Current Knowledge on Microarray Technology - an Overview

Naidu & Suneetha

Available online at http://www.tjpr.org http://dx.doi.org/10.4314/tjpr.v11i1.20 Review Article

Current Knowledge on Microarray Technology - An Overview

* Chitrala Kumaraswamy Naidu and Yeguvapalli Suneetha Department of Zoology, Sri Venkateswara University, Tirupati -517502, India.

Abstract

The completion of whole genome sequencing projects has led to a rapid increase in the availability of genetic information. In the field of transcriptomics, the emergence of microarray-based technologies and the design of DNA biochips allow high-throughput studies of RNA expression in cell and tissue at a given moment. It has emerged as one of the most important technology in the field of molecular biology and transcriptomics. Arrays of oligonucleotide or DNA sequences are being used for genome-wide genotyping and expression profiling, and several potential clinical applications have begun to emerge as our understanding of these techniques and the data they generate improves. From its emergence to date, several database, software and technology updates have been developed in the field of microarray technology. This paper reviews basics and updates of each microarray technology and serves to introduce newly compiled resources that will provide specialist information in this area.

Keywords: Microarray, Databases, cDNA array, Oligonucleotide array

Received: 19 April 2011 Revised accepted: 19 December 2011

*Corresponding author: Email: [email protected]; Tel: +91 9985563644

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INTRODUCTION or radioactive tag and a brighter signal is detected when more copies bind [4]. In The completion of whole genome sequencing general, all microarray assays contain five projects has led to a rapid increase in the discrete experimental steps – biological availability of genetic information. In the field query, sample preparation, biochemical of transcriptomics, the emergence of reaction, detection, data visualization and microarray-based technologies and the modeling [5]. According to Yuk Fai leung et al design of DNA biochips allow high-throughput [6] , a typical microarray experiment involves studies of RNA expression in cell and tissue sample extraction, fluorescent labeling, co- at a given moment [1]. Today, microarray hybridization, scanning and finally statistical technology is one of the popular tools in analysis. Microarray technologies can be molecular biology with its main advantage broadly categorized into DNA microarrays being that, unlike other traditional methods, it and protein microarrays. is not limited to investigating ‘one gene at a time’ [2]. DNA microarrays

In this review, we explain some of the DNA microarrays provide a simple and fundamentals and recent updates on each natural vehicle for exploring the genome in a microarray technology step-by-step. As it will way that is both systematic and be overwhelming to discuss all the updates of comprehensive. The power and universality microarrays since its emergence, we have of DNA microarrays as experimental tools focused on the updates of the past few years. derives from the exquisite specificity and We intend also to expound on current affinity of complementary base-pairing [7]. knowledge of recent databases, data analysis DNA microarrays are of oligonucleotide software and some of the companies in the arrays and a variety of cDNA arrays. field of microarrays. We hope that an understanding of some of the fundamentals, Oligonucleotide arrays recent updates and commercial technologies in microarrays will afford the beginner useful Oligonucleotide arrays or DNA chips are information in this area. miniature parallel analytical devices containing libraries of oligonucleotides MICROARRAY TECHNOLOGY robotically spotted (printed) or synthesized in situ on solid supports (glass, coated glass, Microarray is a technology which allows silicon or plastic) in a such way that the quantitative, simultaneous monitoring and identity of each oligonucleotide is defined by expression of thousands of genes [3]. The its location [8]. Oligonucleotide arrays contain basic principle behind microarray is the base short fragments of DNA (25 base pairs). One complementarity, i.e., the base pair ‘A’ is of the commercially available oligonucleotide complementary to ‘T’ and ‘C’ is microarrays are the Gene Chips developed complementary to ‘G’. In a microarray, many by firms such as Affymetrix. Ten to hundred thousands of spots are placed on a thousands of different oligonucleotide probes rectangular grid with each spot containing a are synthesized on each array. Traditionally, large number of pieces of DNA from a Affymetrix GeneChip Arrays are particular gene. When the sample of interest manufactured as a single array caged in a contains many copies of mRNA, many sealed cartridge with glass as a substrate. bindings will occur, indicating that the gene from the transcribed mRNA is highly The oligonucleotide technology pioneered by expressed. The quantity of hybridization can Affymetrix GeneChips differs from cDNA be determined because each copy of mRNA microarray in two important respects [9]. is labeled in the experiment with a fluorescent First, the probes are a set of 20-25 short

