From hormones to secondary metabolism: The emergence of metabolic gene clusters in plants

Plant Journal

Volumn 66, Issue 1, 2011, Pages 66-79

  Chu, Hoi Yee ^a   Wegel, Eva ^a,b   Osbourn, Anne ^a  

^a JOHN INNES CENTRE   (United Kingdom)

^b UNIVERSITY OF CAMBRIDGE   (United Kingdom)

Author keywords

antibiotics; gene clusters; hormones; maize; oat; rice

Indexed keywords

ADAPTIVE EVOLUTION; COMMON FEATURES; EUKARYOTIC GENES; FILAMENTOUS FUNGI; GENE CLUSTERS; HORIZONTAL GENE TRANSFER; INTRIGUING QUESTIONS; MAIZE; METABOLIC GENES; METABOLIC PATHWAYS; MICROBIAL GENOMES; OAT; RICE; SECONDARY METABOLISM; SECONDARY METABOLITES;

ANTIBIOTICS; ENDOCRINOLOGY; GENE TRANSFER; HORMONES; METABOLISM; METABOLITES;

GENES;

PHYTOHORMONE;

ARTICLE; BACTERIUM; GENE EXPRESSION REGULATION; GENETICS; HORIZONTAL GENE TRANSFER; INHERITANCE; METABOLISM; MOLECULAR EVOLUTION; MULTIGENE FAMILY; OPERON; PLANT; PLANT GENE;

BACTERIA; EVOLUTION, MOLECULAR; GENE EXPRESSION REGULATION, PLANT; GENE TRANSFER, HORIZONTAL; GENES, PLANT; INHERITANCE PATTERNS; METABOLIC NETWORKS AND PATHWAYS; MULTIGENE FAMILY; OPERON; PLANT GROWTH REGULATORS; PLANTS;

ACTINOBACTERIA; ACTINOBACTERIA (CLASS); EUKARYOTA; FUNGI; ZEA MAYS;

EID: 79953237139     PISSN: 09607412     EISSN: 1365313X     Source Type: Journal    
DOI: 10.1111/j.1365-313X.2011.04503.x     Document Type: Article

References (101)

