Abstract
DNA microarrays have the potential to revolutionize medical diagnostics and development of individualized medical treatments. However, accurate quantification of scantily expressed genes and precise measurement of small differences between different treatments is not currently feasible. A major challenge remains the understanding of physicochemical processes and rate-limiting steps of hybridization of complex mixtures of DNA targets on immobilized DNA probes. To this end, we developed a mathematical model to describe the effects of molecular orientation and transport on the kinetics and efficiency of hybridization. First, we calculated the hybridization rate constant based on the distance between the complementary nucleotides of the target and probe DNA. The surface reaction rate was then integrated with translational and rotational transport of target DNA to the surface to calculate the kinetics of hybridization. Our model predicts that hybridization of short DNA targets is diffusion limited but long targets are kinetically limited. In addition, for DNA targets with wide size distribution, it may be difficult to distinguish between specific binding of long targets from nonspecific binding of short ones. Our model provides novel insight into the process of DNA hybridization and suggests operating conditions to improve the sensitivity and accuracy of microarray experiments.
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Allison D. B., Cui X., Page G. P., Sabripour M. 2006 Microarray data analysis: from disarray to consolidation and consensus. Nat. Rev. Genet. 7(1), 55–65. 10.1038/nrg1749
Ames J. S., Murnaghan F. D. 1958 Theoretical Mechanics: An Introduction to Mathematical Physics. Dover, New York, p 80–82
Benn J. A., Hu J., Hogan B. J. Fry R. C., Samson L. D., Thorsen T. 2006 Comparative modeling and analysis of microfluidic and conventional DNA microarrays. Anal. Biochem. 348(2), 284–293. 10.1016/j.ab.2005.10.033
Bird R. B., Stewart W. E., Lightfoot E. N. 2007 Transport Phenomena. 2nd ed. John Wiley & Sons, New York
Borden J. R., Paredes C. J., Papoutsakis E. T. 2005 Diffusion, mixing, and associated dye effects in DNA-microarray hybridizations. Biophys. J. 89(5), 3277–3284. 10.1529/biophysj.105.067934
Brenner H. 1961 The slow motion of a sphere through a viscous fluid towards a plane surface. Chem. Eng. Sci. 16, 242–251. 10.1016/0009-2509(61)80035-3
Brenner H. 1967 Coupling between the translational and rotational Brownian motions of rigid particles of arbitrary shape. J. Colloid Interface Sci. 23, 407–436. 10.1016/0021-9797(67)90185-3
Brenner H., D. W. Condiff (1972) Transport mechanics in systems of orientable particles. 3. Arbitrary particles. J. Colloid Interface Sci. 41(2):228–272. 10.1016/0021-9797(72)90111-7
Brenner H., Condiff D. W. 1974 Transport mechanics in systems of orientable particles .4. Convective transport. J. Colloid Interface Sci. 47(1), 199–264. 10.1016/0021-9797(74)90093-9
Brown P. O., Botstein D. 1999 Exploring the new world of the genome with DNA microarrays. Nat. Genet. 21(1 Suppl), 33–37. doi:10.1038/4462
Chan V., Graves D. J., McKenzie S. E. 1995 The biophysics of DNA hybridization with immobilized oligonucleotide probes. Biophys. J. 69, 2243–2255
Claeys T. L., Brady J. F. 1989 Lubrication singularities of the grand resistance tensor for 2 arbitrary particles. Physicochem. Hydrodyn. 11(3), 261–293
Condiff D. W., Dahler J. S. 1966 Brownian motion of polyatomic molecules: the coupling of rotational and translational motions. J. Chem. Phys. 44(10), 3988–4004. 10.1063/1.1726561
Craig M. E., Crothers D. M., Doty P. 1971 Relaxation kinetics of dimer formation by self complementary oligonucleotides. J. Mol. Biol. 62(2), 383–401. 10.1016/0022-2836(71)90434-7
