Key Points
-
Microarray technology encompasses a few relatively well-established methods and numerous applications that are in various stages of development.
-
Apart from their use as a tool for diagnostic testing in a broad sense, microarrays have also become a means for molecule production.
-
For real diagnostics, data interpretation is frequently the main obstacle.
-
Because of biological complexity, molecular patterns rather than individual markers will be used in the future.
-
For research purposes, microarrays will be transformed from rigid platforms, each made for a specific purpose, to flexible tools. Technical developments and new design formats will enable this transformation.
-
In the long term, technology that originates from microarray technology will allow 'experimental' systems biology.
Abstract
Understanding complex functional mechanisms requires the global and parallel analysis of different cellular processes. DNA microarrays have become synonymous with this kind of study and, in many cases, are the obvious platform to achieve this aim. They have already made important contributions, most notably to gene-expression studies, although the true potential of this technology is far greater. Whereas some assays, such as transcript profiling and genotyping, are becoming routine, others are still in the early phases of development, and new areas of application, such as genome-wide epigenetic analysis and on-chip synthesis, continue to emerge.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Poustka, A. et al. Molecular approaches to mammalian genetics. Cold Spring Harb. Symp. Quant. Biol. 51, 131–139 (1986). The first paper to describe the potential of array technology in genomics.
Cantor, C. R., Mirzabekov, A. & Southern, E. Report on the sequencing by hybridisation workshop. Genomics 13, 1378–1383 (1992).
Schena, M., Shalon, D., Davis, R. W. & Brown, P. O. Quantitative monitoring of gene expression patterns with a complementary DNA microarray. Science 270, 467–470 (1995). A publication that made the wider scientific community aware of the potential of array technology.
He, L. & Hannon, G. J. MicroRNAs: small RNAs with a big role in gene regulation. Nature Rev. Genet. 5, 522–531 (2004).
Lu, J. et al. MicroRNA expression profiles classify human cancers. Nature 435, 834–838 (2005).
Larkin, J. E., Frank, B. C., Gavras, H., Sultana, R. & Quackenbush, J. Independence and reproducibility across microarray platforms. Nature Methods 2, 337–344 (2005).
Irizarry, R. A. et al. Multiple-laboratory comparison of microarray platforms. Nature Methods 2, 345–350 (2005).
Petersen, D. et al. Three microarray platforms: an analysis of their concordance in profiling gene expression. BMC Genomics 6, 63 (2005).
DeRisi, J. et al. Use of a cDNA microarray to analyse gene expression patterns in human cancer. Nature Genet. 14, 457–460 (1996).
Brazma, A. et al. Minimum information about a microarray experiment (MIAME) — toward standards for microarray data. Nature Genet. 29, 365–371 (2001). The first (successful) initiative to bring about at least some basic standardization to a microarray-based assay.
Cleveland, W. S. LOWESS: a program for smoothing scatterplots by robust locally weighted regression. Am. Stat. 35, 54 (1981).
Huber, W., von Heydebreck, A., Sültmann, H., Poustka, A. & Vingron, M. Variance stabilisation applied to microarray data calibration and to the quantification of differential expression. Bioinformatics 18 (Suppl. 1), S96–S104 (2002).
Rocke, D. M. & Durbin, B. Approximate variance-stabilising transformations for gene-expression microarray data. Bioinformatics 19, 966–972 (2003).
The International HapMap Consortium. A haplotype map of the human genome. Nature 437, 1299–1320 (2005).
Syvanen, A. C. From gels to chips: 'minisequencing' primer extension for analysis of point mutations and single nucleotide polymorphisms. Hum. Mutat. 13, 1–10 (1999).
Tõnisson, N. et al. Evaluating the arrayed primer extension resequencing assay of TP53 tumor suppressor gene. Proc. Natl Acad. Sci. USA 99, 5503–5508 (2002).
Jobs, M., Howell, W. M., Strömqvist, L., Mayr, T. & Brookes, A. J. DASH-2: flexible, low-cost, and high-throughput SNP genotyping by dynamic allele-specific hybridization on membrane arrays. Genome Res. 13, 916–924 (2003).
