Transcription analysis of recombinant industrial and laboratory Saccharomyces cerevisiae strains reveals the molecular basis for fermentation of glucose and xylose

Microbial Cell Factories

Volumn 13, Issue 1, 2014, Pages

  Matsushika, Akinori ^a   Goshima, Tetsuya ^a   Hoshino, Tamotsu ^a,b  

^a NATIONAL INSTITUTE OF ADVANCED INDUSTRIAL SCIENCE AND TECHNOLOGY AIST   (Japan)

^b HOKKAIDO UNIVERSITY   (Japan)

Author keywords

DNA microarray; Ethanol production; Saccharomyces cerevisiae; Transcriptomics; Xylose fermentation

Indexed keywords

BATCH CELL CULTURE TECHNIQUES; BIOMASS; ERGOSTEROL; ETHANOL; GLUCOSE; GLUCOSYLTRANSFERASES; RECOMBINANT PROTEINS; SACCHAROMYCES CEREVISIAE; SACCHAROMYCES CEREVISIAE PROTEINS; SUBSTRATE SPECIFICITY; TRANSCRIPTOME; XYLOSE;

EID: 84892934934     PISSN: None     EISSN: 14752859     Source Type: Journal    
DOI: 10.1186/1475-2859-13-16     Document Type: Article

References (93)

