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The birth, evolution and death of metabolic gene clusters in fungi

Nature Reviews Microbiology volume 16, pages 731–744 (2018)Cite this article

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Abstract

Fungi contain a remarkable diversity of both primary and secondary metabolic pathways involved in ecologically specialized or accessory functions. Genes in these pathways are frequently physically linked on fungal chromosomes, forming metabolic gene clusters (MGCs). In this Review, we describe the diversity in the structure and content of fungal MGCs, their population-level and species-level variation, the evolutionary mechanisms that underlie their formation, maintenance and decay, and their ecological and evolutionary impact on fungal populations. We also discuss MGCs from other eukaryotes and the reasons for their preponderance in fungi. Improved knowledge of the evolutionary life cycle of MGCs will advance our understanding of the ecology of specialized metabolism and of the interplay between the lifestyle of an organism and genome architecture.

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Fig. 1: Representative metabolic gene clusters from fungi.
Fig. 2: Distribution of predicted primary and secondary metabolic gene clusters across the genomes of representative fungal species.
Fig. 3: The toxicity avoidance hypothesis.

Figure adapted with permission from ref.29, Proceedings of the National Academy of Sciences of the United States of America.

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References

  1. Whittaker, R. H. New concepts of kingdoms or organisms. Science 163, 150–160 (1969).

    CAS  PubMed  Google Scholar 

  2. Richards, T. A. & Talbot, N. J. Horizontal gene transfer in osmotrophs: playing with public goods. Nat. Rev. Microbiol. 11, 720–727 (2013).

    CAS  PubMed  Google Scholar 

  3. Pusztahelyi, T., Holb, I. J. & Pocsi, I. Secondary metabolites in fungus-plant interactions. Frontiers Plant Sci. 6, 573 (2015).

    Google Scholar 

  4. Stergiopoulos, I., Collemare, J., Mehrabi, R. & De Wit, P. J. Phytotoxic secondary metabolites and peptides produced by plant pathogenic Dothideomycete fungi. FEMS Microbiol. Rev. 37, 67–93 (2013).

    CAS  PubMed  Google Scholar 

  5. Keller, N. P., Turner, G. & Bennett, J. W. Fungal secondary metabolism — from biochemistry to genomics. Nat. Rev. Microbiol. 3, 937–947 (2005).

    CAS  PubMed  Google Scholar 

  6. Keller, N. P. & Hohn, T. M. Metabolic pathway gene clusters in filamentous fungi. Fungal Genet. Biol. 21, 17–29 (1997).

    CAS  PubMed  Google Scholar 

  7. Yue, Q. et al. Functional operons in secondary metabolic gene clusters in Glarea lozoyensis (Fungi, Ascomycota, Leotiomycetes). MBio 6, e00703 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Johnstone, I. L. et al. Isolation and characterisation of the crnA-niiA-niaD gene cluster for nitrate assimilation in Aspergillus nidulans. Gene 90, 181–192 (1990).

    CAS  PubMed  Google Scholar 

  9. Slot, J. C. & Hibbett, D. S. Horizontal transfer of a nitrate assimilation gene cluster and ecological transitions in fungi: a phylogenetic study. PLOS One 2, e1097 (2007). This is the first reported case in fungi of the acquisition of an entire metabolic pathway by horizontal transfer of an MGC.

    PubMed  PubMed Central  Google Scholar 

  10. Wong, S. & Wolfe, K. H. Birth of a metabolic gene cluster in yeast by adaptive gene relocation. Nat. Genet. 37, 777–782 (2005). This is the first study to show that fungal MGCs originate by relocation of native genes.

    CAS  PubMed  Google Scholar 

  11. Slot, J. C. & Rokas, A. Multiple GAL pathway gene clusters evolved independently and by different mechanisms in fungi. Proc. Natl Acad. Sci. USA 107, 10136–10141 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Hall, C. & Dietrich, F. S. The reacquisition of biotin prototrophy in Saccharomyces cerevisiae involved horizontal gene transfer, gene duplication and gene clustering. Genetics 177, 2293–2307 (2007). This study shows that the biotin pathway in the baker’s yeast, whose five of the six genes reside in two subtelomeric gene clusters, was lost in an ancestor but was subsequently rebuilt through acquisition of bacterial genes via HGT and gene duplication followed by neofunctionalization.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Penalva, M. A. A fungal perspective on human inborn errors of metabolism: alkaptonuria and beyond. Fungal Genet. Biol. 34, 1–10 (2001).