Trop J Pharm Res, February2012;11 (1): 154 Naidu & Suneetha oligonucleotides that are specific for each onto a solid support (glass slide or gene or exon, along with the related set with membrane). Some of the basic principles single base mismatches incorporated at the behind preparation of cDNA arrays includes: middle position of each oligonucleotide. i) selection of the targets to be printed on the These are synthesized in situ on each silicon array directly from databases such as chip using genome sequence information to GenBank, dbESt, and UniGene or randomly guide photolithographic deposition. Second, from any library of interest; ii) arraying the the arrays are hybridized to a single selected cDNA targets onto the known biotinylated amplified RNA sample, and the location of coated glass microscope slide intensity measure for each gene is computed using a computer-controlled high speed by an algorithm that messages the difference robot; iii) fluorescently labeling the total RNA between the match and mismatch from both test and reference samples using measurements, and averages over each dyes with a single round of reverse oligonucleotide. Key difference between gene transcription; iv) pooling the florescent target chips and a cDNA microarray is the way for hybridization under stringent conditions; v) genes are represented on the arrays. In in measuring the laser excited incorporated situ photolithographic synthesis method used targets using a scanning confocal laser by Affymetrix gene chip probe arrays, the microscope; and v) finally, analyzing the quality of chips produced depends critically images from scanner by importing into a on the efficiency of photo-deprotection [10]. software in which they are pseudo-colored and merged. Micro spotting, piezoelectric There are many other advantages to printing and photolithography (an ‘ in situ ’ oligonucleotide-based microarrays. The fabrication technique developed by quality and reproducibility of printed Affymetrix) are some of the techniques used oligonucleotide arrays (“print format”) are for arraying cDNA. Invitrogen, Genome superior [11]. Although there is a large initial systems, Biodiscovery, Xeno, Affymetrix, capital outlay to purchase large sets of Silicon genetics, Genetix, etc., are some of oligonucleotides, the printed arrays are the companies which produce commercial inexpensive on a unit basis. Furthermore, arrayers. Open GMS 418 Array Scanner, long oligonucleotide probes can be GeneChip® Scanner 3000 System synthesized directly on an array surface (Affymetrix), DNA Microarray Scanner (photo printed arrays). In either case, whether (Agilent), Typhoon Variable Mode Imager printed or photo printed, the composition of (GE Healthcare), InnoScan 700( INNOPSIS), the array can be absolutely specified and Axon GenePix4000ALMicroarray scanner hence is completely reproducible by others. A (Molecular Devices), and PowerScanner limitation of oligonucleotide arrays is the (Tecan) are some of the commercial requirement of relatively large amounts of scanning devices which detect different levels biological starting materials for gene of fluorescence between the spots on the expression analysis [12]. GE Healthcare, microarray. Apart from applications of cDNA Ocimum Biosolutions, and Agilent are some array in comparative genome analysis and of the other companies which provide functional genome analysis, recent commercially available designs of applications include gene expression profiling Oligonucleotide microarrays. of drug-resistant small cell lung cancer cells [13], characterization of osmotic stress- cDNA arrays induced genes in poplar cells [14] and veterinary diagnostics. cDNA arrays contain long fragments of DNA (from 100 to thousands of base pairs). cDNA arrays are created by robotically spotting Protein microarray individual samples of purified cDNA clones