Brandt, O. et al. PNA-microarrays for hybridisation of unlabelled DNA-samples. Nucleic Acids Res., 31, e119 (2003).
Arntz, Y. et al. Label-free protein assay based on a nanomechanical cantilever array. Nanotechnology 14, 86–90 (2003).
Hahm, J. & Lieber, C. M. Direct ultrasensitive electrical detection of DNA and DNA sequence variations using nanowire nanosensors. Nano Lett. 4, 51–54 (2003).
Hild, M. et al. An integrated gene annotation and transcriptional profiling approach towards the full gene content of the Drosophila genome. Genome Biol. 5, R3 (2004).
Johnson, J. M. et al. Genome-wide survey of human alternative pre-mRNA splicing with exon junction microarrays. Science 302, 2141–2144 (2003).
Shoemaker, D. D. et al. Experimental annotation of the human genome using microarray technology. Nature 409, 922–927 (2001).
Hollich, V. et al. Creation of a minimal tiling path of genomic clones for Drosophila: provision of a common resource. Biotechniques 37, 282–284 (2004).
Milner, N., Mir, K. U. & Southern, E. M. Selecting effective antisense reagents on combinatorial oligonucleotide arrays. Nature Biotechnol. 15, 537–541 (1997). An elucidation of how the three-dimensional structure of nucleic acid influences its functionality.
Ren, B. et al. Genome-wide location and function of DNA binding proteins. Science 290, 2306–2309 (2000).
Buck, M. J. & Lieb, J. D. ChIP-chip: considerations for the design, analysis, and application of genome-wide chromatin immunoprecipitation experiments. Genomics 83, 349–360 (2004).
Radonjic, M. et al. Genome-wide analyses reveal RNA polymerase II located upstream of genes poised for rapid response upon S. cerevisiae stationary phase exit. Mol. Cell 18, 171–183 (2005).
Lichter, P. et al. High resolution mapping of human chromosome 11 by in situ hybridization with cosmid clones. Science 247, 64–69 (1990).
Feuk, L., Carson, A. R. & Scherer, S. W. Structural variation in the human genome. Nature Rev. Genet. 7, 85–97 (2006).
Solinas-Toldo, S. et al. Matrix-based comparative genomic hybridization: biochips to screen for genomic imbalances. Genes Chromosomes Cancer 20, 399–407 (1997).
Ishkanian, A. S. et al. A tiling resolution DNA microarray with complete coverage of the human genome. Nature Genet. 36, 299–303 (2004).
Pollack, J. R. et al. Genome-wide analysis of DNA copy-number changes using cDNA microarrays. Nature Genet. 23, 41–46 (1999).
Bignell, G. R. et al. High-resolution analysis of DNA copy number using oligonucleotide microarrays. Genome Res. 14, 287–295 (2004).
Barrett, M. T. et al. Comparative genomic hybridization using oligonucleotide microarrays and total genomic DNA. Proc. Natl Acad. Sci. USA 101, 17765–17770 (2004).
Brennan, C. et al. High-resolution global profiling of genomic alterations with long oligonucleotide microarray. Cancer Res. 64, 4744–4748 (2004).
Huang T. H., Perry M. R. & Laux D. E. Methylation profiling of CpG islands in human breast cancer cells. Hum. Mol. Genet. 8, 459–470 (1999).
Yan, P. S. et al. Dissecting complex epigenetic alterations in breast cancer using CpG island microarrays. Cancer Res. 61, 8375–8380 (2001).
Adorjan, P. et al. Tumour class prediction and discovery by microarray-based DNA methylation analysis. Nucleic Acids Res. 30, e21 (2002).
Mund, C. et al. Array-based analysis of genomic DNA methylation patterns of the tumour suppressor gene p16 promoter in colon carcinoma cell lines. Nucleic Acids Res. 33, e73 (2005).
Craig, A., Nizetic, D., Hoheisel, J. D., Zehetner, G. & Lehrach, H. Ordering of cosmid clones covering the herpes simplex virus type I (HSV-I) genome: a test case for fingerprinting by hybridisation. Nucleic Acids Res. 18, 2653–2660 (1990).