    CAS  PubMed  Google Scholar 

  14. Hull, E. P., Green, P. M., Arst, H. N. Jr & Scazzocchio, C. Cloning and physical characterization of the L-proline catabolism gene cluster of Aspergillus nidulans. Mol. Microbiol. 3, 553–559 (1989).

    CAS  PubMed  Google Scholar 

  15. Bobrowicz, P., Wysocki, R., Owsianik, G., Goffeau, A. & Ulaszewski, S. Isolation of three contiguous genes. ACR1, ACR2 and ACR3, involved in resistance to arsenic compounds in the yeast Saccharomyces cerevisiae. Yeast 13, 819–828 (1997).

    CAS  PubMed  Google Scholar 

  16. Elmore, M. H. et al. Clustering of two genes putatively involved in cyanate detoxification evolved recently and independently in multiple fungal lineages. Genome Biol. Evol. 7, 789–800 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Yu, J. et al. Clustered pathway genes in aflatoxin biosynthesis. Appl. Environ. Microbiol. 70, 1253–1262 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Brown, D. W., Dyer, R. B., McCormick, S. P., Kendra, D. F. & Plattner, R. D. Functional demarcation of the Fusarium core trichothecene gene cluster. Fungal Genet. Biol. 41, 454–462 (2004).

    CAS  PubMed  Google Scholar 

  19. Schardl, C. L. et al. Plant-symbiotic fungi as chemical engineers: multi-genome analysis of the clavicipitaceae reveals dynamics of alkaloid Loci. PLOS Genet. 9, e1003323 (2013). This is a comprehensive reconstruction of the evolutionary dynamics of MGCs responsible for four classes of alkaloid toxins, which are characterized by conserved cores of genes that specify the chemical skeleton structures of the toxins and various peripheral genes that are likely involved in chemical variations in toxin structures and their pharmacological effects.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Diez, B. et al. The cluster of penicillin biosynthetic genes. Identification and characterization of the pcbAB gene encoding the alpha-aminoadipyl-cysteinyl-valine synthetase and linkage to the pcbC and penDE genes. J. Biol. Chem. 265, 16358–16365 (1990).

    CAS  PubMed  Google Scholar 

  21. Kennedy, J. et al. Modulation of polyketide synthase activity by accessory proteins during lovastatin biosynthesis. Science 284, 1368–1372 (1999).

    CAS  PubMed  Google Scholar 

  22. Kimura, N. & Tsuge, T. Gene cluster involved in melanin biosynthesis of the filamentous fungus Alternaria alternata. J. Bacteriol. 175, 4427–4435 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Terabayashi, Y. et al. Identification and characterization of genes responsible for biosynthesis of kojic acid, an industrially important compound from Aspergillus oryzae. Fungal Genet. Biol. 47, 953–961 (2010).

    CAS  PubMed  Google Scholar 

  24. Lind, A. L. et al. Examining the evolution of the regulatory circuit controlling secondary metabolism and development in the fungal genus Aspergillus. PLOS Genet. 11, e1005096 (2015).

    PubMed  PubMed Central  Google Scholar 

  25. Sanchez, J. F., Somoza, A. D., Keller, N. P. & Wang, C. C. Advances in Aspergillus secondary metabolite research in the post-genomic era. Nat. Prod. Rep. 29, 351–371 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Brakhage, A. A. Regulation of fungal secondary metabolism. Nat. Rev. Microbiol. 11, 21–32 (2013).

    CAS  PubMed  Google Scholar 

  27. Bradshaw, R. E. et al. Fragmentation of an aflatoxin-like gene cluster in a forest pathogen. New Phytol. 198, 525–535 (2013).

    CAS  PubMed  Google Scholar 

  28. Sanchez, J. F. et al. Genome-based deletion analysis reveals the prenyl xanthone biosynthesis pathway in Aspergillus nidulans. J. Am. Chem. Soc. 133, 4010–4017 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. McGary, K. L., Slot, J. C. & Rokas, A. Physical linkage of metabolic genes in fungi is an adaptation against the accumulation of toxic intermediate compounds. Proc. Natl Acad. Sci. USA 110, 11481–11486 (2013). This study shows that fungal metabolic genes that handle toxic compounds are more likely to be clustered, suggesting that the phenotype selection acts on to drive gene clustering is the mitigation of toxicity of pathway intermediates.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Eidem, H. R., McGary, K. L. & Rokas, A. Shared selective pressures on fungal and human metabolic pathways lead to divergent yet analogous genetic responses. Mol. Biol. Evol. 32, 1449–1455 (2015).