1. Kevin AG, Lishan Z, Mark E. Bioethanol. Curr Opin Chem Biol 2006, 10:141-146.
2. Hahn-Hägerdal B, Karhumaa K, Fonseca C, Spencer-Martins I, Gorwa-Grauslund MF. Towards industrial pentose-fermenting yeast strains. Appl Microbiol Biotechnol 2007, 74:937-953.
3. Matsushika A, Inoue H, Kodaki T, Sawayama S. Ethanol production from xylose in engineered Saccharomyces cerevisiae strains: current state and perspectives. Appl Microbiol Biotechnol 2009, 84:37-53.
4. Van Vleet JH, Jeffries TW. Yeast metabolic engineering for hemicellulosic ethanol production. Curr Opin Biotechnol 2009, 20:300-306.
5. Cai Z, Zhang B, Li Y. Engineering Saccharomyces cerevisiae for efficient anaerobic xylose fermentation: reflections and perspectives. Biotechnol J 2012, 7:34-46.
6. Matsushika A, Liu ZL, Sawayama S, Moon J. Improving biomass sugar utilization by engineered Saccharomyces cerevisiae. Microbial Stress Tolerance for Biofuels. Volume 22 2012, 137-160. Springer, Heidelberg, Germany: Microbiology Monographs, Liu ZL.
7. Kötter P, Ciriacy M. Xylose fermentation by Saccharomyces cerevisiae. Appl Microbiol Biotechnol 1993, 38:776-783.
8. Tantirungkij M, Nakashima N, Seki T, Yoshida T. Construction of xylose-assimilating Saccharomyces cerevisiae. J Ferment Bioeng 1993, 75:83-88.
9. Bruinenberg PM, de Bot PHM, van Dijken JP, Scheffers WA. The role of redox balances in the anaerobic fermentation of xylose by yeasts. Eur J Appl Microbiol Biotechnol 1983, 18:287-292.
10. Walfridsson M, Bao X, Anderlund M, Lilius G, Bülow L, Hahn-Hägerdal B. Ethanolic fermentation of xylose with Saccharomyces cerevisiae harboring the Thermus thermophilus xylA gene, which expresses an active xylose (glucose) isomerase. Appl Environ Microbiol 1996, 62:4648-4651.
11. Kuyper M, Harhangi HR, Stave AK, Winkler AA, Jetten MS, de Laat WT, den Ridder JJ, Op den Camp HJ, van Dijken JP, Pronk JT. High-level functional expression of a fungal xylose isomerase: the key to efficient ethanolic fermentation of xylose by Saccharomyces cerevisiae?. FEMS Yeast Res 2003, 4:69-78.
12. Lönn A, Träff-Bjerre KL, Cordero Otero RR, van Zyl WH, Hahn-Hägerdal B. Xylose isomerase activity influences xylose fermentation with recombinant Saccharomyces cerevisiae strains expressing mutated xylA from Thermus thermophilus. Enzyme Microb Technol 2003, 32:567-573.
13. Madhavan A, Tamalampudi S, Ushida K, Kanai D, Katahira S, Srivastava A, Fukuda H, Bisaria VS, Kondo A. Xylose isomerase from polycentric fungus Orpinomyces: gene sequencing, cloning, and expression in Saccharomyces cerevisiae for bioconversion of xylose to ethanol. Appl Microbiol Biotechnol 2009, 82:1067-1078.
14. Karhumaa K, Garcia Sanchez R, Hahn-Hägerdal B, Gorwa-Grauslund MF. Comparison of the xylose reductase-xylitol dehydrogenase and the xylose isomerase pathways for xylose fermentation by recombinant Saccharomyces cerevisiae. Microb Cell Fact 2007, 6:5.
15. van Maris AJ, Winkler AA, Kuyper M, de Laat WT, van Dijken JP, Pronk JT. Development of efficient xylose fermentation in Saccharomyces cerevisiae: xylose isomerase as a key component. Adv Biochem Eng Biotechnol 2007, 108:179-204.
16. Kuyper M, Hartog MM, Toirkens MJ, Almering MJ, Winkler AA, van Dijken JP, Pronk JT. Metabolic engineering of a xylose-isomerase-expressing Saccharomyces cerevisiae strain for rapid anaerobic xylose fermentation. FEMS Yeast Res 2005, 5:399-409.
17. Zhou H, Cheng JS, Wang BL, Fink GR, Stephanopoulos G. Xylose isomerase overexpression along with engineering of the pentose phosphate pathway and evolutionary engineering enable rapid xylose utilization and ethanol production by Saccharomyces cerevisiae. Metab Eng 2012, 14:611-622.
18. Demeke MM, Dietz H, Li Y, Foulquié-Moreno MR, Mutturi S, Deprez S, Den Abt T, Bonini BM, Liden G, Dumortier F, Verplaetse A, Boles E, Thevelein JM. Development of a D-xylose fermenting and inhibitor tolerant industrial Saccharomyces cerevisiae strain with high performance in lignocellulose hydrolysates using metabolic and evolutionary engineering. Biotechnol Biofuels 2013, 6:89.
