Skip to main content
NCBI home page
Philosophical Transactions of the Royal Society B: Biological Sciences logoLink to Philosophical Transactions of the Royal Society B: Biological Sciences
. 2004 Jun 29;359(1446):857–871. doi: 10.1098/rstb.2003.1411

Metabolic profiles to define the genome: can we hear the phenotypes?

Julian L Griffin 1
PMCID: PMC1693382  PMID: 15306403

Abstract

There is an increased reliance on genetically modified organisms as a functional genomic tool to elucidate the role of genes and their protein products. Despite this, many models do not express the expected phenotype thought to be associated with the gene or protein. There is thus an increased need to further define the phenotype resultant from a genetic modification to understand how the transcriptional or proteomic network may conspire to alter the expected phenotype. This is best typified by the description of the silent phenotype in genetic manipulations of yeast. High-resolution proton nuclear magnetic resonance ((1)H NMR) spectroscopy provides an ideal mechanism for the profiling of metabolites within biofluids, tissue extracts or, with recent advances, intact tissues. These metabolic datasets can be readily mined using a range of pattern recognition techniques, including hierarchical cluster analysis, principal components analysis, partial least squares and neural networks, with the combined approach being termed metabolomics. This review describes the application of NMR-based metabolomics or metabonomics to genetic and chemical interventions in a number of different species, demonstrating the versatility of such an approach, as well as suggesting how it may be integrated with other "omic" technologies.

Full Text

The Full Text of this article is available as a PDF (888.5 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Allen Jess, Davey Hazel M., Broadhurst David, Heald Jim K., Rowland Jem J., Oliver Stephen G., Kell Douglas B. High-throughput classification of yeast mutants for functional genomics using metabolic footprinting. Nat Biotechnol. 2003 May 12;21(6):692–696. doi: 10.1038/nbt823. [DOI] [PubMed] [Google Scholar]
  2. Anderson J. L., Head S. I., Rae C., Morley J. W. Brain function in Duchenne muscular dystrophy. Brain. 2002 Jan;125(Pt 1):4–13. doi: 10.1093/brain/awf012. [DOI] [PubMed] [Google Scholar]
  3. Bailey N. J., Cooper P., Hadfield S. T., Lenz E. M., Lindon J. C., Nicholson J. K., Stanley P. D., Wilson I. D., Wright B., Taylor S. D. Application of directly coupled HPLC-NMR-MS/MS to the identification of metabolites of 5-trifluoromethylpyridone (2-hydroxy-5-trifluoromethylpyridine) in hydroponically grown plants. J Agric Food Chem. 2000 Jan;48(1):42–46. doi: 10.1021/jf990387t. [DOI] [PubMed] [Google Scholar]
  4. Barton-Davis E. R., Cordier L., Shoturma D. I., Leland S. E., Sweeney H. L. Aminoglycoside antibiotics restore dystrophin function to skeletal muscles of mdx mice. J Clin Invest. 1999 Aug;104(4):375–381. doi: 10.1172/JCI7866. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Beckwith-Hall B. M., Nicholson J. K., Nicholls A. W., Foxall P. J., Lindon J. C., Connor S. C., Abdi M., Connelly J., Holmes E. Nuclear magnetic resonance spectroscopic and principal components analysis investigations into biochemical effects of three model hepatotoxins. Chem Res Toxicol. 1998 Apr;11(4):260–272. doi: 10.1021/tx9700679. [DOI] [PubMed] [Google Scholar]
  6. Bochner B. R., Gadzinski P., Panomitros E. Phenotype microarrays for high-throughput phenotypic testing and assay of gene function. Genome Res. 2001 Jul;11(7):1246–1255. doi: 10.1101/gr.186501. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bollard M. E., Garrod S., Holmes E., Lindon J. C., Humpfer E., Spraul M., Nicholson J. K. High-resolution (1)H and (1)H-(13)C magic angle spinning NMR spectroscopy of rat liver. Magn Reson Med. 2000 Aug;44(2):201–207. doi: 10.1002/1522-2594(200008)44:2<201::aid-mrm6>3.0.co;2-5. [DOI] [PubMed] [Google Scholar]