    CAS  PubMed  Google Scholar 

  31. Hane, J. K. et al. A novel mode of chromosomal evolution peculiar to filamentous Ascomycete fungi. Genome Biol. 12, R45 (2011).

    PubMed  PubMed Central  Google Scholar 

  32. Siverio, J. M. Assimilation of nitrate by yeasts. FEMS Microbiol. Rev. 26, 277–284 (2002).

    CAS  PubMed  Google Scholar 

  33. Scazzocchio, C. Fungal biology in the post-genomic era. Fungal Biol. Biotechnol. 1, 7 (2014).

    PubMed  PubMed Central  Google Scholar 

  34. Yu, J., Chang, P., Bhatnagar, D. & Cleveland, T. E. Cloning of a sugar utilization gene cluster in Aspergillus parasiticus. Biochim. Biophys. Acta 1493, 211–214 (2000).

    CAS  PubMed  Google Scholar 

  35. Schrettl, M. et al. Self-protection against gliotoxin — a component of the gliotoxin biosynthetic cluster, GliT, completely protects Aspergillus fumigatus against exogenous gliotoxin. PLOS Pathog. 6, e1000952 (2010). This study reports that a gene within the gliotoxin MGC is necessary and sufficient for conferring protection against gliotoxin poisoning, thus providing a competitive advantage for organisms carrying it when grown in the presence of competitors that produce gliotoxin.

    PubMed  PubMed Central  Google Scholar 

  36. Wiemann, P. et al. Biosynthesis of the red pigment bikaverin in Fusarium fujikuroi: genes, their function and regulation. Mol. Microbiol. 72, 931–946 (2009).

    CAS  PubMed  Google Scholar 

  37. Hittinger, C. T., Rokas, A. & Carroll, S. B. Parallel inactivation of multiple GAL pathway genes and ecological diversification in yeasts. Proc. Natl Acad. Sci. USA 101, 14144–14149 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Martchenko, M., Levitin, A., Hogues, H., Nantel, A. & Whiteway, M. Transcriptional rewiring of fungal galactose metabolism circuitry. Curr. Biol. 17, 1007–1013 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Lim, F. Y. et al. Genome-based cluster deletion reveals an endocrocin biosynthetic pathway in Aspergillus fumigatus. Appl. Environ. Microbiol. 78, 4117–4125 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Szewczyk, E. et al. Identification and characterization of the asperthecin gene cluster of Aspergillus nidulans. Appl. Environ. Microbiol. 74, 7607–7612 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Chiang, Y. M. et al. Molecular genetic mining of the Aspergillus secondary metabolome: discovery of the emericellamide biosynthetic pathway. Chem. Biol. 15, 527–532 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Bushley, K. E. et al. The genome of Tolypocladium inflatum: evolution, organization, and expression of the cyclosporin biosynthetic gene cluster. PLOS Genet. 9, e1003496 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Inderbitzin, P., Asvarak, T. & Turgeon, B. G. Six new genes required for production of T-toxin, a polyketide determinant of high virulence of Cochliobolus heterostrophus to maize. Mol. Plant Microbe Interact. 23, 458–472 (2010).

    CAS  PubMed  Google Scholar 

  44. Yin, W. B. et al. A nonribosomal peptide synthetase-derived iron(III) complex from the pathogenic fungus Aspergillus fumigatus. J. Am. Chem. Soc. 135, 2064–2067 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Umemura, M. et al. Characterization of the biosynthetic gene cluster for the ribosomally synthesized cyclic peptide ustiloxin B in Aspergillus flavus. Fungal Genet. Biol. 68, 23–30 (2014).

    CAS  PubMed  Google Scholar 

  46. Gutierrez, S., Fierro, F., Casqueiro, J. & Martin, J. F. Gene organization and plasticity of the beta-lactam genes in different filamentous fungi. Antonie Van Leeuwenhoek 75, 81–94 (1999).