1. Aubourg, S., Lechnarny, A., and, Bohlmann, J., (2002) Genomic analysis of the terpenoid synthase (AtTPS) gene family of Arabidopsis thaliana. Mol. Genet. Genomics, 267, 730-745. (Pubitemid 35013680)
2. Blumenthal, T., and, Gleason, K.S., (2003) Caenorhabditis elegans operons: form and function. Nat. Rev. Genet. 4, 110-118.
3. Bok, J.W., and, Keller, N.P., (2004) LaeA, a regulator of secondary metabolism in Aspergillus spp. Eukaryot. Cell, 3, 527-535. (Pubitemid 38497990)
4. Bok, J.W., Chiang, Y.-M., Szewczyk, E., et al. (2009) Chromatin-level regulation of biosynthetic gene clusters. Nat. Chem. Biol. 5, 462-464.
5. Brown, C.A., Murray, A.W., and, Verstrepen, K.J., (2010) Rapid expansion and functional divergence of subtelomeric gene families in yeasts. Curr. Biol. 20, 895-903.
6. Challis, G.L., and, Hopwood, D.A., (2008) Synergy and contingency as driving forces for the evolution of multiple secondary metabolite production by Streptomyces species. Proc. Natl Acad. Sci. USA, 100, 14555-14561. (Pubitemid 37499281)
7. Chappell, J., (2002) The genetics and molecular genetics of terpene and sterol origami. Curr. Opin. Plant Biol. 5, 151-157. (Pubitemid 34190383)
8. Cichewicz, R.H., (2010) Epigenome manipulation as a pathway to new natural product scaffolds and their congeners. Nat. Prod. Rep. 27, 11-22.
9. Dandekar, T., Snel, B., Huynen, M., and, Bork, P., (1998) Conservation of gene order: a fingerprint of proteins that physically interact. Trends Biochem. Sci. 23, 324-328. (Pubitemid 28461862)
10. Ehlting, J., Sauveplane, V., Olry, A., Ginglinger, J.-F., Provart, N.J., and, Werck-Reichart, D., (2008) An extensive (co)-expression analysis tool for the cytochrome P450 superfamily in Arabidopsis thaliana. BMC Plant Biol. 8, 47.
11. Ehrlich, K.C., Yu, J., and, Cotty, P.J., (2005) Aflatoxin biosynthesis gene clusters and flanking regions. J. Appl. Microbiol. 99, 518-527. (Pubitemid 41215829)
12. Eisenreich, W., Schwarz, M., Cartayrade, A., Arigoni, D., Zenk, M.H., and, Bacher, A., (1998) The deoxyxylulose phosphate pathway of terpenoid biosynthesis in plants and microorganisms. Chem. Biol. 5, R221-R233. (Pubitemid 28436724)
13. Fani, R., Brilli, M., and, Liò, P., (2005) The origin and evolution of operons: the piecewise building of the proteobacterial histidine operon. J. Mol. Evol. 60, 378-390. (Pubitemid 40685129)
14. Field, B., and, Osbourn, A.E., (2008) Metabolic diversification- independent assembly of operon-like gene clusters in different plants. Science, 320, 543-547. (Pubitemid 351590669)
15. Field, B., and, Osbourn, A.E,. (2010) Operons. Nat. Chem. Biol. 19, April 2010, DOI:.
16. Fischbach, M.A., (2009) Antibiotics from microbes: converging to kill. Curr. Opin. Microbiol. 12, 520-527.
17. Fondi, M., Emiliani, G., and, Fani, R., (2009) Origin and evolution of operons and metabolic pathways. Res. Microbiol. 160, 502-512.
18. Fraser, J., Rousseau, M., Shenker, S., Ferraiuolo, M.A., Hayashizaki, Y., Blanchette, M., and, Dostie, J., (2009) Chromatin conformation signatures of cellular differentiation. Genome Biol. 10, R37.
19. Frey, M., Kliem, R., Saedler, H., and, Gierl, G., (1995) Expression of a cytochrome P450 gene family in maize. Mol. Gen. Genet. 246, 100-109.
20. Frey, M., Chomet, P., Glawischnig, E., et al. (1997) Analysis of a chemical plant defense mechanism in grasses. Science, 277, 696-699. (Pubitemid 27373917)
21. Frey, M., Huber, K., Park, W.J., Sicker, D., Lindberg, P., Meeley, R.B., Simmons, C.R., Yalpini, N., and, Gierl, A., (2003) A 2-oxoglutarate-dependent dioxygenase is integrated in DIMBOA biosynthesis. Phytochemistry, 62, 371-376. (Pubitemid 36168939)
22. Frey, M., Schullehner, K., Dick, R., Fiesselmann, A., and, Gierl, A., (2009) Benzoxazinoid biosynthesis, a model for evolution of secondary metabolic pathways in plants. Phytochemistry, 70, 1645-1651.