19. Sedlak M, Edenberg HJ, Ho NWY. DNA microarray analysis of the expression of the genes encoding the major enzymes in ethanol production during glucose and xylose co-fermentation by metabolically engineered Saccharomyces yeast. Enzyme Microb Technol 2003, 33:19-28.
20. Wahlbom CF, Cordero Otero RR, van Zyl WH, Hahn-Hägerdal B, Jönsson LJ. Molecular analysis of a Saccharomyces cerevisiae mutant with improved ability to utilize xylose shows enhanced expression of proteins involved in transport, initial xylose metabolism, and the pentose phosphate pathway. Appl Environ Microbiol 2003, 69:740-746.
21. Salusjärvi L, Poutanen M, Pitkänen JP, Koivistoinen H, Aristidou A, Kalkkinen N, Ruohonen L, Penttilä M. Proteome analysis of recombinant xylose-fermenting Saccharomyces cerevisiae. Yeast 2003, 20:295-314.
22. Jin YS, Laplaza JM, Jeffries TW. Saccharomyces cerevisiae engineered for xylose metabolism exhibits a respiratory response. Appl Environ Microbiol 2004, 70:6816-6825.
23. Sonderegger M, Jeppsson M, Hahn-Hägerdal B, Sauer U. Molecular basis for anaerobic growth of Saccharomyces cerevisiae on xylose, investigated by global gene expression and metabolic flux analysis. Appl Environ Microbiol 2004, 70:2307-2317.
24. Salusjärvi L, Pitkänen JP, Aristidou A, Ruohonen L, Penttilä M. Transcription analysis of recombinant Saccharomyces cerevisiae reveals novel responses to xylose. Appl Biochem Biotechnol 2006, 128:237-261.
25. Salusjärvi L, Kankainen M, Soliymani R, Pitkänen JP, Penttilä M, Ruohonen L. Regulation of xylose metabolism in recombinant Saccharomyces cerevisiae. Microb Cell Fact 2008, 7:18.
26. Karhumaa K, Påhlman AK, Hahn-Hägerdal B, Levander F, Gorwa-Grauslund MF. Proteome analysis of the xylose-fermenting mutant yeast strain TMB 3400. Yeast 2009, 26:371-382.
27. Runquist D, Hahn-Hägerdal B, Bettiga M. Increased expression of the oxidative pentose phosphate pathway and gluconeogenesis in anaerobically growing xylose-utilizing Saccharomyces cerevisiae. Microb Cell Fact 2009, 8:49.
28. Klimacek M, Krahulec S, Sauer U, Nidetzky B. Limitations in xylose-fermenting Saccharomyces cerevisiae, made evident through comprehensive metabolite profiling and thermodynamic analysis. Appl Environ Microbiol 2010, 76:7566-7574.
29. Bergdahl B, Heer D, Sauer U, Hahn-Hägerdal B, van Niel EW. Dynamic metabolomics differentiates between carbon and energy starvation in recombinant Saccharomyces cerevisiae fermenting xylose. Biotechnol Biofuels 2012, 5:34.
30. Matsushika A, Nagashima A, Goshima T, Hoshino T. Fermentation of xylose causes inefficient metabolic state due to carbon/energy starvation and reduced glycolytic flux in recombinant industrial Saccharomyces cerevisiae. PLoS ONE 2013, 8:e69005.
31. Matsushika A, Inoue H, Murakami K, Takimura O, Sawayama S. Bioethanol production performance of five recombinant strains of laboratory and industrial xylose-fermenting Saccharomyces cerevisiae. Bioresour Technol 2009, 100:2392-2398.
32. Matsushika A, Sawayama S. Characterization of a recombinant flocculent Saccharomyces cerevisiae strain that co-ferments glucose and xylose: I. Influence of the ratio of glucose/xylose on ethanol production. Appl Biochem Biotechnol 2013, 169:712-721.
33. Hiser L, Basson ME, Rine J. ERG10 from Saccharomyces cerevisiae encodes acetoacetyl-CoA thiolase. J Biol Chem 1994, 269:31383-31389.
34. Basson ME, Thorsness M, Rine J. Saccharomyces cerevisiae contains two functional genes encoding 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Proc Natl Acad Sci U S A 1986, 83:5563-5567.
35. Landl KM, Klösch B, Turnowsky F. ERG1, encoding squalene epoxidase, is located on the right arm of chromosome VII of Saccharomyces cerevisiae. Yeast 1996, 12:609-613.
36. Ashman WH, Barbuch RJ, Ulbright CE, Jarrett HW, Bard M. Cloning and disruption of the yeast C-8 sterol isomerase gene. Lipids 1991, 26:628-632.