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Though DNA microarray is very useful, it has used ones. In antibody microarrays, bait several limitations. The expression levels of molecules are numerous individual antibodies many genes are subject to significant post- (< 500 antibodies/array) which act as probes transcriptional regulation and many proteins for the targeted protein analytes immobilized are grossly affected by post-translational on a surface. This surface can be glass or modification such as phosphorylation, ceramic base as in the case of CombiMatrix glycosylation, acetylation, proteolysis etc. ElectraSense microarray. Obviously, a nucleic acid-based array is blind to such effects and for certain applications, The main problems with antibody-mediated the tedious sample preparation requirements analytical protein microarrays are specificity, of DNA microarrays make them impractical quantization and most of the antibodies [15]. The solution for this is to analyze cross-react with proteins other than the proteins rather than make inferences based antigen of interest which leads to poor on RNA levels directly which can be done quantification. Clontech, Eurogentec, through protein microarrays. Protein Labvision corporation, Arrayit, Sigma Life microarrays also known as protein chips are sciences, Abnova, etc, are some of the nothing but grids that contain small amounts companies which prepare antibody arrays. of purified proteins in ahigh density. The Among these, Abnova is the largest proteins can be screened in a high- manufacturer of antibody arrays with 41 throughput fashion for biochemical activity, products. Current antibody microarray protein–protein, protein–DNA, protein–RNA designs provide a unique tool for rapid, and protein–ligand interactions [16]. The common element for each type of microarray, sensitive and selective profiling of crude, non- whether it is tissue array or antibody array or fractionated proteomes, targeting upto protein arrays, is the immobilization of bait hundreds of protein analytes in one molecules on a substratum, either as a experiment [19], e.g., Clontech’s “Ab homogeneous or heterogeneous spot. Bait Microarray 500” technology allows profiling of molecules may be aptamers, antibodies, cell 507 antibodies in a one-day experiment. In lysates, phage or recombinant recent years, these antibody microarrays play protein/peptide, a nucleic acid, or a tissue a key role for specific detection of depending upon the type of microarray. The bioterrorism agents, as exemplified by ricin, capture molecule may be a complex biologic cholera toxin (CT) and staphylococcal mixture, such as serum or a cell lysate, an enterotoxin B (SEB) [20]. Some of the antibody or ligand [17]. The substratum can companies which prepare antibody arrays, be glass slides, porous gel slides and along with their products, are listed in Table microwells. 1.

Protein microarrays can be major categorized The second type of microarray is functional into three types [18]: analytical microarrays, protein microarrays which are composed of functional microarrays, and reverse phase arrays containing full-length functional microarrays. Analytical microarrays are the proteins or protein domains. These spotted ones in which biomolecular recognition arrays are used to probe the function or molecules are immobilized on a binding properties of native proteins. heterogeneous matrix using micro printing or Functional protein microarrays have been micro structuring process. Hapten and successfully applied to identify protein– antibody microarrays are some of the most common analytical microarrays. Among the protein, protein–small molecule and protein– several subgroups of protein biochips such DNA interactions to reveal or characterize as peptide arrays, antibody arrays, cell based enzymatic activities of proteins. arrays, etc, antibody arrays are the widely

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Table 1: Summary of antibody microarray firms

Firm Technology Comments Affymetrix Human Cytokine Facilitates, simultaneous detection of multiple human Antibody Array cytokines from a variety of sources, including cell lysates, EXPANDED ver 3.0 conditioned media, patient sera, plasma and urine. Clontech Antibody Microarrays Screens 380 or 507 antibodies in one day. 380 & 500 Full Moon Phospho Explorer S1 Consists of 562 well-characterized phospho-specific Biosystems Antibody Array antibodies, a subset of the Phospho Explorer Array (PEX100). It allows researchers to study and analyze hundreds of commonly examined proteins on a single slide. Gentel APiX Profiling Simultaneously profile the relative concentration of up to Biosciences Antibody Arrays 97 cytokines and related proteins. Hypromatrix Signal Transduction Each Signal Transduction AntibodyArray contains 400 high AntibodyArray quality antibodies against well-studied signaling proteins. MicroBioChips Plasmascan 380 Targets 380 native and low-abundant human serum proteins. RayBiotech, Inc RayBio Antibody Array The principle of G series antibody arrays (glass slide G Series based antibody arrays) is similar to membrane-based antibody arrays. Scientists can detect the expression of 174 cytokines in a single experiment. R&D Systems Proteome Profiler 96 Proteome Profiler 96 Antibody Arrays are 96-well Microplate-based microplate-based assays with up to 16 antibodies per well Antibody Arrays for simultaneous detection of multiple analytes.

Sigma Life Panorama® Antibody Contains 224 human antibodies to key cellular proteins sciences Array with a special emphasis on cell signaling proteins.

US Biomax, Inc Explorer Antibody Allows investigators to examine their samples against 656 Array antibodies in a single experiment.