  8. Brindle Joanne T., Antti Henrik, Holmes Elaine, Tranter George, Nicholson Jeremy K., Bethell Hugh W. L., Clarke Sarah, Schofield Peter M., McKilligin Elaine, Mosedale David E. Rapid and noninvasive diagnosis of the presence and severity of coronary heart disease using 1H-NMR-based metabonomics. Nat Med. 2002 Nov 25;8(12):1439–1444. doi: 10.1038/nm1202-802. [DOI] [PubMed] [Google Scholar]
  9. Buchholz Arne, Hurlebaus Jochen, Wandrey Christian, Takors Ralf. Metabolomics: quantification of intracellular metabolite dynamics. Biomol Eng. 2002 Jun;19(1):5–15. doi: 10.1016/s1389-0344(02)00003-5. [DOI] [PubMed] [Google Scholar]
  10. Bundy Jacob G., Spurgeon David J., Svendsen Claus, Hankard Peter K., Osborn Daniel, Lindon John C., Nicholson Jeremy K. Earthworm species of the genus Eisenia can be phenotypically differentiated by metabolic profiling. FEBS Lett. 2002 Jun 19;521(1-3):115–120. doi: 10.1016/s0014-5793(02)02854-5. [DOI] [PubMed] [Google Scholar]
  11. Burton Edward A., Davies Kay E. Muscular dystrophy--reason for optimism? Cell. 2002 Jan 11;108(1):5–8. doi: 10.1016/s0092-8674(01)00626-2. [DOI] [PubMed] [Google Scholar]
  12. Carmichael P. L. Mechanisms of action of antiestrogens: relevance to clinical benefits and risks. Cancer Invest. 1998;16(8):604–611. doi: 10.3109/07357909809032891. [DOI] [PubMed] [Google Scholar]
  13. Castrillo Juan I., Hayes Andrew, Mohammed Shabaz, Gaskell Simon J., Oliver Stephen G. An optimized protocol for metabolome analysis in yeast using direct infusion electrospray mass spectrometry. Phytochemistry. 2003 Mar;62(6):929–937. doi: 10.1016/s0031-9422(02)00713-6. [DOI] [PubMed] [Google Scholar]
  14. Cemal Cemal K., Carroll Christopher J., Lawrence Lorraine, Lowrie Margaret B., Ruddle Piers, Al-Mahdawi Sahar, King Rosalind H. M., Pook Mark A., Huxley Clare, Chamberlain Susan. YAC transgenic mice carrying pathological alleles of the MJD1 locus exhibit a mild and slowly progressive cerebellar deficit. Hum Mol Genet. 2002 May 1;11(9):1075–1094. doi: 10.1093/hmg/11.9.1075. [DOI] [PubMed] [Google Scholar]
  15. Cordier L., Hack A. A., Scott M. O., Barton-Davis E. R., Gao G., Wilson J. M., McNally E. M., Sweeney H. L. Rescue of skeletal muscles of gamma-sarcoglycan-deficient mice with adeno-associated virus-mediated gene transfer. Mol Ther. 2000 Feb;1(2):119–129. doi: 10.1006/mthe.1999.0019. [DOI] [PubMed] [Google Scholar]
  16. Dawson G., Cho S. Batten's disease: clues to neuronal protein catabolism in lysosomes. J Neurosci Res. 2000 Apr 15;60(2):133–140. doi: 10.1002/(SICI)1097-4547(20000415)60:2<133::AID-JNR1>3.0.CO;2-3. [DOI] [PubMed] [Google Scholar]
  17. De Luca V., St Pierre B. The cell and developmental biology of alkaloid biosynthesis. Trends Plant Sci. 2000 Apr;5(4):168–173. doi: 10.1016/s1360-1385(00)01575-2. [DOI] [PubMed] [Google Scholar]
  18. Devaux P. G., Horning M. G., Hill R. M., Horning E. C. O-benzyloximes: derivatives for the study of ketosteroids by gas chromatography. Application to urinary steroids of the newborn human. Anal Biochem. 1971 May;41(1):70–82. doi: 10.1016/0003-2697(71)90193-x. [DOI] [PubMed] [Google Scholar]
  19. Dürr A., Stevanin G., Cancel G., Duyckaerts C., Abbas N., Didierjean O., Chneiweiss H., Benomar A., Lyon-Caen O., Julien J. Spinocerebellar ataxia 3 and Machado-Joseph disease: clinical, molecular, and neuropathological features. Ann Neurol. 1996 Apr;39(4):490–499. doi: 10.1002/ana.410390411. [DOI] [PubMed] [Google Scholar]