    CAS  PubMed  Google Scholar 

  47. Lo, H. C. et al. Two separate gene clusters encode the biosynthetic pathway for the meroterpenoids austinol and dehydroaustinol in Aspergillus nidulans. J. Am. Chem. Soc. 134, 4709–4720 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Proctor, R. H., McCormick, S. P., Alexander, N. J. & Desjardins, A. E. 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 (2009).

    CAS  PubMed  Google Scholar 

  49. Nicholson, M. J. et al. Identification of two aflatrem biosynthesis gene loci in Aspergillus flavus and metabolic engineering of Penicillium paxilli to elucidate their function. Appl. Environ. Microbiol. 75, 7469–7481 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Wiemann, P. et al. Prototype of an intertwined secondary-metabolite supercluster. Proc. Natl Acad. Sci. USA 110, 17065–17070 (2013). This study is the first to report the existence of intertwined MGCs responsible for the production of at least two distinct secondary metabolites in fungal genomes.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Lind, A. L. et al. Drivers of genetic diversity in secondary metabolic gene clusters within a fungal species. PLOS Biol. 15, e2003583 (2017). This is the first study, together with that by Gibbons et al. (2012), to report that two non-homologous MGCs occupy the same locus (that is, an idiomorph polymorphism) and is the first to describe patterns of genome-wide variation of secondary MGCs in a fungal species.

    PubMed  PubMed Central  Google Scholar 

  52. Medini, D., Donati, C., Tettelin, H., Masignani, V. & Rappuoli, R. The microbial pan-genome. Curr. Opin. Genet. Dev. 15, 589–594 (2005).

    CAS  PubMed  Google Scholar 

  53. Chang, P. K., Horn, B. W. & Dorner, J. W. Sequence breakpoints in the aflatoxin biosynthesis gene cluster and flanking regions in nonaflatoxigenic Aspergillus flavus isolates. Fungal Genet. Biol. 42, 914–923 (2005).

    CAS  PubMed  Google Scholar 

  54. Wiemann, P. et al. Deciphering the cryptic genome: genome-wide analyses of the rice pathogen Fusarium fujikuroi reveal complex regulation of secondary metabolism and novel metabolites. PLOS Pathog. 9, e1003475 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Chiara, M. et al. Genome sequencing of multiple isolates highlights subtelomeric genomic diversity within Fusarium fujikuroi. Genome Biol. Evol. 7, 3062–3069 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Castella, G., Bragulat, M. R., Puig, L., Sanseverino, W. & Cabanes, F. J. Genomic diversity in ochratoxigenic and non ochratoxigenic strains of Aspergillus carbonarius. Sci. Rep. 8, 5439 (2018).

    PubMed  PubMed Central  Google Scholar 

  57. Hartmann, F. E. & Croll, D. Distinct trajectories of massive recent gene gains and losses in populations of a microbial eukaryotic pathogen. Mol. Biol. Evol. 34, 2808–2822 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Campbell, M. A., Rokas, A. & Slot, J. C. Horizontal transfer and death of a fungal secondary metabolic gene cluster. Genome Biol. Evol. 4, 289–293 (2012).

    PubMed  PubMed Central  Google Scholar 

  59. Campbell, M. A., Staats, M., van Kan, J. L. A., Rokas, A. & Slot, J. C. Repeated loss of an anciently horizontally transferred gene cluster in Botrytis. Mycologia 105, 1126–1134 (2013).

    PubMed  Google Scholar 

  60. Schumacher, J. et al. A functional bikaverin biosynthesis gene cluster in rare strains of Botrytis cinerea is positively controlled by VELVET. PLOS One 8, e53729 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Hittinger, C. T. et al. Remarkably ancient balanced polymorphisms in a multi-locus gene network. Nature 464, 54–58 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Gibbons, J. G. et al. The evolutionary imprint of domestication on genome variation and function of the filamentous fungus Aspergillus oryzae. Curr. Biol. 22, 1403–1409 (2012). Together with the study by Lind et al., these are the first studies to report that two non-homologous MGCs occupy the same locus (that is, an idiomorph polymorphism) in the genome of a fungal species.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Keller-Seitz, M. U. et al. Transcriptional response of yeast to aflatoxin B1: recombinational repair involving RAD51 and RAD1. Mol. Biol. Cell 15, 4321–4336 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Fedorova, N. D. et al. Genomic islands in the pathogenic filamentous fungus Aspergillus fumigatus. PLOS Genet. 4, e1000046 (2008).