Dai H., Meyer M., Stepaniants S., Ziman M., Stoughton R. 2002 Use of hybridization kinetics for differentiating specific from non-specific binding to oligonucleotide microarrays. Nucleic Acids Res. 30(16), e86. 10.1093/nar/gnf085
Deeb G., Baer M. R., Gaile D. P., Sait S. N., Barcos M., Wetzler M., Conroy J. M., Nowak N. J., Cowell J. K., Cheney R. T. 2005 Genomic profiling of myeloid sarcoma by array comparative genomic hybridization. Genes Chromosomes Cancer 44(4), 373–383. doi:10.1002/gcc.20239
Demeter J., Beauheim C., Gollub J., Hernandez-Boussard T., Jin H., Maier D., Matese J. C., Nitzberg M., Wymore F., Zachariah Z. K., Brown P. O., Sherlock G., Ball C. A. 2007 The Stanford Microarray Database: implementation of new analysis tools and open source release of software. Nucleic Acids Res. 35(Database issue), D766–770. doi:10.1093/nar/gkl1019
DeRisi J. L., Iyer V. R., Brown P. O. 1997 Exploring the metabolic and genetic control of gene expression on a genomic scale. Science 278(5338), 680–686. doi:10.1126/science.278.5338.680
DeRisi J., Penland L., Brown P. O., Bittner M. L., Meltzer P. S., Ray M., Chen Y., Su Y. A., Trent J. M. 1996 Use of a cDNA microarray to analyse gene expression patterns in human cancer. Nat. Genet. 14(4), 457–460. doi:10.1038/ng1296-457
Erickson D., Li D., Krull U. J. 2003 Modeling of DNA hybridization kinetics for spatially resolved biochips. Anal. Biochem. 317(2), 186–200. 10.1016/S0003-2697(03)00090-3
Gadgil C., Yeckel A., Derby J. J., Hu W. S. 2004 A diffusion-reaction model for DNA microarray assays. J. Biotechnol. 114(1–2), 31–45. 10.1016/j.jbiotec.2004.05.008
Goldstein H. 2002 Classical Mechanics. 3rd ed.; Addison Wesley, San Francisco
Golub T. R., Slonim D. K., Tamayo P., Huard C., Gaasenbeek M., Mesirov J. P., Coller H., Loh M. L., Downing J. R., Caligiuri M. A., Bloomfield C. D., Lander E. S. 1999 Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science 286(5439), 531–537. doi:10.1126/science.286.5439.531
Graves D. J. 1999 Powerful tools for genetic analysis come of age. Trends Biotechnol. 17(3), 127–134. doi:10.1016/S0167-7799(98)01241-4
Happel J., Brenner H. 1983 Low Reynolds Number Hydrodynamics: With Special Applications to Particulate Media. M. Nijhoff/Kluwer, Boston, MA
Held G. A., Grinstein G., Tu Y. 2003 Modeling of DNA microarray data by using physical properties of hybridization. Proc. Natl. Acad. Sci. USA 100(13), 7575–7580. 10.1073/pnas.0832500100
Irizarry R. A., Bolstad B. M., Collin F., Cope L. M., Hobbs B., Speed T. P. 2003 Summaries of affymetrix GeneChip probe level data. Nucleic Acids Res. 31(4), e15. 10.1093/nar/gng015
Iyer V. R., Eisen M. B., Ross D. T., Schuler G., Moore T., Lee J. C. F., Trent J. M., Staudt L. M., Hudson J. Jr., Boguski M. S., Lashkari D., Shalon D., Botstein D., Brown P. O. 1999 The transcriptional program in the response of human fibroblasts to serum [see comments]. Science 283(5398): 83–87. doi:10.1126/science.283.5398.83
Koria P., Andreadis S. T. 2006 Epidermal morphogenesis: the transcriptional program of human keratinocytes during stratification. J. Invest. Dermatol. 126(8), 1834–1841. doi:10.1038/sj.jid.5700325
Koria P., Brazeau D., Kirkwood K., Hayden P., Klausner M., Andreadis S. T. 2003 Gene expression profile of tissue engineered skin subjected to acute barrier disruption. J. Invest. Dermatol. 121(2), 368–382. doi:10.1046/j.1523-1747.2003.12364.x
Lashkari D. A., DeRisi J. L., McCusker J. H., Namath A. F., Gentile C., Hwang S. Y., Brown P. O., Davis R. W. 1997 Yeast microarrays for genome wide parallel genetic and gene expression analysis. Proc. Natl. Acad. Sci. USA 94(24), 13057–13062. doi:10.1073/pnas.94.24.13057
Li, S., Lao J., Chen B. P., Li Y. S., Zhao Y., Chu J., Chen K. D., Tsou T. C., Peck K., Chien S. 2003 Genomic analysis of smooth muscle cells in 3-dimensional collagen matrix. FASEB J. 17(1), 97–99