  20. Evans G. A. Designer science and the "omic" revolution. Nat Biotechnol. 2000 Feb;18(2):127–127. doi: 10.1038/72480. [DOI] [PubMed] [Google Scholar]
  21. Even P. C., Decrouy A., Chinet A. Defective regulation of energy metabolism in mdx-mouse skeletal muscles. Biochem J. 1994 Dec 1;304(Pt 2):649–654. doi: 10.1042/bj3040649. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Evert B. O., Wüllner U., Klockgether T. Cell death in polyglutamine diseases. Cell Tissue Res. 2000 Jul;301(1):189–204. doi: 10.1007/s004410000228. [DOI] [PubMed] [Google Scholar]
  23. Fiehn O., Kopka J., Dörmann P., Altmann T., Trethewey R. N., Willmitzer L. Metabolite profiling for plant functional genomics. Nat Biotechnol. 2000 Nov;18(11):1157–1161. doi: 10.1038/81137. [DOI] [PubMed] [Google Scholar]
  24. Fiehn Oliver. Metabolic networks of Cucurbita maxima phloem. Phytochemistry. 2003 Mar;62(6):875–886. doi: 10.1016/s0031-9422(02)00715-x. [DOI] [PubMed] [Google Scholar]
  25. Fiehn Oliver. Metabolomics--the link between genotypes and phenotypes. Plant Mol Biol. 2002 Jan;48(1-2):155–171. [PubMed] [Google Scholar]
  26. Florian C. L., Preece N. E., Bhakoo K. K., Williams S. R., Noble M. D. Cell type-specific fingerprinting of meningioma and meningeal cells by proton nuclear magnetic resonance spectroscopy. Cancer Res. 1995 Jan 15;55(2):420–427. [PubMed] [Google Scholar]
  27. Florian C. L., Preece N. E., Bhakoo K. K., Williams S. R., Noble M. Characteristic metabolic profiles revealed by 1H NMR spectroscopy for three types of human brain and nervous system tumours. NMR Biomed. 1995 Sep;8(6):253–264. doi: 10.1002/nbm.1940080605. [DOI] [PubMed] [Google Scholar]
  28. Garrod S., Humpher E., Connor S. C., Connelly J. C., Spraul M., Nicholson J. K., Holmes E. High-resolution (1)H NMR and magic angle spinning NMR spectroscopic investigation of the biochemical effects of 2-bromoethanamine in intact renal and hepatic tissue. Magn Reson Med. 2001 May;45(5):781–790. doi: 10.1002/mrm.1106. [DOI] [PubMed] [Google Scholar]
  29. Gavaghan C. L., Holmes E., Lenz E., Wilson I. D., Nicholson J. K. An NMR-based metabonomic approach to investigate the biochemical consequences of genetic strain differences: application to the C57BL10J and Alpk:ApfCD mouse. FEBS Lett. 2000 Nov 10;484(3):169–174. doi: 10.1016/s0014-5793(00)02147-5. [DOI] [PubMed] [Google Scholar]
  30. Gieseler K., Grisoni K., Ségalat L. Genetic suppression of phenotypes arising from mutations in dystrophin-related genes in Caenorhabditis elegans. Curr Biol. 2000 Sep 21;10(18):1092–1097. doi: 10.1016/s0960-9822(00)00691-6. [DOI] [PubMed] [Google Scholar]
  31. Gillet B., Doan B. T., Verre-Serrie C., Barbere B., Berenger G., Morin S., Koenig J., Peres M., Sebille A., Beloeil J. C. In vivo 2D 1H NMR of mdx mouse muscle and myoblast cells during fusion: evidence for a characteristic signal of long chain fatty acids. Neuromuscul Disord. 1993 Sep-Nov;3(5-6):433–438. doi: 10.1016/0960-8966(93)90091-w. [DOI] [PubMed] [Google Scholar]
  32. Goffeau A., Barrell B. G., Bussey H., Davis R. W., Dujon B., Feldmann H., Galibert F., Hoheisel J. D., Jacq C., Johnston M. Life with 6000 genes. Science. 1996 Oct 25;274(5287):546, 563-7. doi: 10.1126/science.274.5287.546. [DOI] [PubMed] [Google Scholar]
  33. Goodacre R., Shann B., Gilbert R. J., Timmins E. M., McGovern A. C., Alsberg B. K., Kell D. B., Logan N. A. Detection of the dipicolinic acid biomarker in Bacillus spores using Curie-point pyrolysis mass spectrometry and Fourier transform infrared spectroscopy. Anal Chem. 2000 Jan 1;72(1):119–127. doi: 10.1021/ac990661i. [DOI] [PubMed] [Google Scholar]