The most promising task in functional anti-invasion mechanisms and anti-metastatic microarray is fabrication of proteins in activities, e.g., 3-(50-hydroxymethyl-20-furyl)- functional form or correctly folded form. 1-benzyl-indazole [24], quantitative analysis Recent advances in fabrication of proteins of down regulated genes, disease include atmospheric pressure plasma (AP) progression and in discovering biomarkers. treatment technique [21], surface-attached hydrogel microstructures in high concen- Detection strategies of Protein microarrays trations [22], etc. The third type of microarray on the other hand can be of (1) label-free is reverse phase protein microarray (RPA). methods and (2) labeled probe methods. Unlike functional and antibody arrays, these Label-free methods are mass spectrometry, RPA involves the immobilization of all surface plasmon resonance imaging (SPR) proteins present in an individual tissue or cell and atomic force microscopy. Labeled probe population instead of a single probe. Some of detection methods are of three types i.e., the recent applications of RPA include direct, indirect and sandwich. In direct understanding the pathobiology of complex detection strategies, a labeled probe directly disorders such as cancer, stroke and binds to the target molecule immobilized on a traumatic brain injury [23], identifying novel substratum. Amplification strategies based on

Trop J Pharm Res, February2012;11 (1): 157 Naidu & Suneetha avidin–biotin binding enhance the sensitivity Normalization or scaling involves conversion of detection in direct detection methods. In, of raw data into normalized or scaled data. It indirect detection strategies an immobilized is an important step for microarray data probe is used for capturing labeled, specific analysis to minimize biological and technical molecules from a complex mixture of query variations. Gene Expression Pattern Analysis molecules. In Sandwich assays, two distinct Suite (GEPAS) and Ginkgo are some of the probes are used for detection of a capture software used for normalization of microarray molecule. The first probe is immobilized on data. Statistical analysis or calculating the substratum and the molecule of interest differential expression involves controlling the binds to its cognate probe. A second, labeled false positives, selecting a significant cutoff, probe detects the bound probe-capture multiple testing correction, etc. Clustering, on molecule complex. the other hand, is nothing but, unsupervised grouping of similar profiles together based on MICROARRAY DATA ANALYSIS a distance metric while supervised grouping is called classification. CAGED and DNA-chip Microarray technologies generate huge analyzer are some of the software used for amount of data. A typical microarray data set clustering analysis. Some of the software that includes expression levels for thousands of are used at various stages of microarray data genes across hundreds of conditions. analysis are illustrated in the Figure 1 while a Converting the data provided in a microarray short description of these software is dataset into meaningful biological information provided in the Table 2. involves several steps including [25]: i) normalization ii) prediction of differentially MICROARRAY DATABASES expressed genes using comparison statistics iii) identification and partition of expression A huge amount of data obtained through patterns based on up and down regulation, microarray technologies analyzed as magnitude and clustering of genes iv) described above are maintained in two ways summarizing the identified gene expression [47]: (a) using a software, usually installed patterns using gene annotation tools, and v) locally, that allows storage, querying and deriving the biological significance of analysis of data captured on-site, and (b) summarized genes using ontology report or databases that act as repositories for publicly pathway report. Precise microarray data available data, in particular, published data. analysis involves quality control, Three important elements to be considered normalization, statistical analysis, clustering for sharing microarray data are i) a data and classification. annotation standard ii) a common data exchange format, and iii) public repositories Quality control involves, background analogous to DDBJ/EMBL/GenBank. The correction and filtering to include only positive common microarray data standard used is values above the background. ERCC Minimum Information About a Microarray (External RNA Control Consortium), The Experiment (MIAME) and the standard data Norwegian Microarray Consortiums (NMC) exchange format is Microarray Gene and MAQC (Microarray Quality Control) Expression Markup Language (MAGE-ML) project are some of the groups which aim to which is an XML based data exchange format provide quality control (QC) tools to the developed by Microarray Gene Expression microarray community for avoiding Data (MGED) Society and Object procedural failures. Multicheck, LaserCheck, Management Group (OMG) [48]. In Table 3 QC Pac 1, and Simpleaffy are some of the some of the recent database repositories and commercial software packages provided by data management systems have been companies such as Tecan Group Ltd and surmmarised as it would well be beyond the Affymetrix, and are used for quality control.

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Figure 1: Various software used in microarray data analysis

Table 2: Summary of microarray data analysis software

Category Software Comments References ArrayQuality- Bioconductor package used for assessing the [26] Metrics quality and identifying apparent outlier arrays. Goober Software package available to help critical [27] tasks, such as data quality control and inventory management. Lumi It is a bioconductor package especially [28] designed to process the Illumina microarray data which includes data input, quality

control, variance stabilization, normalization and gene annotation portions. Quality control and Robin It is a noncommercial, easy-to-use graphical [29] assessment application. Provides functions for thorough quality assessment of the data and automatically generates warnings to notify the user of potential outliers, low-quality chips, or low statistical power. QC Pac 1 Comprehensive quality control package for [30] and QC Pac Tecan’s absorbance readers. 2

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Table 2: Summary of microarray data analysis software (contd)

Category Software Comments References Gene ARMADA It is a suite which integrates all steps of [31] microarray data analysis including automated data import, noise correction and filtering, normalization, statistical selection of differentially expressed genes, clustering, classification and annotation.

