Position dependent mismatch discrimination on DNA microarrays – experiments and model

BackgroundThe propensity of oligonucleotide strands to form stable duplexes with complementary sequences is fundamental to a variety of biological and biotechnological processes as various as microRNA signalling, microarray hybridization and PCR. Yet our understanding of oligonucleotide hybridization, in particular in presence of surfaces, is rather limited. Here we use oligonucleotide microarrays made in-house by optically controlled DNA synthesis to produce probe sets comprising all possible single base mismatches and base bulges for each of 20 sequence motifs under study.ResultsWe observe that mismatch discrimination is mostly determined by the defect position (relative to the duplex ends) as well as by the sequence context. We investigate the thermodynamics of the oligonucleotide duplexes on the basis of double-ended molecular zipper. Theoretical predictions of defect positional influence as well as long range sequence influence agree well with the experimental results.ConclusionMolecular zipping at thermodynamic equilibrium explains the binding affinity of mismatched DNA duplexes on microarrays well. The position dependent nearest neighbor model (PDNN) can be inferred from it. Quantitative understanding of microarray experiments from first principles is in reach.

[1]  A. Ott,et al.  Impact of point-mutations on the hybridization affinity of surface-bound DNA/DNA and RNA/DNA oligonucleotide-duplexes: Comparison of single base mismatches and base bulges , 2008, BMC biotechnology.

[2]  R. S. Foote,et al.  Photolabile protecting groups for nucleosides: Synthesis and photodeprotection rates , 1997 .

[3]  Michael Zuker,et al.  DINAMelt web server for nucleic acid melting prediction , 2005, Nucleic Acids Res..

[4]  D. Tautz,et al.  Tests of rRNA hybridization to microarrays suggest that hybridization characteristics of oligonucleotide probes for species discrimination cannot be predicted , 2006, Nucleic Acids Research.

[5]  P. Stadler,et al.  Sensitivity of Microarray Oligonucleotide Probes: Variability and Effect of Base Composition , 2004 .

[6]  S. Preibisch,et al.  Base pair interactions and hybridization isotherms of matched and mismatched oligonucleotide probes on microarrays. , 2005, Langmuir : the ACS journal of surfaces and colloids.

[7]  H. Blöcker,et al.  Predicting DNA duplex stability from the base sequence. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[8]  E. Carlon,et al.  Thermodynamics of RNA/DNA hybridization in high-density oligonucleotide microarrays , 2004, q-bio/0411011.

[9]  John J. Kelly,et al.  Single-Base-Pair Discrimination of Terminal Mismatches by Using Oligonucleotide Microarrays and Neural Network Analyses , 2002, Applied and Environmental Microbiology.

[10]  D. Turner,et al.  Thermodynamics of single mismatches in RNA duplexes. , 1999, Biochemistry.

[11]  J. SantaLucia,et al.  The thermodynamics of DNA structural motifs. , 2004, Annual review of biophysics and biomolecular structure.

[12]  Modeling of microarray data with zippering , 2004, q-bio/0406039.

[13]  D. Dorris,et al.  Oligodeoxyribonucleotide probe accessibility on a three-dimensional DNA microarray surface and the effect of hybridization time on the accuracy of expression ratios , 2003, BMC biotechnology.

[14]  J. H. Gibbs,et al.  Statistical Mechanics of Helix‐Coil Transitions in Biological Macromolecules , 1959 .

[15]  K. Aldape,et al.  A model of molecular interactions on short oligonucleotide microarrays , 2003, Nature Biotechnology.

[16]  Alexander W Peterson,et al.  Hybridization of mismatched or partially matched DNA at surfaces. , 2002, Journal of the American Chemical Society.

[17]  A. Brookes,et al.  Effect of oligonucleotide truncation on single-nucleotide distinction by solid-phase hybridization. , 2002, Analytical chemistry.

[18]  A. Buhot,et al.  Sensitivity, specificity, and the hybridization isotherms of DNA chips. , 2003, Biophysical journal.

[19]  C. Kittel,et al.  Phase Transition of a Molecular Zipper , 1969 .

[20]  J. Fidanza,et al.  Kinetics of oligonucleotide hybridization to photolithographically patterned DNA arrays. , 2006, Analytical biochemistry.

[21]  Enrico Carlon,et al.  Thermodynamic behavior of short oligonucleotides in microarray hybridizations can be described using Gibbs free energy in a nearest-neighbor model. , 2007, The journal of physical chemistry. B.

[22]  Robert P. Searles,et al.  DNA multiplex hybridization on microarrays and thermodynamic stability in solution: a direct comparison , 2007, Nucleic acids research.