  34. Griffin J. L., Muller D., Woograsingh R., Jowatt V., Hindmarsh A., Nicholson J. K., Martin J. E. Vitamin E deficiency and metabolic deficits in neuronal ceroid lipofuscinosis described by bioinformatics. Physiol Genomics. 2002 Dec 3;11(3):195–203. doi: 10.1152/physiolgenomics.00100.2002. [DOI] [PubMed] [Google Scholar]
  35. Griffin J. L., Pole J. C. M., Nicholson J. K., Carmichael P. L. Cellular environment of metabolites and a metabonomic study of tamoxifen in endometrial cells using gradient high resolution magic angle spinning 1H NMR spectroscopy. Biochim Biophys Acta. 2003 Jan 20;1619(2):151–158. doi: 10.1016/s0304-4165(02)00475-0. [DOI] [PubMed] [Google Scholar]
  36. Griffin J. L., Sang E., Evens T., Davies K., Clarke K. Metabolic profiles of dystrophin and utrophin expression in mouse models of Duchenne muscular dystrophy. FEBS Lett. 2002 Oct 23;530(1-3):109–116. doi: 10.1016/s0014-5793(02)03437-3. [DOI] [PubMed] [Google Scholar]
  37. Griffin J. L., Walker L. A., Garrod S., Holmes E., Shore R. F., Nicholson J. K. NMR spectroscopy based metabonomic studies on the comparative biochemistry of the kidney and urine of the bank vole (Clethrionomys glareolus), wood mouse (Apodemus sylvaticus), white toothed shrew (Crocidura suaveolens) and the laboratory rat. Comp Biochem Physiol B Biochem Mol Biol. 2000 Nov;127(3):357–367. doi: 10.1016/s0305-0491(00)00276-5. [DOI] [PubMed] [Google Scholar]
  38. Griffin J. L., Walker L. A., Shore R. F., Nicholson J. K. Metabolic profiling of chronic cadmium exposure in the rat. Chem Res Toxicol. 2001 Oct;14(10):1428–1434. doi: 10.1021/tx015521u. [DOI] [PubMed] [Google Scholar]
  39. Griffin J. L., Walker L. A., Troke J., Osborn D., Shore R. F., Nicholson J. K. The initial pathogenesis of cadmium induced renal toxicity. FEBS Lett. 2000 Jul 28;478(1-2):147–150. doi: 10.1016/s0014-5793(00)01843-3. [DOI] [PubMed] [Google Scholar]
  40. Griffin J. L., Walker L., Shore R. F., Nicholson J. K. High-resolution magic angle spinning 1H-NMR spectroscopy studies on the renal biochemistry in the bank vole (Clethrionomys glareolus) and the effects of arsenic (As3+) toxicity. Xenobiotica. 2001 Jun;31(6):377–385. doi: 10.1080/00498250110055938. [DOI] [PubMed] [Google Scholar]
  41. Griffin J. L., Williams H. J., Sang E., Clarke K., Rae C., Nicholson J. K. Metabolic profiling of genetic disorders: a multitissue (1)H nuclear magnetic resonance spectroscopic and pattern recognition study into dystrophic tissue. Anal Biochem. 2001 Jun 1;293(1):16–21. doi: 10.1006/abio.2001.5096. [DOI] [PubMed] [Google Scholar]
  42. Griffin J. L., Williams H. J., Sang E., Nicholson J. K. Abnormal lipid profile of dystrophic cardiac tissue as demonstrated by one- and two-dimensional magic-angle spinning (1)H NMR spectroscopy. Magn Reson Med. 2001 Aug;46(2):249–255. doi: 10.1002/mrm.1185. [DOI] [PubMed] [Google Scholar]
  43. Griffin Julian L., Bollard Mary, Nicholson Jeremy K., Bhakoo Kishore. Spectral profiles of cultured neuronal and glial cells derived from HRMAS (1)H NMR spectroscopy. NMR Biomed. 2002 Oct;15(6):375–384. doi: 10.1002/nbm.792. [DOI] [PubMed] [Google Scholar]
  44. Gussoni E., Soneoka Y., Strickland C. D., Buzney E. A., Khan M. K., Flint A. F., Kunkel L. M., Mulligan R. C. Dystrophin expression in the mdx mouse restored by stem cell transplantation. Nature. 1999 Sep 23;401(6751):390–394. doi: 10.1038/43919. [DOI] [PubMed] [Google Scholar]
  45. Hall Robert, Beale Mike, Fiehn Oliver, Hardy Nigel, Sumner Lloyd, Bino Raoul. Plant metabolomics: the missing link in functional genomics strategies. Plant Cell. 2002 Jul;14(7):1437–1440. doi: 10.1105/tpc.140720. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Hoffman E. P., Beggs A. H., Koenig M., Kunkel L. M., Angelini C. Cross-reactive protein in Duchenne muscle. Lancet. 1989 Nov 18;2(8673):1211–1212. doi: 10.1016/s0140-6736(89)91812-6. [DOI] [PubMed] [Google Scholar]