    PubMed  PubMed Central  Google Scholar 

  65. Metzenberg, R. L. & Glass, N. L. Mating type and mating strategies in Neurospora. Bioessays 12, 53–59 (1990).

    CAS  PubMed  Google Scholar 

  66. Mukherjee, P. K., Horwitz, B. A. & Kenerley, C. M. Secondary metabolism in Trichoderma—a genomic perspective. Microbiology 158, 35–45 (2012).

    CAS  PubMed  Google Scholar 

  67. Rank, C. et al. Distribution of sterigmatocystin in filamentous fungi. Fungal Biol. 115, 406–420 (2011).

    CAS  PubMed  Google Scholar 

  68. Khaldi, N. et al. SMURF: genomic mapping of fungal secondary metabolite clusters. Fungal Genet. Biol. 47, 736–741 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. de Vries, R. P. et al. Comparative genomics reveals high biological diversity and specific adaptations in the industrially and medically important fungal genus Aspergillus. Genome Biol. 18, 28 (2017).

    PubMed  PubMed Central  Google Scholar 

  70. Riley, R. et al. Comparative genomics of biotechnologically important yeasts. Proc. Natl Acad. Sci. USA 113, 9882–9887 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Khaldi, N., Collemare, J., Lebrun, M. H. & Wolfe, K. H. Evidence for horizontal transfer of a secondary metabolite gene cluster between fungi. Genome Biol. 9, R18 (2008).

    PubMed  PubMed Central  Google Scholar 

  72. Reynolds, H. T. et al. Differential retention of gene functions in a secondary metabolite cluster. Mol. Biol. Evol. 34, 2002–2015 (2017).

    CAS  PubMed  Google Scholar 

  73. Zhang, H., Rokas, A. & Slot, J. C. Two different secondary metabolism gene clusters occupied the same ancestral locus in fungal dermatophytes of the Arthrodermataceae. PLOS One 7, e41903 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Dalal, C. K. et al. Transcriptional rewiring over evolutionary timescales changes quantitative and qualitative properties of gene expression. elife 5, e18981 (2016).

    PubMed  PubMed Central  Google Scholar 

  75. Proctor, R. H. et al. Evolution of structural diversity of trichothecenes, a family of toxins produced by plant pathogenic and entomopathogenic fungi. PLOS Pathog. 14, e1006946 (2018).

    PubMed  PubMed Central  Google Scholar 

  76. Carbone, I., Ramirez-Prado, J. H., Jakobek, J. L. & Horn, B. W. Gene duplication, modularity and adaptation in the evolution of the aflatoxin gene cluster. BMC Evol. Biol. 7, 111 (2007).

    PubMed  PubMed Central  Google Scholar 

  77. Slot, J. C. & Rokas, A. Horizontal transfer of a large and highly toxic secondary metabolic gene cluster between fungi. Curr. Biol. 21, 134–139 (2011). This study reports the horizontal transfer of a large MGC (at least 57 kb of sequence, 24 genes) involved in the making of the mycotoxin sterigmatocystin between fungi.

    CAS  PubMed  Google Scholar 

  78. Ehrlich, K. C., Chang, P. K., Yu, J. & Cotty, P. J. Aflatoxin biosynthesis cluster gene cypA is required for G aflatoxin formation. Appl. Environ. Microbiol. 70, 6518–6524 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Proctor, R. H., Busman, M., Seo, J. A., Lee, Y. W. & Plattner, R. D. A fumonisin biosynthetic gene cluster in Fusarium oxysporum strain O-1890 and the genetic basis for B versus C fumonisin production. Fungal Genet. Biol. 45, 1016–1026 (2008).

    CAS  PubMed  Google Scholar 

  80. Rosewich, U. L. & Kistler, H. C. Role of horizontal gene transfer in the evolution of fungi. Annu. Rev. Phytopathol. 38, 325–363 (2000).

    CAS  PubMed  Google Scholar 

  81. Wisecaver, J. H. & Rokas, A. Fungal metabolic gene clusters-caravans traveling across genomes and environments. Front. Microbiol. 6, 161 (2015).