37. Andreasen AA, Stier TJ. Anaerobic nutrition of Saccharomyces cerevisiae. I. Ergosterol requirement for growth in a defined medium. J Cell Physiol 1953, 41:23-36.
38. Inoue T, Iefuji H, Fujii T, Soga H, Satoh K. Cloning and characterization of a gene complementing the mutation of an ethanol-sensitive mutant of sake yeast. Biosci Biotechnol Biochem 2000, 64:229-236.
39. Mauricio JC, Moreno J, Zea L, Ortega JM, Medina M. The effect of grape must fermentation conditions on volatile alcohols and esters formed by Saccharomyces cerevisiae. J Sci Food Agr 1997, 75:155-160.
40. Thorsness M, Schafer W, D'Ari L, Rine J. Positive and negative transcriptional control by heme of genes encoding 3-hydroxy-3-methylglutaryl coenzyme A reductase in Saccharomyces cerevisiae. Mol Cell Biol 1989, 9:5702-5712.
41. Kennedy MA, Barbuch R, Bard M. Transcriptional regulation of the squalene synthase gene (ERG9) in the yeast Saccharomyces cerevisiae. Biochim Biophys Acta 1999, 1445:110-122.
42. Tamura K, Gu Y, Wang Q, Yamada T, Ito K, Shimoi H. A hap1 mutation in a laboratory strain of Saccharomyces cerevisiae results in decreased expression of ergosterol-related genes and cellular ergosterol content compared to sake yeast. J Biosci Bioeng 2004, 98:159-166.
43. Rodríguez A, De La Cera T, Herrero P, Moreno F. The hexokinase 2 protein regulates the expression of the GLK1, HXK1 and HXK2 genes of Saccharomyces cerevisiae. Biochem J 2001, 355:625-631.
44. Delgado ML, O'Connor JE, Azorín I, Renau-Piqueras J, Gil ML, Gozalbo D. The glyceraldehyde-3-phosphate dehydrogenase polypeptides encoded by the Saccharomyces cerevisiae TDH1, TDH2 and TDH3 genes are also cell wall proteins. Microbiology 2001, 147:411-417.
45. Träff KL, Jönsson LJ, Hahn-Hägerdal B. Putative xylose and arabinose reductases in Saccharomyces cerevisiae. Yeast 2002, 19:1233-1241.
46. Richard P, Toivari MH, Penttilä M. Evidence that the gene YLR070c of Saccharomyces cerevisiae encodes a xylitol dehydrogenase. FEBS Lett 1999, 457:135-138.
47. Juhnke H, Krems B, Kötter P, Entian KD. Mutants that show increased sensitivity to hydrogen peroxide reveal an important role for the pentose phosphate pathway in protection of yeast against oxidative stress. Mol Gen Genet 1996, 252:456-464.
48. Slekar KH, Kosman DJ, Culotta VC. The yeast copper/zinc superoxide dismutase and the pentose phosphate pathway play overlapping roles in oxidative stress protection. J Biol Chem 1996, 271:28831-28836.
49. Matsushika A, Goshima T, Fujii T, Inoue H, Sawayama S, Yano S. Characterization of non-oxidative transaldolase and transketolase enzymes in the pentose phosphate pathway with regard to xylose utilization by recombinant Saccharomyces cerevisiae. Enzyme Microb Technol 2012, 51:16-25.
50. Boy-Marcotte E, Lagniel G, Perrot M, Bussereau F, Boudsocq A, Jacquet M, Labarre J. The heat shock response in yeast: differential regulations and contributions of the Msn2p/Msn4p and Hsf1p regulons. Mol Microbiol 1999, 33:274-283.
51. Kelley R, Ideker T. Genome-wide fitness and expression profiling implicate Mga2 in adaptation to hydrogen peroxide. PLoS Genet 2009, 5:e1000488.
52. Forsburg SL, Guarente L. Identification and characterization of HAP4: a third component of the CCAAT-bound HAP2/HAP3 heteromer. Genes Dev 1989, 3:1166-1178.
53. Gasch AP. The Environmental Stress Response: a common yeast response to environmental stresses. Yeast Stress Responses. Volume 1 2002, 11-70. Springer, Heidelberg, Germany: Topics in Current Genetics, Hohmann S.
54. Boer VM, de Winde JH, Pronk JT, Piper MD. The genome-wide transcriptional responses of Saccharomyces cerevisiae grown on glucose in aerobic chemostat cultures limited for carbon, nitrogen, phosphorus, or sulfur. J Biol Chem 2003, 278:3265-3274.
55. Vallari RC, Cook WJ, Audino DC, Morgan MJ, Jensen DE, Laudano AP, Denis CL. Glucose repression of the yeast ADH2 gene occurs through multiple mechanisms, including control of the protein synthesis of its transcriptional activator, ADR1. Mol Cell Biol 1992, 12:1663-1673.