  47. Holmes E., Foxall P. J., Nicholson J. K., Neild G. H., Brown S. M., Beddell C. R., Sweatman B. C., Rahr E., Lindon J. C., Spraul M. Automatic data reduction and pattern recognition methods for analysis of 1H nuclear magnetic resonance spectra of human urine from normal and pathological states. Anal Biochem. 1994 Aug 1;220(2):284–296. doi: 10.1006/abio.1994.1339. [DOI] [PubMed] [Google Scholar]
  48. Hu Jian Zhi, Rommereim Donald N., Wind Robert A. High-resolution 1H NMR spectroscopy in rat liver using magic angle turning at a 1 Hz spinning rate. Magn Reson Med. 2002 May;47(5):829–836. doi: 10.1002/mrm.10139. [DOI] [PubMed] [Google Scholar]
  49. Huxtable R. J. Physiological actions of taurine. Physiol Rev. 1992 Jan;72(1):101–163. doi: 10.1152/physrev.1992.72.1.101. [DOI] [PubMed] [Google Scholar]
  50. Kacser H., Burns J. A. The control of flux. Symp Soc Exp Biol. 1973;27:65–104. [PubMed] [Google Scholar]
  51. Kato T., Nishina M., Matsushita K., Hori E., Akaboshi S., Takashima S. Increased cerebral choline-compounds in Duchenne muscular dystrophy. Neuroreport. 1997 Apr 14;8(6):1435–1437. doi: 10.1097/00001756-199704140-00022. [DOI] [PubMed] [Google Scholar]
  52. Kawaguchi Y., Okamoto T., Taniwaki M., Aizawa M., Inoue M., Katayama S., Kawakami H., Nakamura S., Nishimura M., Akiguchi I. CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nat Genet. 1994 Nov;8(3):221–228. doi: 10.1038/ng1194-221. [DOI] [PubMed] [Google Scholar]
  53. Kell Douglas B. Metabolomics and machine learning: explanatory analysis of complex metabolome data using genetic programming to produce simple, robust rules. Mol Biol Rep. 2002;29(1-2):237–241. doi: 10.1023/a:1020342216314. [DOI] [PubMed] [Google Scholar]
  54. Kemp G. J., Taylor D. J., Dunn J. F., Frostick S. P., Radda G. K. Cellular energetics of dystrophic muscle. J Neurol Sci. 1993 Jun;116(2):201–206. doi: 10.1016/0022-510x(93)90326-t. [DOI] [PubMed] [Google Scholar]
  55. Keun Hector C., Beckonert Olaf, Griffin Julian L., Richter Christian, Moskau Detlef, Lindon John C., Nicholson Jeremy K. Cryogenic probe 13C NMR spectroscopy of urine for metabonomic studies. Anal Chem. 2002 Sep 1;74(17):4588–4593. doi: 10.1021/ac025691r. [DOI] [PubMed] [Google Scholar]
  56. Khurana T. S., Watkins S. C., Chafey P., Chelly J., Tomé F. M., Fardeau M., Kaplan J. C., Kunkel L. M. Immunolocalization and developmental expression of dystrophin related protein in skeletal muscle. Neuromuscul Disord. 1991;1(3):185–194. doi: 10.1016/0960-8966(91)90023-l. [DOI] [PubMed] [Google Scholar]
  57. Klose Joachim, Nock Christina, Herrmann Marion, Stühler Kai, Marcus Katrin, Blüggel Martin, Krause Eberhard, Schalkwyk Leonard C., Rastan Sohaila, Brown Steve D. M. Genetic analysis of the mouse brain proteome. Nat Genet. 2002 Mar 25;30(4):385–393. doi: 10.1038/ng861. [DOI] [PubMed] [Google Scholar]
  58. Kose F., Weckwerth W., Linke T., Fiehn O. Visualizing plant metabolomic correlation networks using clique-metabolite matrices. Bioinformatics. 2001 Dec;17(12):1198–1208. doi: 10.1093/bioinformatics/17.12.1198. [DOI] [PubMed] [Google Scholar]
  59. Krag T. O., Gyrd-Hansen M., Khurana T. S. Harnessing the potential of dystrophin-related proteins for ameliorating Duchenne's muscular dystrophy. Acta Physiol Scand. 2001 Mar;171(3):349–358. doi: 10.1046/j.1365-201x.2001.00838.x. [DOI] [PubMed] [Google Scholar]