GeneTrailExpress Web based tool box which provide powerful [32]

normalization and statistical procedures.

µ-CS It is a cross-platform tool used for automatic [33]

normalization, summarization and annotation Normalization of Affymetrix binary data.

SNOMAD Consists of a collection of algorithms directed [34] (Standardization and at the normalization and standardiz-ation of Normalization of data) DNA microarray data. BRB-ArrayTools An integrated package for the visualization and [35] statistical analysis of DNA microarray gene expression data.

Genespring GX Provides powerful, accessible statistical tools [36] for fast visualization and analysis of expression and genomic structural variation data.

IronChip Evaluation It is a collection of Perl utilities developed for [37] Statistical Package (ICEP) the statistical and bioinformatics analysis of Analysis the custom cDNA microarray. Nexus Expression Statistical analysis software which provides [38] functional annotation and enrichment analysis as well as gene set analysis in real time allowing the user to input custom lists of genes for advanced signature analysis. APiX Profiling Simultaneously profile the relative [39] Antibody Arrays concentration of up to 97 cytokines and related proteins. AutoSOME It is a unsupervised multi dimensional [40]

clustering method used to identify clusters from large numerical datasets without prior knowledge of cluster number.

Clustering analysis of It is a web server application for clustering [41] Clustering Large Microarray data large size of microarray dataset. and with Individual Classification dimension-based Clustering (CLIC) ConsensusCluster A stand-alone software tool for the analysis of [42] high-dimensional single nucleotide polymorphism (SNP) and gene expression microarray data.

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Table 2: Summary of microarray data analysis software (contd)

Category Software Comments References Filter-based It is a web-based workbench where user can [43] Clustering Gene conveniently compare the classification performances Selection of many different filter-based gene selection and (FIGS) procedures. Classification GcExplorer A tool to visualize cluster results and investigate [44] (contd) additional properties of clusters using interactive neighborhood graphs. SEURAT It is a software tool which provides interactive visualiza- [45] tion for the integrated analysis of high-dimensional gene expression data and performs clustering. Clustering VisHic It is a public web server for clustering and interpreting [46] and gene expression data. Performs the labor-intensive task Classification of evaluating hundreds of redundant clusters in a rapid automated manner.

Table 3: Summary of Microarray Databases

Database Comment References aeGEPUCI aeGEPUCI is a publicly-accessible database and data-mining tool, that [49] integrates microarray analyses of sex- and stage-specific gene expression in Ae. aegypti . ANEXdb ANEXdb (an integrated animal ANnotation and microarray EXpression [50] database) is an open-source web application that supports integrated access of two databases that house microarray expression (ExpressDB) and EST annotation (AnnotDB) data. Currently supports storage and querying of Affymetrix-based expression data as well as retrieval of experiments in a form ready for NCBI-GEO submission. GATExplorer GATExplorer (Genomic and Transcriptomic Explorer) is a database and [51] web platform that integrates a gene loci browser with nucleotide level mappings of oligo probes from expression microarrays. Microarray M2DB is a human curated microarray database designed for easy [52] meta- querying based on clinical information and for interactive retrieval of analysis either raw or uniformly pre-processed data, along with a set of quality- database control metrics. The database contains more than 10,000 previously (M 2DB) published Affymetrix GeneChip arrays, performed using human clinical specimens. OligoArrayDb OligoArrayDb is a comprehensive database containing pangenomic [53] oligonucleotide microarray probe sets designed for most of the sequenced genomes that are not covered by commercial catalog arrays. Contains more than 2.8 probes per gene in average for more than 600 organisms, mostly archaea and bacteria strains available from public database. PathEx PathEx main goal was to develop a novel concept to offer less exploited [54] opportunities for the analysis of deposited microarray data. Deposited microarray data comes with description files. These metadata files contain some key information that can be used to link the microarray data to other biologically related information.

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