56. Walther K, Schüller HJ. Adr1 and Cat8 synergistically activate the glucose-regulated alcohol dehydrogenase gene ADH2 of the yeast Saccharomyces cerevisiae. Microbiology 2001, 147:2037-2044.
57. Kratzer S, Schüller HJ. Transcriptional control of the yeast acetyl-CoA synthetase gene, ACS1, by the positive regulators CAT8 and ADR1 and the pleiotropic repressor UME6. Mol Microbiol 1997, 26:631-641.
58. Buu LM, Chen YC, Lee FJ. Functional characterization and localization of acetyl-CoA hydrolase, Ach1p, in Saccharomyces cerevisiae. J Biol Chem 2003, 278:17203-17209.
59. Grauslund M, Lopes JM, Rønnow B. Expression of GUT1, which encodes glycerol kinase in Saccharomyces cerevisiae, is controlled by the positive regulators Adr1p, Ino2p and Ino4p and the negative regulator Opi1p in a carbon source-dependent fashion. Nucleic Acids Res 1999, 27:4391-4398.
60. Grauslund M, Rønnow B. Carbon source-dependent transcriptional regulation of the mitochondrial glycerol-3-phosphate dehydrogenase gene, GUT2, from Saccharomyces cerevisiae. Can J Microbiol 2000, 46:1096-1100.
61. Hamacher T, Becker J, Gárdonyi M, Hahn-Hägerdal B, Boles E. Characterization of the xylose-transporting properties of yeast hexose transporters and their influence on xylose utilization. Microbiology 2002, 148:2783-2788.
62. Reifenberger E, Boles E, Ciriacy M. Kinetic characterization of individual hexose transporters of Saccharomyces cerevisiae and their relation to the triggering mechanisms of glucose repression. Eur J Biochem 1997, 245:324-333.
63. Diderich JA, Schuurmans JM, Van Gaalen MC, Kruckeberg AL, Van Dam K. Functional analysis of the hexose transporter homologue HXT5 in Saccharomyces cerevisiae. Yeast 2001, 18:1515-1524.
64. Ozcan S, Johnston M. Function and regulation of yeast hexose transporters. Microbiol Mol Biol Rev 1999, 63:554-569.
65. Bengtsson O, Jeppsson M, Sonderegger M, Parachin NS, Sauer U, Hahn-Hägerdal B, Gorwa-Grauslund MF. Identification of common traits in improved xylose-growing Saccharomyces cerevisiae for inverse metabolic engineering. Yeast 2008, 25:835-847.
66. Wahlbom CF, van Zyl WH, Jönsson LJ, Hahn-Hägerdal B, Cordero Otero RR. Generation of the improved recombinant xylose-utilizing Saccharomyces cerevisiae TMB 3400 by random mutagenesis and physiological comparison with Pichia stipitis CBS 6054. FEMS Yeast Res 2003, 3:319-326.
67. Nehlin JO, Ronne H. Yeast MIG1 repressor is related to the mammalian early growth response and Wilms' tumour finger proteins. EMBO J 1990, 9:2891-2898.
68. Freese EB, Chu MI, Freese E. Initiation of yeast sporulation of partial carbon, nitrogen, or phosphate deprivation. J Bacteriol 1982, 149:840-851.
69. Law DT, Segall J. The SPS100 gene of Saccharomyces cerevisiae is activated late in the sporulation process and contributes to spore wall maturation. Mol Cell Biol 1988, 8:912-922.
70. Briza P, Eckerstorfer M, Breitenbach M. The sporulation-specific enzymes encoded by the DIT1 and DIT2 genes catalyze a two-step reaction leading to a soluble LL-dityrosine-containing precursor of the yeast spore wall. Proc Natl Acad Sci U S A 1994, 91:4524-4528.
71. Ishihara S, Hirata A, Nogami S, Beauvais A, Latge JP, Ohya Y. Homologous subunits of 1,3-beta-glucan synthase are important for spore wall assembly in Saccharomyces cerevisiae. Eukaryot Cell 2007, 6:143-156.
72. Nickas ME, Neiman AM. Ady3p links spindle pole body function to spore wall synthesis in Saccharomyces cerevisiae. Genetics 2002, 160:1439-1450.
73. Palková Z, Devaux F, Icicová M, Mináriková L, Le Crom S, Jacq C. Ammonia pulses and metabolic oscillations guide yeast colony development. Mol Biol Cell 2002, 13:3901-3914.
74. Martínez-Pastor MT, Marchler G, Schüller C, Marchler-Bauer A, Ruis H, Estruch F. The Saccharomyces cerevisiae zinc finger proteins Msn2p and Msn4p are required for transcriptional induction through the stress response element (STRE). EMBO J 1996, 15:2227-2235.
75. Schmitt AP, McEntee K. Msn2p, a zinc finger DNA-binding protein, is the transcriptional activator of the multistress response in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A 1996, 93:5777-5782.