Bains, W. & Smith, G. A novel method for nucleic acid sequence determination. J. Theor. Biol. 135, 303–307 (1988). The first publication on sequencing by hybridization.
Drmanac, R., Labat, I., Brukner, I. & Crkvenjakov, R. Sequencing of megabase plus DNA by hybridisation: theory of the method. Genomics 4, 114–128 (1989).
Khrapko, K. et al. An oligonucleotide hybridization approach to DNA sequencing. FEBS Lett. 256, 118–122 (1989).
Meier-Ewert, S., Maier, E., Ahmadi, A. R., Curtis, J. & Lehrach, H. An automated approach to generating expressed sequence catalogues. Nature 361, 375–376 (1993).
Green Tringe, S & Rubin, E. Metagenomics: DNA sequencing of environmental samples. Nature Rev. Genet. 6, 805–814 (2005).
Rondon, M. R. et al. Cloning the soil metagenome: a strategy for assessing the genetic and functional diversity of uncultured microorganisms. Appl. Environ. Microbiol. 66, 2541–2547 (2000).
Venter, J. C. et al. Environmental genome shotgun sequencing of the Saragosso Sea. Science 304, 66–74 (2004).
Sebat, J. L., Colwell, F. S. & Crawford, R. L. Metagenomic profiling: microarray analysis of an environmental library. Appl. Environ. Microbiol. 69, 4927–4934 (2003).
Drmanac, R. et al. DNA sequencing by hybridisation with arrays of samples or probes. Methods Mol. Biol. 170, 173–179 (2001).
Bains, W. Selection of oligonucleotide probes and experimental conditions for multiplex hybridization experiments. GATA 11, 49–62 (1994).
Lipshutz, R. J. et al. Using oligonucleotide probe arrays to access genetic diversity. Biotechniques 19, 442–447 (1995).
Maitra, A. et al. The human mitochip: a high-throughput sequencing microarray for mitochondrial mutation detection. Genome Res. 14, 812–819 (2004).
Baum, M. et al. Validation of a novel, fully integrated and flexible microarray benchtop facility for gene expression profiling. Nucleic Acids Res. 31, e151 (2003).
Singh-Gasson, S. et al. Maskless fabrication of light-directed oligonucleotide microarrays using a digital micromirror array. Nature Biotechnol. 17, 974–978 (1999).
Canard, B., Cardona, B. & Sarfati, R. S. Catalytic editing properties of DNA polymerases. Proc. Natl Acad. Sci. USA 92, 10859–10863 (1995).
Bennett, S. Array of hope for personalised medicine. Curr. Drug Discov. 15–19 (2004).
Brenner, S. et al. In vitro cloning of complex mixtures of DNA on microbeads: physical separation of differentially expressed cDNAs. Proc. Natl Acad. Sci. USA 97, 1665–1670 (2000).
Shendure, J., Mitra, R. D., Varma, C. & Church, G. M. Advanced sequencing technologies: methods and goals. Nature Rev. Genet. 5, 335–344 (2004). A comprehensive coverage of high-throughput sequencing methods.
Velculescu, V. E., Zhang, L., Vogelstein, B. & Kinzler, K. Serial analysis of gene expression. Science 270, 484–487 (1995).
Beaucage, S. L. & Caruthers, M. H. Deoxynucleoside phosphoramidites — a new class of key intermediates for deoxynucleotide synthesis. Tetrahedron Lett. 22, 1859–1862 (1980).
Sindelar, L. E. & Jaklevic, J. M. High-throughput DNA synthesis in a multichannel format. Nucleic Acids Res. 23, 982–987 (1995).
Lashkari, D. A., McCusker, J. H. & Davis, R. W. Whole genome analysis: experimental access to all genome sequenced segments through larger-scale efficient oligonucleotide synthesis and PCR. Proc. Natl Acad. Sci. USA, 94, 8945–8947 (1997).
Weiler, J. & Hoheisel, J. D. Combining the preparation of oligonucleotide arrays and synthesis of high quality primers. Anal. Biochem. 243, 218–227 (1996).