  60. Lederfein D., Levy Z., Augier N., Mornet D., Morris G., Fuchs O., Yaffe D., Nudel U. A 71-kilodalton protein is a major product of the Duchenne muscular dystrophy gene in brain and other nonmuscle tissues. Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5346–5350. doi: 10.1073/pnas.89.12.5346. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Lindon John C., Nicholson Jeremy K., Holmes Elaine, Antti Henrik, Bollard Mary E., Keun Hector, Beckonert Olaf, Ebbels Timothy M., Reily Michael D., Robertson Donald. Contemporary issues in toxicology the role of metabonomics in toxicology and its evaluation by the COMET project. Toxicol Appl Pharmacol. 2003 Mar 15;187(3):137–146. doi: 10.1016/s0041-008x(02)00079-0. [DOI] [PubMed] [Google Scholar]
  62. McIntosh L. M., Baker R. E., Anderson J. E. Magnetic resonance imaging of regenerating and dystrophic mouse muscle. Biochem Cell Biol. 1998;76(2-3):532–541. doi: 10.1139/bcb-76-2-3-532. [DOI] [PubMed] [Google Scholar]
  63. McIntosh L. M., Garrett K. L., Megeney L., Rudnicki M. A., Anderson J. E. Regeneration and myogenic cell proliferation correlate with taurine levels in dystrophin- and MyoD-deficient muscles. Anat Rec. 1998 Oct;252(2):311–324. doi: 10.1002/(SICI)1097-0185(199810)252:2<311::AID-AR17>3.0.CO;2-Q. [DOI] [PubMed] [Google Scholar]
  64. Mokhtarian A., Decrouy A., Chinet A., Even P. C. Components of energy expenditure in the mdx mouse model of Duchenne muscular dystrophy. Pflugers Arch. 1996 Feb;431(4):527–532. doi: 10.1007/BF02191899. [DOI] [PubMed] [Google Scholar]
  65. Mole S. E., Mitchison H. M., Munroe P. B. Molecular basis of the neuronal ceroid lipofuscinoses: mutations in CLN1, CLN2, CLN3, and CLN5. Hum Mutat. 1999;14(3):199–215. doi: 10.1002/(SICI)1098-1004(1999)14:3<199::AID-HUMU3>3.0.CO;2-A. [DOI] [PubMed] [Google Scholar]
  66. Moolenaar S. H., Engelke U. F. H., Wevers R. A. Proton nuclear magnetic resonance spectroscopy of body fluids in the field of inborn errors of metabolism. Ann Clin Biochem. 2003 Jan;40(Pt 1):16–24. doi: 10.1258/000456303321016132. [DOI] [PubMed] [Google Scholar]
  67. Nicholson J. K., Higham D. P., Timbrell J. A., Sadler P. J. Quantitative high resolution 1H NMR urinalysis studies on the biochemical effects of cadmium in the rat. Mol Pharmacol. 1989 Sep;36(3):398–404. [PubMed] [Google Scholar]
  68. Nicholson J. K., Lindon J. C., Holmes E. 'Metabonomics': understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data. Xenobiotica. 1999 Nov;29(11):1181–1189. doi: 10.1080/004982599238047. [DOI] [PubMed] [Google Scholar]
  69. Nicholson Jeremy K., Connelly John, Lindon John C., Holmes Elaine. Metabonomics: a platform for studying drug toxicity and gene function. Nat Rev Drug Discov. 2002 Feb;1(2):153–161. doi: 10.1038/nrd728. [DOI] [PubMed] [Google Scholar]
  70. Nicholson Jeremy K., Wilson Ian D. Opinion: understanding 'global' systems biology: metabonomics and the continuum of metabolism. Nat Rev Drug Discov. 2003 Aug;2(8):668–676. doi: 10.1038/nrd1157. [DOI] [PubMed] [Google Scholar]
  71. Nudel U., Zuk D., Einat P., Zeelon E., Levy Z., Neuman S., Yaffe D. Duchenne muscular dystrophy gene product is not identical in muscle and brain. Nature. 1989 Jan 5;337(6202):76–78. doi: 10.1038/337076a0. [DOI] [PubMed] [Google Scholar]
  72. Oliver S. G. From DNA sequence to biological function: the new "Voyage of the Beagle'. Biochem Soc Trans. 1996 Feb;24(1):291–292. doi: 10.1042/bst0240291. [DOI] [PubMed] [Google Scholar]
  73. Oliver S. G., Winson M. K., Kell D. B., Baganz F. Systematic functional analysis of the yeast genome. Trends Biotechnol. 1998 Sep;16(9):373–378. doi: 10.1016/s0167-7799(98)01214-1. [DOI] [PubMed] [Google Scholar]