76. Simões T, Mira NP, Fernandes AR, Sá-Correia I. The SPI1 gene, encoding a glycosylphosphatidylinositol-anchored cell wall protein, plays a prominent role in the development of yeast resistance to lipophilic weak-acid food preservatives. Appl Environ Microbiol 2006, 72:7168-7175.
77. Kobayashi N, McClanahan TK, Simon JR, Treger JM, McEntee K. Structure and functional analysis of the multistress response gene DDR2 from Saccharomyces cerevisiae. Biochem Biophys Res Commun 1996, 229:540-547.
78. Winderickx J, de Winde JH, Crauwels M, Hino A, Hohmann S, Van Dijck P, Thevelein JM. Regulation of genes encoding subunits of the trehalose synthase complex in Saccharomyces cerevisiae: novel variations of STRE-mediated transcription control?. Mol Gen Genet 1996, 252:470-482.
79. Pereira MD, Eleutherio EC, Panek AD. Acquisition of tolerance against oxidative damage in Saccharomyces cerevisiae. BMC Microbiol 2001, 1:11.
80. Patton-Vogt JL, Henry SA. GIT1, a gene encoding a novel transporter for glycerophosphoinositol in Saccharomyces cerevisiae. Genetics 1998, 149:1707-1715.
81. Fisher E, Almaguer C, Holic R, Griac P, Patton-Vogt J. Glycerophosphocholine-dependent growth requires Gde1p (YPL110c) and Git1p in Saccharomyces cerevisiae. J Biol Chem 2005, 280:36110-36117.
82. Singleton CK. Identification and characterization of the thiamine transporter gene of Saccharomyces cerevisiae. Gene 1997, 199:111-121.
83. Hauser M, Narita V, Donhardt AM, Naider F, Becker JM. Multiplicity and regulation of genes encoding peptide transporters in Saccharomyces cerevisiae. Mol Membr Biol 2001, 18:105-112.
84. Kolarov J, Kolarova N, Nelson N. A third ADP/ATP translocator gene in yeast. J Biol Chem 1990, 265:12711-12716.
85. Macreadie IG, Novitski CE, Maxwell RJ, John U, Ooi BG, McMullen GL, Lukins HB, Linnane AW, Nagley P. Biogenesis of mitochondria: the mitochondrial gene (aap1) coding for mitochondrial ATPase subunit 8 in Saccharomyces cerevisiae. Nucleic Acids Res 1983, 11:4435-4451.
86. Marzuki S, Watkins LC, Choo WM. Mitochondrial H+-ATPase in mutants of Saccharomyces cerevisiae with defective subunit 8 of the enzyme complex. Biochim Biophys Acta 1989, 975:222-230.
87. Matsushika A, Inoue H, Watanabe S, Kodaki T, Makino K, Sawayama S. Efficient bioethanol production by recombinant flocculent Saccharomyces cerevisiae with genome-integrated NADP+-dependent xylitol dehydrogenase gene. Appl Environ Microbiol 2009, 75:3818-3822.
88. Matsushika A, Watanabe S, Kodaki T, Makino K, Inoue H, Murakami K, Takimura O, Sawayama S. Expression of protein engineered NADP+-dependent xylitol dehydrogenase increase ethanol production from xylose in recombinant Saccharomyces cerevisiae. Appl Microbiol Biotechnol 2008, 81:243-255.
89. Bergdahl B, Sandström AG, Borgström C, Boonyawan T, van Niel EW, Gorwa-Grauslund MF. Engineering yeast hexokinase 2 for improved tolerance toward xylose-induced inactivation. PLoS ONE 2013, 8:e75055.
90. Iwahashi H, Kitagawa E, Suzuki Y, Ueda Y, Ishizawa YH, Nobumasa H, Kuboki Y, Hosoda H, Iwahashi Y. Evaluation of toxicity of the mycotoxin citrinin using yeast ORF DNA microarray and Oligo DNA microarray. BMC Genomics 2007, 8:95.
91. Hirasawa T, Ookubo A, Yoshikawa K, Nagahisa K, Furusawa C, Sawai H, Shimizu H. Investigating the effectiveness of DNA microarray analysis for identifying the genes involved in L-lactate production by Saccharomyces cerevisiae. Appl Microbiol Biotechnol 2009, 84:1149-1159.
92. Ueda Y, Ikushima S, Sugiyama M, Matoba R, Kaneko Y, Matsubara K, Harashima S. Large-scale genome reorganization in Saccharomyces cerevisiae through combinatorial loss of mini-chromosomes. J Biosci Bioeng 2012, 113:675-682.
93. Workman C, Jensen LJ, Jarmer H, Berka R, Gautier L, Nielser HB, Saxild HH, Nielsen C, Brunak S, Knudsen S. A new non-linear normalization method for reducing variability in DNA microarray experiments. Genome Biol 2002, 3:research0048.