23. Galande, S., Purbey, P.K., Notani, D., and, Kumar, P.P., (2007) The third dimension of gene regulation: organization of dynamic chromatin loopscape by SATB1. Curr. Opin. Genet. Dev. 17, 408-414. (Pubitemid 350019562)
24. Garcia, R.O., Krug, D., and, Muller, R., (2009) Chapter 3. Discovering natural products from myxobacteria with emphasis on rare producer strains in combination with improved analytical methods. In Methods in Enzymology (, Hopwood, D.A., ed.) 459. New York: Academic Press, pp. 59-91.
25. Gierl, A., and, Frey, M., (2001) Evolution of benzoxazinone biosynthesis and indole production in maize. Planta, 213, 493-498. (Pubitemid 32792465)
26. Gross, J., Cho, W.K., Lezhneva, L., Falk, J., Krupinska, K., Shinozaki, K., Seki, M., Herrmann, R.G., and, Meurer, J., (2006) A plant locus essential for phylloquinone (vitamin K1) biosynthesis originated from a fusion of four eubacterial genes. J. Biol. Chem. 281, 17189-17196.
27. Haralampidis, K., Bryan, G., Qi, X., Papadopoulou, K., Bakht, S., Melton, R., and, Osbourn, A.E., (2001) A new class of oxidosqualene cyclases directs synthesis of antimicrobial phytoprotectants in monocots. Proc. Natl Acad. Sci. USA, 98, 13431-13436. (Pubitemid 33051380)
28. Hawkins, A.R., (1987) The complex Arom locus of Aspergillus nidulans. Evidence for multiple gene fusions and convergent evolution. Curr. Genet. 11, 491-498. (Pubitemid 17040055)
29. Hazkani-Covo, E., and, Graur, D., (2005) Evolutionary conservation of bacterial operons: does transcriptional connectivity matter? Genetica, 124, 145-166.
30. Hittinger, C.T., Rokas, A., and, Carroll, S.B., (2004) Parallel inactivation of multiple GAL pathway genes and ecological diversification in yeasts. Proc. Natl Acad. Sci. USA, 101, 14144-14149. (Pubitemid 39305044)
31. Hoffmeister, D., and, Keller, N.P., (2007) Natural products of filamentous fungi: enzymes, genes, and their regulation. Nat. Prod. Rep. 24, 393-416. (Pubitemid 46496563)
32. Hopwood, D.A., (2009a) Complex enzymes in microbial natural product biosynthesis, part A: overview articles and peptides. In Methods in Enzymology (, Hopwood, D.A., ed.) 459. New York: Academic Press, pp. xix-xxi.
33. Hopwood, D.A., (2009b) Complex enzymes in microbial natural product biosynthesis, part B: polyketides, aminocoumarins and carbohydrates. In Methods in Enzymology (, Hopwood, D.A., ed.) 459. New York: Academic Press, pp. xvii-xix.
34. Horton, R., Wilming, L., Rand, V., et al. (2004) Gene map of the extended human MHC. Nat. Rev. Genet. 5, 889-899. (Pubitemid 39564252)
35. Hurst, L.D., Pal, C., and, Lercher, M.J., (2004) The evolutionary dynamics of eukaryotic gene order. Nat. Rev. Genet. 5, 299-310. (Pubitemid 38435625)
36. Jacob, F., and, Monod, J., (1961) Genetic regulatory mechanisms in the synthesis of proteins. J. Mol. Biol. 3, 318-356.
37. Janga, S.C., Collado-Vides, J., and, Babu, M., (2008) Transcriptional regulation constrains the organization of genes on eukaryotic chromosomes. Proc. Natl Acad. Sci. USA, 105, 15761-15766.
38. Jonczyk, R., Schmidt, H., Osterrieder, A., et al. (2008) Elucidation of the final reactions of DIMBOA-glucoside biosynthesis in maize: characterization of Bx6 and Bx7. biosynthesis in maize: characterization of Bx6 and Bx7. Plant Physiol. 146, 1053-1063. (Pubitemid 352844122)
39. Khaldi, N., Collemare, J., Lebrun, M.H., and, Wolfe, K.H., (2008) Evidence for horizontal transfer of a secondary metabolite gene cluster between fungi. Genome Biol. 9, R18.
40. Koonin, E.V., (2009) Evolution of genome architecture. Int. J. Biochem. Cell Biol. 41, 298-306.
41. Kovács, K., Hurst, L.D., and, Papp, B., (2009) Stochasticity in protein levels drives colinearity of gene order in metabolic operons of Escherichia coli. PLoS Biol. 7, e1000115.