    PubMed  PubMed Central  Google Scholar 

  82. Reynolds, H. T. et al. Horizontal gene cluster transfer increased hallucinogenic mushroom diversity. Evol. Lett. 2, 88–101 (2018).

    PubMed  PubMed Central  Google Scholar 

  83. Patron, N. J. et al. Origin and distribution of epipolythiodioxopiperazine (ETP) gene clusters in filamentous ascomycetes. BMC Evol. Biol. 7, 174 (2007).

    PubMed  PubMed Central  Google Scholar 

  84. Matasyoh, J. C., Dittrich, B., Schueffler, A. & Laatsch, H. Larvicidal activity of metabolites from the endophytic Podospora sp. against the malaria vector Anopheles gambiae. Parasitol. Res. 108, 561–566 (2011).

    PubMed  Google Scholar 

  85. Matsuzawa, T. et al. New insights into galactose metabolism by Schizosaccharomyces pombe: isolation and characterization of a galactose-assimilating mutant. J. Biosci. Bioeng. 111, 158–166 (2011).

    CAS  PubMed  Google Scholar 

  86. Ortiz, J. F. & Rokas, A. CTDGFinder: a novel homology-based algorithm for identifying closely spaced clusters of tandemly duplicated genes. Mol. Biol. Evol. 34, 215–229 (2017).

    CAS  PubMed  Google Scholar 

  87. Nei, M. Modification of linkage intensity by natural selection. Genetics 57, 625–641 (1967).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Ward, T. J., Bielawski, J. P., Kistler, H. C., Sullivan, E. & O’Donnell, K. Ancestral polymorphism and adaptive evolution in the trichothecene mycotoxin gene cluster of phytopathogenic Fusarium. Proc. Natl Acad. Sci. USA 99, 9278–9283 (2002). This is the first study to report evidence for trans-specific polymorphism in the gene cluster of the trichothecene mycotoxin, which is maintained by balancing selection acting on chemotype differences.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Carbone, I., Jakobek, J. L., Ramirez-Prado, J. H. & Horn, B. W. Recombination, balancing selection and adaptive evolution in the aflatoxin gene cluster of Aspergillus parasiticus. Mol. Ecol. 16, 4401–4417 (2007).

    CAS  PubMed  Google Scholar 

  90. Hartmann, F. E., McDonald, B. A. & Croll, D. Genome-wide evidence for divergent selection between populations of a major agricultural pathogen. Mol. Ecol. 27, 2725–2741 (2018).

    PubMed  PubMed Central  Google Scholar 

  91. Grandaubert, J., Dutheil, J. Y. & Stukenbrock, E. H. The genomic determinants of adaptive evolution in a fungal pathogen. Preprint at bioRxiv. https://doi.org/10.1101/176727 (2018).

    Article  Google Scholar 

  92. Morris, J. J., Lenski, R. E. & Zinser, E. R. The Black Queen hypothesis: evolution of dependencies through adaptive gene loss. MBio 3, e00036–12 (2012).

    PubMed  PubMed Central  Google Scholar 

  93. Hurst, L. D., Pal, C. & Lercher, M. J. The evolutionary dynamics of eukaryotic gene order. Nat. Rev. Genet. 5, 299–310 (2004).

    CAS  PubMed  Google Scholar 

  94. Gibbons, J. G. et al. Global transcriptome changes underlying colony growth in the opportunistic human pathogen Aspergillus fumigatus. Eukaryot. Cell 11, 68–78 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Lind, A. L., Smith, T. D., Saterlee, T., Calvo, A. M. & Rokas, A. Regulation of secondary metabolism by the Velvet complex is temperature-responsive in Aspergillus. G3 6, 4023–4033 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Yu, J. J. et al. Tight control of mycotoxin biosynthesis gene expression in Aspergillus flavus by temperature as revealed by RNA-Seq. FEMS Microbiol. Lett. 322, 145–149 (2011).

    CAS  PubMed  Google Scholar 

  97. Andersen, M. R. et al. Accurate prediction of secondary metabolite gene clusters in filamentous fungi. Proc. Natl Acad. Sci. USA 110, E99–E107 (2013).