[23]  Albrecht Ott,et al.  Versatile maskless microscope projection photolithography system and its application in light-directed fabrication of DNA microarrays , 2006, q-bio/0608038.

[24]  Hans Binder,et al.  Thermodynamics of competitive surface adsorption on DNA microarrays , 2006 .

[25]  S. P. Fodor,et al.  Light-directed, spatially addressable parallel chemical synthesis. , 1991, Science.

[26]  I. Tinoco,et al.  Stability of ribonucleic acid double-stranded helices. , 1974, Journal of molecular biology.

[27]  A. Buhot,et al.  Brush effects on DNA chips: thermodynamics, kinetics, and design guidelines. , 2005, Biophysical journal.

[28]  J. SantaLucia,et al.  A unified view of polymer, dumbbell, and oligonucleotide DNA nearest-neighbor thermodynamics. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[29]  Franco Cerrina,et al.  Gene expression analysis using oligonucleotide arrays produced by maskless photolithography. , 2002, Genome research.

[30]  D. Hoyle,et al.  Strong position-dependent effects of sequence mismatches on signal ratios measured using long oligonucleotide microarrays , 2008, BMC Genomics.

[31]  J. SantaLucia,et al.  Thermodynamics and NMR of internal G.T mismatches in DNA. , 1997, Biochemistry.

[32]  Erdogan Gulari,et al.  On-chip non-equilibrium dissociation curves and dissociation rate constants as methods to assess specificity of oligonucleotide probes , 2006, Nucleic acids research.

[33]  I. Tinoco,et al.  The stability of helical polynucleotides: base contributions. , 1962, Journal of molecular biology.

[34]  Nam Quoc Ngo,et al.  The Efficiency of Light-Directed Synthesis of DNA Arrays on Glass Substrates , 1997 .

[35]  K. Itakura,et al.  Detection of sickle cell beta S-globin allele by hybridization with synthetic oligonucleotides. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[36]  Felix Naef,et al.  Solving the riddle of the bright mismatches: labeling and effective binding in oligonucleotide arrays. , 2002, Physical review. E, Statistical, nonlinear, and soft matter physics.

[37]  H. Garner,et al.  Digital Optical Chemistry: A Novel System for the Rapid Fabrication of Custom Oligonucleotide Arrays , 2002 .

[38]  I. Tinoco,et al.  DNA and RNA oligomer thermodynamics: The effect of mismatched bases on double‐helix stability , 1981, Biopolymers.

[39]  Sequence context and thermodynamic stability of a single base pair mismatch in short deoxyoligonucleotide duplexes. , 2001, Journal of the American Chemical Society.

[40]  G. Grinstein,et al.  Modeling of DNA microarray data by using physical properties of hybridization , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[41]  D. Patel,et al.  Structure, dynamics, and energetics of deoxyguanosine . thymidine wobble base pair formation in the self-complementary d(CGTGAATTCGCG) duplex in solution. , 1982, Biochemistry.

[42]  M. Sussman,et al.  Maskless fabrication of light-directed oligonucleotide microarrays using a digital micromirror array , 1999, Nature Biotechnology.

[43]  Susan R. Wilson,et al.  Statistical Analysis of Adsorption Models for Oligonucleotide Microarrays , 2004, Statistical applications in genetics and molecular biology.

[44]  A. Ott,et al.  Hybridization to surface-bound oligonucleotide probes: Influence of point defects , 2006, q-bio/0612043.

[45]  Teresa A. Webster,et al.  Probe selection for high-density oligonucleotide arrays , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[46]  B Montgomery Pettitt,et al.  Coulomb blockage of hybridization in two-dimensional DNA arrays. , 2002, Physical review. E, Statistical, nonlinear, and soft matter physics.

[47]  Arnaud Buhot,et al.  On the hybridization isotherms of DNA microarrays: the Langmuir model and its extensions , 2006 .

[48]  G. Grinstein,et al.  Relationship between gene expression and observed intensities in DNA microarrays—a modeling study , 2006, Nucleic acids research.

[49]  A. Caminade,et al.  Dendrimeric coating of glass slides for sensitive DNA microarrays analysis. , 2003, Nucleic acids research.

[50]  D. Stern,et al.  Thermodynamics of Duplex Formation and Mismatch Discrimination on Photolithographically Synthesized Oligonucleotide Arrays , 1997 .

[51]  D M Crothers,et al.  Relaxation kinetics of dimer formation by self complementary oligonucleotides. , 1971, Journal of molecular biology.

[52]  R. Wartell,et al.  The effect of base sequence on the stability of RNA and DNA single base bulges. , 1999, Biochemistry.