42. Krattinger, S.G., Laguda, E.S., Spielmeyer, W., Singh, R.P., Huerta-Espino, J., McFadden, H., Bossolini, E., Selter, L.L., and, Keller, B., (2009) A putative ABC transporter confers durable resistance to multiple fungal pathogens in wheat. Science, 323, 1360-1363.
43. Lawrence, J., (1999) Selfish operons: the evolutionary impact of gene clustering in prokaryotes and eukaryotes. Curr. Opin. Genet. Dev. 9, 642-648.
44. Lawrence, J.G., and, Roth, J.R., (1996) Selfish operons: horizontal transfer may drive the evolution of gene clusters. Genetics, 143, 1843-1860. (Pubitemid 26286959)
45. Lee, J.M., and, Sonnhammer, E.L., (2003) Genomic gene clustering analysis of pathways in eukaryotes. Genome Res. 13, 875-882. (Pubitemid 36621748)
46. Lichtenthaler, H.K., (1999) The 1-deoxy-d-xylulose 5-phosphate pathway of isoprenoid biosynthesis in plants. Annu. Rev. Plant Physiol. Plant Mol. Biol. 50, 47-65. (Pubitemid 129493120)
47. Lin, Y.-S., Kieser, H.M., Hopwood, D.A., and, Chen, C.W., (1993) The chromosomal DNA of Streptomyces lividans 66 is linear. Mol. Microbiol. 10, 923-933. (Pubitemid 24040870)
48. Malpartida, F., and, Hopwood, D.A., (1984) Molecular cloning of the whole biosynthetic pathway of a Streptomyces antibiotic and its expression in a heterologous host. Nature, 309, 462-464. (Pubitemid 14102453)
49. McArthur, M., and, Bibb, M., (2006) In vivo DNase I sensitivity of the Streptomyces coelicolor chromosome correlates with gene expression: implications for bacterial chromosome structure. Nucleic Acids Res. 34, 5395-5401. (Pubitemid 44742429)
50. McArthur, M., and, Bibb, M., (2007) Evidence for chromatin structure in Streptomyces coelicolor A3(2). Abstract, 14th International Symposium on the Biology of Actinomycetes, Newcastle, August 2007, 57.
51. Mochizuki, S., Hiratsu, K., Suwa, M., Ishii, T., Sugino, F., Yamada, K., and, Kinashi, H,. (2003) The large linear plasmid pSLA2-L of Streptomyces rochei has an unusually condensed gene organization for secondary metabolism. Mol. Microbiol. 48, 1501-1510. (Pubitemid 36751057)
52. Mugford, S.T., Qi, X., Bakht, S., et al. (2009) A serine carboxypeptidase-like acyltransferase is required for synthesis of antimicrobial compounds and disease resistance in oats. Plant Cell, 21, 2473-2484.
53. Mylona, P., Owatworakit, A., Papadopoulou, K., et al. (2008) Sad3 and Sad4 are required for saponin biosynthesis and root development in oat. Plant Cell, 20, 201-212. (Pubitemid 352844043)
54. Nei, M.M., (1967) Modification of linkage intensity by natural selection. Genetics, 57, 625-641.
55. Nei, M., (2003) Let's stick together. Heredity, 90, 411-412. (Pubitemid 36720235)
56. Niemeyer, H.M., (1988) Hydroxamic acids (4-Hydroxy-1,4-benzoxazin-3-ones) , defense chemicals in the Gramineae. Phytochemistry, 27, 3349-3358.
57. Nomura, T., Ishihara, A., Imaishi, H., Endo, T., Ohkawa, H., and, Iwamura, H., (2002) Molecular characterization and chromosomal localization of cytochrome P450 genes involved in the biosynthesis of cyclic hydroxamic acids in hexaploid wheat. Mol. Genet. Genomics, 267, 210-217. (Pubitemid 34437996)
58. Nomura, T., Ishihara, A., Imaishi, H., Ohkawa, H., Endo, T., and, Iwamura, H., (2003) Rearrangement of the genes for the biosynthesis of benzoxazinones in the evolution of Triticeae species. Planta, 217, 776-782. (Pubitemid 37181468)
59. Ober, D., (2010) Gene duplications and the time thereafter-examples from plant secondary metabolism. Plant Biol. 12, 570-577.
60. Okada, A., Okada, K., Miyamoto, K., Koga, J., Shibuya, N., Nojiri, H., and, Yamane, H., (2009) OsTGAP1, a bZIP transcription factor, co-ordinately regulates the inductive production of diterpenoid phytoalexins in rice. J. Biol. Chem. 284, 26510-26518.
61. Osbourn, A., (2010a) Secondary metabolic gene clusters: evolutionary toolkits for chemical innovation. Trends Genet. 26, 449-457.