    CAS  PubMed  Google Scholar 

  98. Lawler, K., Hammond-Kosack, K., Brazma, A. & Coulson, R. M. Genomic clustering and co-regulation of transcriptional networks in the pathogenic fungus Fusarium graminearum. BMC Syst. Biol. 7, 52 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Wisecaver, J. H. et al. A global coexpression network approach for connecting genes to specialized metabolic pathways in plants. Plant Cell 29, 944–959 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Kensche, P. R., Oti, M., Dutilh, B. E. & Huynen, M. A. Conservation of divergent transcription in fungi. Trends Genet. 24, 207–211 (2008).

    CAS  PubMed  Google Scholar 

  101. Fernandes, M., Keller, N. P. & Adams, T. H. Sequence-specific binding by Aspergillus nidulans AflR, a C6 zinc cluster protein regulating mycotoxin biosynthesis. Mol. Microbiol. 28, 1355–1365 (1998).

    CAS  PubMed  Google Scholar 

  102. Gacek, A. & Strauss, J. The chromatin code of fungal secondary metabolite gene clusters. Appl. Microbiol. Biotechnol. 95, 1389–1404 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Moore, G. G., Singh, R., Horn, B. W. & Carbone, I. Recombination and lineage-specific gene loss in the aflatoxin gene cluster of Aspergillus flavus. Mol. Ecol. 18, 4870–4887 (2009). Extensive analysis of patterns of linkage disequilibrium in the aflatoxin gene cluster of A. flavus suggests that recombination events are unevenly distributed across the cluster, including the absence of recombination for the subcluster of genes acting early in the aflatoxin synthesis pathway.

    CAS  PubMed  Google Scholar 

  104. Olarte, R. A. et al. Effect of sexual recombination on population diversity in aflatoxin production by Aspergillus flavus and evidence for cryptic heterokaryosis. Mol. Ecol. 21, 1453–1476 (2012).

    PubMed  Google Scholar 

  105. Walton, J. D. Horizontal gene transfer and the evolution of secondary metabolite gene clusters in fungi: an hypothesis. Fungal Genet. Biol. 30, 167–171 (2000).

    CAS  PubMed  Google Scholar 

  106. Lang, G. I. & Botstein, D. A test of the coordinated expression hypothesis for the origin and maintenance of the GAL cluster in yeast. PLOS One 6, e25290 (2011). This study reports that disruption of the clustering in the galactose pathway does not reduce fitness, arguing against the hypothesis that gene clustering increases fitness because it enables greater coordination of gene expression.

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Naseeb, S. & Delneri, D. Impact of chromosomal inversions on the yeast DAL cluster. PLOS One 7, e42022 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Leslie, N. D. Insights into the pathogenesis of galactosemia. Annu. Rev. Nutr. 23, 59–80 (2003).

    CAS  PubMed  Google Scholar 

  109. Alam, M. K. & Kaminskyj, S. G. W. Aspergillus galactose metabolism is more complex than that of Saccharomyces: the story of GalD(GAL7) and GalE(GAL1). Botany 91, 467–477 (2013).

    CAS  Google Scholar 

  110. Slot, J. C. Fungal gene cluster diversity and evolution. Adv. Genet. 100, 141–178 (2017).

    PubMed  Google Scholar 

  111. Wisecaver, J. H., Slot, J. C. & Rokas, A. The evolution of fungal metabolic pathways. PLOS Genet. 10, e1004816 (2014).

    PubMed  PubMed Central  Google Scholar 

  112. Gibbons, J. G. & Rokas, A. The function and evolution of the Aspergillus genome. Trends Microbiol. 21, 14–22 (2013).

    CAS  PubMed  Google Scholar 

  113. Lynch, M. The Origins of Genome Architecture. (Sinauer, 2007).

  114. Lewontin, R. C. On measures of gametic disequilibrium. Genetics 120, 849–852 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Fridovich-Keil, J. L. Galactosemia: the good, the bad, and the unknown. J. Cell. Physiol. 209, 701–705 (2006).

    CAS  PubMed  Google Scholar 

  116. Mumma, J. O. et al. Distinct roles of galactose-1P in galactose-mediated growth arrest of yeast deficient in galactose-1P uridylyltransferase (GALT) and UDP-galactose 4′-epimerase (GALE). Mol. Genet. Metab. 93, 160–171 (2008).

    CAS  PubMed  Google Scholar 

  117. del Campo, J. et al. The others: our biased perspective of eukaryotic genomes. Trends Ecol. Evol. 29, 252–259 (2014).