Tian, J. et al. Accurate multiplex gene synthesis from programmable DNA microchips. Nature 432, 1050–1054 (2004). Describes the clever use of microarrays for gene synthesis and quality assessment.
Zhou, X et al. Microfluidic PicoArray synthesis of oligodeoxynucleotides and simultaneous assembling of multiple DNA sequences. Nucleic Acids Res. 32, 5409–5417 (2004).
Richmond, K. E. et al. Amplification and assembly of chip-eluted DNA (AACED): a method for high-throughput gene synthesis. Nucleic Acids Res. 32, 5011–5018 (2004).
Beier, M. & Hoheisel, J. D. Production by quantitative photolithographic synthesis of individually quality-checked DNA microarrays. Nucleic Acids Res. 28, e11 (2000).
Beier, M., Stephan, A. & Hoheisel, J. D. Synthesis of photolabile 5'-O-phosphoramidites for the production of microarrays of inversely oriented oligonucleotides. Hel. Chim. Acta 84, 2089–2095 (2001).
Yelin, R. et al. Widespread occurance of antisense transcription in the human genome. Nature Biotechnol. 21, 379–386 (2003).
Paddison, P. J. et al. A resource for large-scale RNA-interference-based screens in mammals. Nature 428, 427–431 (2004).
Boutros, M. et al. Genome-wide RNAi analysis of growth and viability in Drosophila cells. Science 303, 382–385 (2004).
Arjomand, A. & Kumar, A. Integration of RNAi into drug discovery. Curr. Drug Discov. 1–4 (2003).
Sauer, S. et al. Miniaturisation in functional genomics and proteomics. Nature Rev. Genet. 6, 465–476 (2005).
He, M. & Taussig, M. J. Single step generation of protein arrays from DNA by cell-free expression and in situ immobilisation (PISA method). Nucleic Acids Res. 29, e73 (2001).
Ramachandran, N. et al. Self-assembling protein microarrays. Science 305, 86–90 (2004).
Mukherjee, S. et al. Rapid analysis of the DNA-binding specificities of transcription factors with DNA microarrays. Nature genet. 36, 1331–1339 (2004).
Bulyk, M. L., Gentalen, E., Lockhart, D. J. & Church, G. M. Quantifying DNA-protein interactions by double-stranded DNA-arrays. Nature Biotechnol. 17, 573–577 (1999).
Gerry, N. P. et al. Universal DNA microarray method for multiplex detection of low abundance point mutations. J. Mol. Biol. 292, 251–262 (1999).
Shoemaker, D. D., Lashkari, D. A., Morris, D., Mittmann, M. & Davis, R. W. Quantitative phenotypic analysis of yeast deletion mutants using a highly parallel molecular bar-coding strategy. Nature Genet. 14, 450–456 (1996).
Fan, J. B. et al. Parallel genotyping of human SNPs using generic high-density oligonucleotide tag array. Genome Res. 10, 853–860 (2000).
Hardenbol, P. et al. Multiplexed genotyping with sequence-tagged molecular inversion probes. Nature Biotechnol. 21, 673–678 (2003).
Urata, H., Ogura, E., Shinohara, K., Ueda, Y. & Akagi, M. Synthesis and properties of mirror-image DNA. Nucleic Acids Res. 20, 3325–3332 (1992). This paper describes the interesting L -form derivative of nucleic acids that could be useful to microarray applications.
Zhong, X. B. et al. Visualisation of oligonucleotide probes and point mutations in interphase nuclei and DNA fibers using rolling circle DNA amplification. Proc. Natl Acad. Sci. USA 98, 3940–3945 (2001).
Dudley, A. M., Aach, J., Steffen, M. A. & Church, G. M. Measuring absolute expression with microarrays using a calibrated reference sample and an extended signal intensity range. Proc. Natl Acad. Sci. USA 99, 7554–7559 (2002).
Brors, B., Hauser, N. C. & Vingron, M. Determination of absolute concentrations of biological molecules in complex samples; a real comparison of microarray experiments. European Patent PCT/EP03/03291 (2002).