62. Osbourn, A., (2010b) Gene clusters for secondary metabolic pathways: an emerging theme in plant biology. Plant Physiol. 154, 531-535.
63. Osbourn, A.E., and, Field, B., (2009) Operons. Cell. Mol. Life Sci. 66, 3755-3775.
64. Ottaviani, D., Lever, E., Mitter, R., et al. (2008) Reconfiguration of genomic anchors upon transcriptional activation of the human major histocompatibility complex. Genome Res. 18, 1778-1786.
65. Pál, C., and, Hurst, L.D., (2004) Evidence against the selfish operon theory. Trends Genet. 20, 232-234. (Pubitemid 38625680)
66. Papadopoulou, K., Melton, R.E., Leggett, M., Daniels, M.J., and, Osbourn, A.E., (1999) Compromised disease resistance in saponin-deficient plants. Proc. Natl Acad. Sci. USA, 96, 12923-12928. (Pubitemid 29513604)
67. Patron, N., Waller, R., Cozijnsen, A., Straney, D., Gardiner, D., Nierman, W., and, Howlett, B., (2007) Origin and distribution of epipolythiodioxopiperazine (ETP) gene clusters in filamentous ascomycetes. BMC Evol. Biol. 7, 174.
68. Perrin, R.M., Fedorova, N.D., Bok, J.W., Cramer, R.A., Wortman, J.R., Kim, H.S., Nierman, W.C., and, Keller, N.P., (2007) Transcriptional regulation of chemical diversity in Aspergillus fumigatus by LaeA. PLoS Pathog. 3, e50.
69. Peters, R.J., (2006) Uncovering the complex metabolic network underlying diterpenoid phytoalexin biosynthesis in rice and other cereal crop plants. Phytochemistry, 67, 2307-2317. (Pubitemid 44527936)
70. Price, M.N., Huang, K.H., Arkin, A.P., and, Alm, E.J., (2005) Operon formation is driven by co-regulation and not by horizontal gene transfer. Genome Res. 15, 809-819. (Pubitemid 41007056)
71. Price, M.N., Arkin, A.P., and, Alm, E.J., (2006) The life-cycle of operons. PLoS Genet. 2, e96.
72. Proctor, R.H., McCormick, S.P., Alexander, N.J., and, Desjardins, A.E., (2009) Evidence that a secondary metabolic biosynthetic gene cluster has grown by gene relocation during evolution of the filamentous fungus Fusarium. Mol. Microbiol. 74, 1128-1142.
73. Qi, X., Bakht, S., Leggett, M., Maxwell, C., Melton, R., and, Osbourn, A., (2004) A gene cluster for secondary metabolism in oat: implications for the evolution of metabolic diversity in plants. Proc. Natl Acad. Sci. USA, 101, 8233-8238. (Pubitemid 38698083)
74. Qi, X., Bakht, S., Qin, B., et al. (2006) A different function for a member of an ancient and highly conserved cytochrome P450 family: from essential sterol to plant defense. Proc. Natl Acad. Sci. USA, 103, 18848-18853. (Pubitemid 44913498)
75. Qin, B., Eagles, J., Mellon, F.A., Mylona, P., Peña-Rodriguez, L., and, Osbourn, A.E., (2010) High throughput screening of mutants of oat that are defective in triterpene synthesis. Phytochemistry, 71, 1245-1252.
76. Reyes-Dominguez, Y., Bok, J.W., Berger, H., Shwab, E.K., Basheer, A., Gallmetzer, A., Scazzocchio, C., Keller, N., and, Strauss, J., (2010) Heterochromatic marks are associated with the repression of secondary metabolism clusters in Aspergillus nidulans. Mol. Microbiol. 76, 1376-1386.
77. Rocha, E.P., (2008) The organization of the bacterial genome. Annu. Rev. Genet. 42, 211-233.
78. Rohmer, M., (1999) The discovery of a mevalonate-independent pathway for isoprenoid biosynthesis in bacteria, algae and higher plants. Nat. Prod. Rep. 16, 565-574. (Pubitemid 29501611)
79. Sakamoto, T., Miura, K., Itoh, H., et al. (2004) An overview of gibberellin metabolism enzyme genes and their related mutants in rice. Plant Physiol. 134, 1642-1653. (Pubitemid 38527372)
80. Schullehner, K., Dick, R., Vitzthum, F., Schwab, W., Brandt, W., Frey, M., and, Gierl, A., (2008) Benzoxazinoid biosynthesis in dicot plants. Phytochemistry, 69, 2668-2677.
81. Shaaban, M., Palmer, J.M., El-Naggar, W.A., El-Sokkary, M.A., Habib el, S.E., and, Keller, N.P., (2010) Involvement of transposon-like elements in penicillin gene cluster regulation. Fungal Genet. Biol. 47, 423-432.