  74. Oliver Stephen G. Functional genomics: lessons from yeast. Philos Trans R Soc Lond B Biol Sci. 2002 Jan 29;357(1417):17–23. doi: 10.1098/rstb.2001.1049. [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. Pichersky E., Gang D. R. Genetics and biochemistry of secondary metabolites in plants: an evolutionary perspective. Trends Plant Sci. 2000 Oct;5(10):439–445. doi: 10.1016/s1360-1385(00)01741-6. [DOI] [PubMed] [Google Scholar]
  76. Raamsdonk L. M., Teusink B., Broadhurst D., Zhang N., Hayes A., Walsh M. C., Berden J. A., Brindle K. M., Kell D. B., Rowland J. J. A functional genomics strategy that uses metabolome data to reveal the phenotype of silent mutations. Nat Biotechnol. 2001 Jan;19(1):45–50. doi: 10.1038/83496. [DOI] [PubMed] [Google Scholar]
  77. Rae C., Scott R. B., Thompson C. H., Dixon R. M., Dumughn I., Kemp G. J., Male A., Pike M., Styles P., Radda G. K. Brain biochemistry in Duchenne muscular dystrophy: a 1H magnetic resonance and neuropsychological study. J Neurol Sci. 1998 Oct 8;160(2):148–157. doi: 10.1016/s0022-510x(98)00190-7. [DOI] [PubMed] [Google Scholar]
  78. Ravasz E., Somera A. L., Mongru D. A., Oltvai Z. N., Barabási A. L. Hierarchical organization of modularity in metabolic networks. Science. 2002 Aug 30;297(5586):1551–1555. doi: 10.1126/science.1073374. [DOI] [PubMed] [Google Scholar]
  79. Robertson D. G., Reily M. D., Sigler R. E., Wells D. F., Paterson D. A., Braden T. K. Metabonomics: evaluation of nuclear magnetic resonance (NMR) and pattern recognition technology for rapid in vivo screening of liver and kidney toxicants. Toxicol Sci. 2000 Oct;57(2):326–337. doi: 10.1093/toxsci/57.2.326. [DOI] [PubMed] [Google Scholar]
  80. Roessner U., Wagner C., Kopka J., Trethewey R. N., Willmitzer L. Technical advance: simultaneous analysis of metabolites in potato tuber by gas chromatography-mass spectrometry. Plant J. 2000 Jul;23(1):131–142. doi: 10.1046/j.1365-313x.2000.00774.x. [DOI] [PubMed] [Google Scholar]
  81. Rosenberg R. N. Machado-Joseph disease: an autosomal dominant motor system degeneration. Mov Disord. 1992;7(3):193–203. doi: 10.1002/mds.870070302. [DOI] [PubMed] [Google Scholar]
  82. Rybakova Inna N., Patel Jitandrakumar R., Davies Kay E., Yurchenco Peter D., Ervasti James M. Utrophin binds laterally along actin filaments and can couple costameric actin with sarcolemma when overexpressed in dystrophin-deficient muscle. Mol Biol Cell. 2002 May;13(5):1512–1521. doi: 10.1091/mbc.01-09-0446. [DOI] [PMC free article] [PubMed] [Google Scholar]
  83. Schoolnik Gary K. Microarray analysis of bacterial pathogenicity. Adv Microb Physiol. 2002;46:1–45. doi: 10.1016/s0065-2911(02)46001-8. [DOI] [PubMed] [Google Scholar]
  84. Shockcor John P., Holmes Elaine. Metabonomic applications in toxicity screening and disease diagnosis. Curr Top Med Chem. 2002 Jan;2(1):35–51. doi: 10.2174/1568026023394498. [DOI] [PubMed] [Google Scholar]
  85. Smith L. L. Key challenges for toxicologists in the 21st century. Trends Pharmacol Sci. 2001 Jun;22(6):281–285. doi: 10.1016/s0165-6147(00)01714-4. [DOI] [PubMed] [Google Scholar]
  86. Stoyanova R., Brown T. R. NMR spectral quantitation by principal component analysis. III. A generalized procedure for determination of lineshape variations. J Magn Reson. 2002 Feb;154(2):163–175. doi: 10.1006/jmre.2001.2486. [DOI] [PubMed] [Google Scholar]
  87. Stoyanova R., Brown T. R. NMR spectral quantitation by principal component analysis. NMR Biomed. 2001 Jun;14(4):271–277. doi: 10.1002/nbm.700. [DOI] [PubMed] [Google Scholar]
  88. Sze D. Y., Jardetzky O. High-resolution proton NMR studies of lymphocyte extracts. Immunomethods. 1994 Apr;4(2):113–126. doi: 10.1006/immu.1994.1013. [DOI] [PubMed] [Google Scholar]