Calladine, C. R. & Drew, H. R. Understanding DNA; the Molecule and How it Works (Academic Press, San Diego, 1997).
Rich, A. & Zhang, S. G. Z-DNA: the long road to biological function. Nature Rev. Genet. 4, 566–572 (2003).
Pohl, F. M. Hysteretic behaviour of a Z-DNA–antibody complex. Biophys. Chem. 26, 385–390 (1987).
MacBeath, G. & Schreiber, S. L. Printing proteins as microarrays for high-throughput function determination. Science 289, 1760–1763 (2000).
Zhu, H. et al. Global analysis of protein activities using proteome chips. Science 293, 2101–2105 (2001).
Kononen, J. et al. Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nature Med. 4, 844–847 (1998).
Wheeler, D. B., Carpenter, A. E. & Sabatini, D. M. Cell microarrays and RNA interference chip away at gene function. Nature Genet. 37, S25–S30 (2005).
Angenendt, P., Glöcker, J., Konthur, Z., Lehrach, H. & Cahill, D. J. 3D protein microarrays: performing multiplex immunoassays on a single chip. Anal. Chem. 75, 4368–4372 (2003).
Kusnezow, W., Syagailo, Y. V., Goychuk, I., Hoheisel, J. D. & Wild, D. G. Antibody microarrays; the crucial impact of mass transport on assay kinetics and sensitivity. Expert Rev. Mol. Diag. 6, 111–124 (2006).
Acknowledgements
The author thanks colleagues for sharing unpublished results and many interesting discussions. Relevant work in his laboratory was funded by grants from the Federal German Ministry of Education and Research (BMBF), the Deutsche Forschungsgemeinschaft and the European Commission.
Author information
Authors and Affiliations
Ethics declarations
Competing interests
The author declares no competing financial interests.
Related links
Glossary
- Secondary-ion mass spectrometry
-
A technique in which a focused ion beam is directed to a solid surface, removing material in the form of neutral and ionized atoms and molecules. The secondary ions are then accelerated into a mass spectrometer and separated according to their mass-to-charge ratio.
- Tiling path
-
The coverage of a given genomic region by a set of overlapping DNA fragments.
- Serial analysis of gene expression
-
A method for analysing transcription patterns. A short cDNA tag sequence of 10 to 14 bp is isolated for each transcript. They are linked at random to form long concatemeric molecules that can be sequenced to determine the frequency of each tag sequence, and therefore the respective RNA, in the entire population.
- Solid-phase synthesis
-
A chemical synthesis reaction during which the synthesized molecules are continuously attached to a solid support medium.
- Phosphoramidite chemistry
-
The chemistry of choice for oligonucleotide synthesis; the stable tri-coordinated phosphorous function of one nucleoside phosphoramidite is activated by a weak acid and reacts with the hydroxyl moiety of another nucleoside.
- RNAi
-
RNA-mediated, sequence-specific transcriptional silencing of gene expression.
- Padlock probes
-
Linear DNA molecules of 70–100 nucleotides that become circularized by DNA ligation in the presence of a target sequence that is complementary to both terminal sequences of the probe molecule.
Rights and permissions
About this article
Cite this article
Hoheisel, J. Microarray technology: beyond transcript profiling and genotype analysis. Nat Rev Genet 7, 200–210 (2006). https://doi.org/10.1038/nrg1809
Issue Date:
DOI: https://doi.org/10.1038/nrg1809
This article is cited by
-
PSMD8 can serve as potential biomarker and therapeutic target of the PSMD family in ovarian cancer: based on bioinformatics analysis and in vitro validation
BMC Cancer (2023)
-
Short and long-term effect of dexamethasone on the transcriptome profile of primary human trabecular meshwork cells in vitro
Scientific Reports (2022)
-
K-seq, an affordable, reliable, and open Klenow NGS-based genotyping technology
Plant Methods (2021)
-
Genome-wide Identification of DNA-protein Interaction to Reconstruct Bacterial Transcription Regulatory Network
Biotechnology and Bioprocess Engineering (2020)