Li C., Wong W. H. 2001 Model-based analysis of oligonucleotide arrays: expression index computation and outlier detection. Proc. Natl. Acad. Sci. USA 98(1), 31–36. doi:10.1073/pnas.011404098
Liu Y., Rauch C. B. 2003 DNA probe attachment on plastic surfaces and microfluidic hybridization array channel devices with sample oscillation. Anal. Biochem. 317(1), 76–84. 10.1016/S0003-2697(03)00051-4
Mehlmann M., Townsend M. B., Stears R. L., Kuchta R. D., Rowlen K. L. 2005 Optimization of fragmentation conditions for microarray analysis of viral RNA. Anal. Biochem. 347(2), 316–323. 10.1016/j.ab.2005.09.036
Nitsche J. M., Brenner H. 1990 On the formulation of boundary conditions for rigid nonspherical Brownian particles near solid walls: applications to orientation-specific reactions with immobilized enzymes. J. Colloid Interface Sci. 138, 21–41. 10.1016/0021-9797(90)90177-P
Nowak N. J., Gaile D., Conroy J. M., McQuaid D., Cowell J., Carter R., Goggins M. G., Hruban R. H., Maitra A. 2005 Genome-wide aberrations in pancreatic adenocarcinoma. Cancer Genet. Cytogenet. 161(1), 36–50. doi:10.1016/j.cancergencyto.2005.01.009
Pappaert K., Ottevaere H., Thienpont H., Van Hummelen P., Desmet G. 2006 Diffusion limitation: a possible source for the occurrence of doughnut patterns on DNA microarrays. Biotechniques 41(5), 609–616
Pappaert K., Van Hummelen P., Vanderhoeven J., Baron G. V., Desmet G. 2003 Diffusion-reaction modeling of DNA hybridization kinetics on biochips. Chem. Eng. Sci. 58(21), 4921–4930. 10.1016/j.ces.2002.12.007
Pappaert K., Vanderhoeven J., Van Hummelen P., Dutta B., Clicq D., Baron G. V., Desmet G. 2003 Enhancement of DNA micro-array analysis using a shear-driven micro-channel flow system. J. Chromatogr. A 1014(1–2), 1–9. 10.1016/S0021-9673(03)00715-5
Parkinson H., Kapushesky M., Shojatalab M., Abeygunawardena N., Coulson R., Farne A., Holloway E., Kolesnykov N., Lilja P., Lukk M., Mani R., Rayner T., Sharma A., William E., Sarkans U., Brazma A. 2007 ArrayExpress—a public database of microarray experiments and gene expression profiles. Nucleic Acids Res. 35(Database issue), D747–750. doi:10.1093/nar/gkl995
Parvathy V. R., Bhaumik S. R., Chary K. V., Govil G., Liu K., Howard F. B., Miles H. T. 2002 NMR structure of a parallel-stranded DNA duplex at atomic resolution. Nucleic Acids Res. 30(7), 1500–1511. 10.1093/nar/30.7.1500
Pavlova A., Stuart R. O., Pohl M., Nigam S. K. 1999 Evolution of gene expression patterns in a model of branching morphogenesis. Am. J. Physiol. 277(4 Pt 2), F650–663
Perou C. M., Jeffrey S. S., van de Rijn M., Rees C. A., Eisen M. B., Ross D. T., Pergamenschikov A., Williams C. F., Zhu S. X., Lee J. C., Lashkari D., Shalon D., Brown P. O., Botstein D. 1999 Distinctive gene expression patterns in human mammary epithelial cells and breast cancers. Proc. Natl. Acad. Sci. USA 96(16), 9212–9217. doi:10.1073/pnas.96.16.9212
Peterson A. W., Heaton R. J., Georgiadis R. M. 2001 The effect of surface probe density on DNA hybridization. Nucleic Acids Res. 29(24), 5163–5168. 10.1093/nar/29.24.5163
Peterson A. W., Wolf L. K., Georgiadis R. M. 2002 Hybridization of mismatched or partially matched DNA at surfaces. J. Am. Chem. Soc. 124(49), 14601–14607. 10.1021/ja0279996
Rhodes D. R., Yu J., Shanker K., Deshpande N., Varambally R., Ghosh D., Barrette T., Pandey A., Chinnaiyan A. M. 2004 ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia 6(1), 1–6
SantaLucia J. Jr., Allawi H. T., Seneviratne P. A. 1996 Improved nearest-neighbor parameters for predicting DNA duplex stability. Biochemistry 35(11), 3555–3562. 10.1021/bi951907q
Shalon D., Smith S. J., Brown P. O. 1996 A DNA microarray system for analyzing complex DNA samples using two-color fluorescent probe hybridization. Genome Res. 6(7), 639–645. doi:10.1101/gr.6.7.639