82. Shimura, K., Okada, A., Okada, K., et al. (2007) Identification of a biosynthetic gene cluster in rice for momilactones. J. Biol. Chem. 282, 34013-34018. (Pubitemid 350159470)
83. Sicker, D., Frey, M., Schulz, M., and, Gierl, A., (2000) Role of natural benzoxazinones in the survival strategy of plants. Int. Rev. Cytol. 198, 319-346. (Pubitemid 30248868)
84. Slot, J.C., and, Hibbett, D.S., (2007) Horizontal transfer of a nitrate assimilation gene cluster and ecological transitions in fungi: a phylogenetic study. PLoS ONE, 2, e1097.
85. Slot, J.C., and, Rokas, A., (2010) Multiple GAL pathway gene clusters evolved independently and by different mechanisms in fungi. Proc. Natl Acad. Sci. USA, 107, 10136-10141.
86. Spieth, J., Brooke, G., Kuersten, S., Lea, K., and, Blumenthal, T., (1993) Operons in C. elegans: polycistronic mRNA precursors are processed by trans-splicing of SL2 to downstream coding regions. Cell, 73, 521-532. (Pubitemid 23143351)
87. Sproul, D., Gilbert, N., and, Bickmore, W.A., (2005) The role of chromatin structure in regulating the expression of clustered genes. Nat. Rev. Genet. 6, 775-781. (Pubitemid 41400835)
88. Swain, P.S., (2004) Efficient attenuation of stochasticity in gene expression through post-transcriptional control. J. Mol. Biol. 344, 965-976. (Pubitemid 39491243)
89. Swaminathan, S., Morrone, D., Wang, Q., Fulton, B., and, Peters, R.J., (2009) CYP76M7 is an ent-cassadiene C11α-hydroxylase defining a second multifunctional diterpenoid biosynthetic gene cluster in rice. Plant Cell, 21, 3315-3325.
90. Toyomasu, T., (2008) Recent advances regarding diterpene cyclase genes in higher plants and fungi. Biosci. Biotechnol. Biochem. 72, 1168-1175. (Pubitemid 351877005)
91. Trefzer, A., Pelzer, S., Schimana, J., Stockert, S., Bihlmaier, C., Fiedler, H.P., Welzel, K., Vente, A., and, Bechthold, A., (2002) Biosynthetic gene cluster of simocyclinone, a natural multihybrid antibiotic. Antimicrob. Agents Chemother. 46, 1174-1182. (Pubitemid 34415288)
92. Turgeon, B.G., and, Bushley, K.E., (2010) Secondary metabolism. In Cellular and Molecular Biology of Filamentous Fungi (, Borkovich, K., Ebbole, D., and, Momany, M., eds). Washington, DC: American Society of Microbiology, pp. 376-395.
93. Von Rad, U., Hüttl, R., Lottspeich, F., Gierl, A., and, Frey, M., (2001) Two glucosyltransferases are involved in detoxification of benzoxazinoids in maize. Plant J. 28, 633-642. (Pubitemid 34114970)
94. Walton, J., (2000) Horizontal gene transfer and the evolution of secondary metabolite gene clusters in fungi: an hypothesis. Fungal Genet. Biol. 30, 167-171.
95. Wegel, E., Koumproglou, R., Shaw, P., and, Osbourn, A., (2009) Cell-type specific chromatin decondensation of a metabolic gene cluster in oats. Plant Cell, 21, 3926-3936.
96. Wilderman, P.R., Xu, M., Jin, Y., Coates, R.M., and, Peters, R.J., (2004) Identification of syn-imara-7,15-diene synthase reveals functional clustering of terpene synthases involved in rice phytoalexin/allelochemical biosynthesis. Plant Physiol. 135, 2098-2105. (Pubitemid 39182789)
97. Wong, S., and, Wolfe, K.H., (2005) Birth of a metabolic gene cluster in yeast by adaptive gene relocation. Nat. Genet. 37, 777-782. (Pubitemid 41754898)
98. Yekta, S., Tabin, C.J., and, Bartel, D.P., (2008) MicroRNAs in the Hox network: an apparent link to posterior prevalence. Nat. Rev. Genet. 9, 789-796.
99. Zhang, X., and, Smith, T.F., (1998) Yeast 'operons'. Microb. Comp. Genomics, 3, 133-140.
100. Zheng, Y., Szustakowski, J.D., Fortnow, L., Roberts, R.J., and, Kasif, S., (2002) Computational identification of operons in microbial genomes. Genome Res. 12, 1221-1230. (Pubitemid 41264424)
101. Zorio, D.A.R., Cheng, N.S.N., Blumenthal, T., and, Spieth, J., (1994) Operons as a common form of chromosomal organization in C. elegans. Nature, 372, 270-272. (Pubitemid 24352449)