of bitplane-based methods and finite-context modeling for the lossless compression of microarray images," the authors conclude.

Journal: Journal of Medical Genetics. 2009 Feb;46(2):123-31.
Title: Detection of cryptic pathogenic copy number variations and constitutional loss of heterozygosity using high resolution SNP microarray analysis in 117 patients referred for cytogenetic analysis and impact on clinical practice.

Authors: D Bruno; D Ganesamoorthy; J Schoumans; A Bankier; D Coman; M Delatycki; R Gardner; M Hunter; P James; P Kannu; G McGillivray; N Pachter; H Peters; C Rieubland; R Savarirayan; I Scheffer; L Sheffield; T Tan; S White; A Yeung; Z Bowman; C Ngo; K Choy; V Cacheux; L Wong; D Amor; H Slater

Abstract: The aim of this study was to investigate replacement of "time-consuming, locus-specific testing for specific microdeletion and microduplication syndromes with microarray analysis, which theoretically should detect all known syndromes with CNV aetiologies as well as new ones." Genome-wide copy number analysis was performed on 117 patients using Affymetrix 250K microarrays, and 434 CNVs were found, including 18 pathogenic CNVs and 9 identified as "potentially pathogenic." Almost all pathogenic CNVs were larger than 500 kb, significantly larger than the median size of all CNVs detected. Segmental regions of loss of heterozygosity larger than 5 Mb were found in 5 patients. In conclusion, the authors state that microarray analysis has "improved diagnostic success in this group of patients." The study also "revealed the potential to make genetic diagnoses that were not evident in the clinical presentation, with implications for pretest counseling and the consent process."

Journal: Journal of Neurogenetics. 2009 Feb 18:1-12. [Epub ahead of print]
Title: Survey of schizophrenia and bipolar disorder candidate genes using chromatin immunoprecipitation and tiled microarrays (ChIP-chip).
Authors: E Pedrosa; J Locker; H Lachman

Abstract: According to the paper, it has been difficult to identify disease-causing alleles in schizophrenia and bipolar disorder candidate genes, possibly because functional variants may exist in unidentified regulatory domains. However, it is feasible to screen genes for such regulatory domains by using chromatin immunoprecipitation-based methodologies, such as ChIP-chip and ChIP-seq. As a "first step toward demonstrating the feasibility of this approach in psychiatric genetics," the authors used ChIP-chip to identify regulatory domains in several candidate genes: NRG1, DTNBP1, DISC1, DAO, DAOA, PDE4B, and COMT. Immunoprecipitates were generated with antibodies to histone H3 acetylated at lysine 9 (H3K9Ac) and histone H3 monomethylated at lysine 4 (H3K4me1), which mark promoters and some enhancers, using fetal brain chromatin as a substrate. Several novel putative regulatory elements, as well as the core and proximal promoters for each gene, were enriched in the immunoprecipitates. The authors note that genetic variants within these regions would be of interest to study as potential disease-associated alleles.

Journal: Molecular Psychiatry. 2009 Feb 17. [Epub ahead of print].
Title: Genomewide linkage scan of schizophrenia in a large multicenter pedigree sample using single nucleotide polymorphisms.
Authors: P Holmans; B Riley; A Pulver; M Owen; D Wildenauer; P Gejman; B Mowry; C Laurent; K Kendler; G Nestadt; N Williams; S Schwab; A Sanders; D Nertney; J Mallet; B Wormley; V Lasseter; M O'Donovan; J Duan; M Albus; M Alexander; S Godard; R Ribble; K Liang; N Norton; W Maier; G Papadimitriou; D Walsh; M Jay; A O'Neill; F Lerer; D Dikeos; R Crowe; J Silverman; D Levinson

Abstract: In this paper, a genome-wide linkage scan was carried out in eight clinical samples of informative schizophrenia families. After all quality control checks, the analysis of 707 European-ancestry families included 1,615 affected and 1,602 unaffected genotyped individuals, and the analysis of all 807 families included 1,900 affected and 1,839 unaffected individuals. Multipoint linkage analysis with correction for marker-marker linkage disequilibrium was carried out with 5,861 single nucleotide polymorphisms. The authors found "suggestive evidence for linkage" on chromosomes 8p21, 8q24.1, 9q34 and 12q24.1 in nonparametric and/or parametric analyses. In a logistic regression allele-sharing analysis of linkage allowing for intersite heterogeneity, genome-wide significant evidence for linkage was observed on chromosome 10p12. Significant heterogeneity was also observed on chromosome 22q11.1. Evidence for linkage across family sets and analyses was most consistent on chromosome 8p21, with a one-LOD support interval that does not include the candidate gene NRG1, suggesting that one or more other susceptibility loci might exist in the region, according to the authors.

Journal: Proceedings of the National Academy of Sciences. 2009 Feb 24;106(8):2543-8.
Title: Large-scale detection of ubiquitination substrates using cell extracts and protein microarrays.
Authors: Y Merbl; M Kirschner

Abstract: Identification of protein targets of post-translational modification is an important analytical problem in biology, according to the authors. Protein microarrays exposed to cellular extracts could offer a means of identifying modified proteins, dependent on a faithful reconstruction of in vivo conditions. Over several years, concentrated cellular extracts have been developed, principally for cell cycle studies that reproduce very complex cellular states. The authors used these extracts to replicate the mitotic checkpoint and anaphase release to identify differentially regulated poyubiquitination. Protein microarrays were then exposed to these complex extracts, and the polyubiquitinated products were detected by specific antibodies. The authors expected that among the substrates revealed by the microarray should be substrates of the anaphase promoting complex. Among 8,000 proteins on the chip, 10 percent were polyubiquitinated. Among those, the authors found 11 known APC substrates to be polyubiquitinated. The yield of potential APC substrates from a simple assay with concentrated cell extracts "suggests that combining microarray analysis of the products of post-translational modifications with extracts that preserve the physiological state of the cell can yield information on protein modification under various in vivo conditions," the authors conclude.

The Scan

Renewed Gain-of-Function Worries

The New York Times writes that the pandemic is renewing concerns about gain-of-function research.

Who's Getting the Patents?

A trio of researchers has analyzed gender trends in biomedical patents issued between 1976 and 2010 in the US, New Scientist reports.

Other Uses

CBS Sunday Morning looks at how mRNA vaccine technology could be applied beyond SARS-CoV-2.

PLOS Papers Present Analysis of Cervicovaginal Microbiome, Glycosylation in Model Archaea, More

In PLOS this week: functional potential of the cervicovaginal microbiome, glycosylation patterns in model archaea, and more.