  89. Takiyama Y., Oyanagi S., Kawashima S., Sakamoto H., Saito K., Yoshida M., Tsuji S., Mizuno Y., Nishizawa M. A clinical and pathologic study of a large Japanese family with Machado-Joseph disease tightly linked to the DNA markers on chromosome 14q. Neurology. 1994 Jul;44(7):1302–1308. doi: 10.1212/wnl.44.7.1302. [DOI] [PubMed] [Google Scholar]
  90. Tate A. R., Crabb S., Griffiths J. R., Howells S. L., Mazucco R. A., Rodrigues L. M., Watson D. Lipid metabolite peaks in pattern recognition analysis of tumour in vivo MR spectra. Anticancer Res. 1996 May-Jun;16(3B):1575–1579. [PubMed] [Google Scholar]
  91. Teusink B., Walsh M. C., van Dam K., Westerhoff H. V. The danger of metabolic pathways with turbo design. Trends Biochem Sci. 1998 May;23(5):162–169. doi: 10.1016/s0968-0004(98)01205-5. [DOI] [PubMed] [Google Scholar]
  92. Tinsley J., Deconinck N., Fisher R., Kahn D., Phelps S., Gillis J. M., Davies K. Expression of full-length utrophin prevents muscular dystrophy in mdx mice. Nat Med. 1998 Dec;4(12):1441–1444. doi: 10.1038/4033. [DOI] [PubMed] [Google Scholar]
  93. Tracey I., Dunn J. F., Radda G. K. Brain metabolism is abnormal in the mdx model of Duchenne muscular dystrophy. Brain. 1996 Jun;119(Pt 3):1039–1044. doi: 10.1093/brain/119.3.1039. [DOI] [PubMed] [Google Scholar]
  94. Tweeddale H., Notley-McRobb L., Ferenci T. Effect of slow growth on metabolism of Escherichia coli, as revealed by global metabolite pool ("metabolome") analysis. J Bacteriol. 1998 Oct;180(19):5109–5116. doi: 10.1128/jb.180.19.5109-5116.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  95. Valafar Faramarz. Pattern recognition techniques in microarray data analysis: a survey. Ann N Y Acad Sci. 2002 Dec;980:41–64. doi: 10.1111/j.1749-6632.2002.tb04888.x. [DOI] [PubMed] [Google Scholar]
  96. Vance J. E., Stone S. J., Faust J. R. Abnormalities in mitochondria-associated membranes and phospholipid biosynthetic enzymes in the mnd/mnd mouse model of neuronal ceroid lipofuscinosis. Biochim Biophys Acta. 1997 Feb 18;1344(3):286–299. doi: 10.1016/s0005-2760(96)00153-1. [DOI] [PubMed] [Google Scholar]
  97. Waters N. J., Holmes E., Williams A., Waterfield C. J., Farrant R. D., Nicholson J. K. NMR and pattern recognition studies on the time-related metabolic effects of alpha-naphthylisothiocyanate on liver, urine, and plasma in the rat: an integrative metabonomic approach. Chem Res Toxicol. 2001 Oct;14(10):1401–1412. doi: 10.1021/tx010067f. [DOI] [PubMed] [Google Scholar]
  98. Waters Nigel J., Holmes Elaine, Waterfield Catherine J., Farrant R. Duncan, Nicholson Jeremy K. NMR and pattern recognition studies on liver extracts and intact livers from rats treated with alpha-naphthylisothiocyanate. Biochem Pharmacol. 2002 Jul 1;64(1):67–77. doi: 10.1016/s0006-2952(02)01016-x. [DOI] [PubMed] [Google Scholar]
  99. Weybright P., Millis K., Campbell N., Cory D. G., Singer S. Gradient, high-resolution, magic angle spinning 1H nuclear magnetic resonance spectroscopy of intact cells. Magn Reson Med. 1998 Mar;39(3):337–345. doi: 10.1002/mrm.1910390302. [DOI] [PubMed] [Google Scholar]
  100. Wind R. A., Hu J. Z., Rommereim D. N. High-resolution (1)H NMR spectroscopy in organs and tissues using slow magic angle spinning. Magn Reson Med. 2001 Aug;46(2):213–218. doi: 10.1002/mrm.1181. [DOI] [PubMed] [Google Scholar]
  101. Winzeler E. A., Shoemaker D. D., Astromoff A., Liang H., Anderson K., Andre B., Bangham R., Benito R., Boeke J. D., Bussey H. Functional characterization of the S. cerevisiae genome by gene deletion and parallel analysis. Science. 1999 Aug 6;285(5429):901–906. doi: 10.1126/science.285.5429.901. [DOI] [PubMed] [Google Scholar]

Articles from Philosophical Transactions of the Royal Society B: Biological Sciences are provided here courtesy of The Royal Society

RESOURCES