Spellman P. T., Sherlock G., Zhang M. Q., Iyer V. R., Anders K., Eisen M. B., Brown P. O., Botstein D., Futcher B. 1998 Comprehensive identification of cell cycle-regulated genes of the yeast Saccharomyces cerevisiae by microarray hybridization. Mol. Biol. Cell 9(12), 3273–3297
Stillman B. A., Tonkinson J. L. 2001 Expression microarray hybridization kinetics depend on length of the immobilized DNA but are independent of immobilization substrate. Anal. Biochem. 295(2), 149–157. 10.1006/abio.2001.5212
Tamayo P., Slonim D., Mesirov J., Zhu Q., Kitareewan S., Dmitrovsky E., Lander E. S., Golub T. R. 1999 Interpreting patterns of gene expression with self-organizing maps: methods and application to hematopoietic differentiation. Proc. Natl. Acad. Sci. USA 96(6), 2907–2912. doi:10.1073/pnas.96.6.2907
Tinland B., Pluen A., Sturm J., Weill G. 1997 Persistence length of single stranded DNA. Macromolecules 30, 5763–5765. 10.1021/ma970381+
Toronen P., Kolehmainen M., Wong G., Castren E. 1999 Analysis of gene expression data using self-organizing maps. FEBS Lett. 451(2): 142–146. doi:10.1016/S0014-5793(99)00524-4
Vanderhoeven J., Pappaert K., Dutta B., Van Hummelen P., Desmet G. 2005 DNA microarray enhancement using a continuously and discontinuously rotating microchamber. Anal. Chem. 77(14), 4474–4480. 10.1021/ac0502091
Vanderhoeven J., Pappaert K., Dutta B., Van Hummelen P., Desmet G. 2005 Comparison of a pump-around, a diffusion-driven, and a shear-driven system for the hybridization of mouse lung and testis total RNA on microarrays. Electrophoresis 26(19), 3773–3779
Wang J. Y., Drlica K. 2003 Modeling hybridization kinetics. Math. Biosci. 183(1), 37–47. 10.1016/S0025-5564(02)00221-3
Weinberger H. F. 1965 A First Course in Partial Differential Equations Wiley, New York
Wen X., Fuhrman S., Michaels G. S., Carr D. B., Smith S., Barker J. L., Somogyi R. 1998 Large-scale temporal gene expression mapping of central nervous system development. Proc. Natl. Acad. Sci. USA 95(1), 334–339. doi:10.1073/pnas.95.1.334
Whittaker E. T. 1944 A Treatise on the Analytical Dynamics of Particles and Rigid Bodies. 4th ed.; Dover, New York, p 9–10
Yang Y. H., Dudoit S., Luu P., Lin D. M., Peng V., Ngai J., Speed T. P. 2002 Normalization for cDNA microarray data: a robust composite method addressing single and multiple slide systematic variation. Nucleic Acids Res. 30(4), e15. doi:10.1093/nar/30.4.e15
Zhang Y., Hammer D. A., Graves D. J. 2005 Competitive hybridization kinetics reveals unexpected behavior patterns. Biophys. J. 89(5), 2950–2959. 10.1529/biophysj.104.058552
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Appendix A
Appendix A
At z = r g the flux, β, entering the microscopic diffusion layer is equal to the rate of reaction:
Note that the flux, β entering the reaction zone layer is the same as the flux far from the surface (z→∞) (see Eq. 20). From Eq. (27) we substitute the dimensionless variables \( \xi = C \mathord{\left/ {\vphantom {C {\beta r_{{\text{g}}} }}} \right. \kern-\nulldelimiterspace} {\beta r_{{\text{g}}} } \) and \( \eta = z \mathord{\left/ {\vphantom {z {r_{{\text{g}}} }}} \right. \kern-\nulldelimiterspace} {r_{{\text{g}}} } \) into Eq. (A1) to obtain:
The value of \( \left. \xi \right|_{{\eta = 1}} \) is obtained as the intercept of the linear part of ξ(η) curve (Fig. 4) to η = 1.
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Singh, R., Nitsche, J. & Andreadis, S.T. An Integrated Reaction-Transport Model for DNA Surface Hybridization: Implications for DNA Microarrays. Ann Biomed Eng 37, 255–269 (2009). https://doi.org/10.1007/s10439-008-9584-y
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DOI: https://doi.org/10.1007/s10439-008-9584-y