    PubMed  PubMed Central  Google Scholar 

  118. Loftus, B. et al. The genome of the protist parasite Entamoeba histolytica. Nature 433, 865–868 (2005).

    CAS  PubMed  Google Scholar 

  119. Brayton, K. A. et al. Genome sequence of Babesia bovis and comparative analysis of apicomplexan hemoprotozoa. PLOS Pathog. 3, 1401–1413 (2007).

    CAS  PubMed  Google Scholar 

  120. Corradi, N., Pombert, J. F., Farinelli, L., Didier, E. S. & Keeling, P. J. The complete sequence of the smallest known nuclear genome from the microsporidian Encephalitozoon intestinalis. Nat. Commun. 1, 77 (2010).

    PubMed  Google Scholar 

  121. Eichinger, L. et al. The genome of the social amoeba Dictyostelium discoideum. Nature 435, 43–57 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Zhu, G. et al. Cryptosporidium parvum: the first protist known to encode a putative polyketide synthase. Gene 298, 79–89 (2002).

    CAS  PubMed  Google Scholar 

  123. John, U. et al. Novel insights into evolution of protistan polyketide synthases through phylogenomic analysis. Protist 159, 21–30 (2008).

    CAS  PubMed  Google Scholar 

  124. Monroe, E. A., Johnson, J. G., Wang, Z. H., Pierce, R. K. & Van Dolah, F. M. Characterization and expression of nuclear-encoded polyketide synthases in the brevetoxin-producing dinoflagellate. Karenia brevis. J. Phycol. 46, 541–552 (2010).

    CAS  Google Scholar 

  125. Wang, H., Fewer, D. P., Holm, L., Rouhiainen, L. & Sivonen, K. Atlas of nonribosomal peptide and polyketide biosynthetic pathways reveals common occurrence of nonmodular enzymes. Proc. Natl Acad. Sci. USA 111, 9259–9264 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Rokas, A. & Hittinger, C. T. Transcriptional rewiring: the proof is in the eating. Curr. Biol. 17, R626–628 (2007).

    CAS  PubMed  Google Scholar 

  127. Johnston, M. A model fungal gene regulatory mechanism: the GAL genes of Saccharomyces cerevisiae. Microbiol. Rev. 51, 458–476 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Rubio-Texeira, M. A comparative analysis of the GAL genetic switch between not-so-distant cousins: Saccharomyces cerevisiae versus Kluyveromyces lactis. FEMS Yeast Res. 5, 1115–1128 (2005).

    CAS  PubMed  Google Scholar 

  129. Wolfe, K. H. et al. Clade- and species-specific features of genome evolution in the Saccharomycetaceae. FEMS Yeast Res. 15, fov035 (2015).

    PubMed  PubMed Central  Google Scholar 

  130. Moyrand, F., Fontaine, T. & Janbon, G. Systematic capsule gene disruption reveals the central role of galactose metabolism on Cryptococcus neoformans virulence. Mol. Microbiol. 64, 771–781 (2007).

    CAS  PubMed  Google Scholar 

  131. Moyrand, F., Lafontaine, I., Fontaine, T. & Janbon, G. UGE1 and UGE2 regulate the UDP-glucose/UDP-galactose equilibrium in Cryptococcus neoformans. Eukaryot. Cell 7, 2069–2077 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Christensen, U. et al. Unique regulatory mechanism for d-galactose utilization in Aspergillus nidulans. Appl. Environ. Microbiol. 77, 7084–7087 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Boycheva, S., Daviet, L., Wolfender, J. L. & Fitzpatrick, T. B. The rise of operon-like gene clusters in plants. Trends Plant Sci. 19, 447–459 (2014).

    CAS  PubMed  Google Scholar 

  134. Nutzmann, H. W., Huang, A. & Osbourn, A. Plant metabolic clusters — from genetics to genomics. New Phytol. 211, 771–789 (2016).

    PubMed  PubMed Central  Google Scholar 

  135. Frey, M. et al. Analysis of a chemical plant defense mechanism in grasses. Science 277, 696–699 (1997).

    CAS  PubMed  Google Scholar 

  136. Handrick, V. et al. Biosynthesis of 8-O-methylated benzoxazinoid defense compounds in maize. Plant Cell 28, 1682–1700 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Schneider, L. M. et al. The Cer-cqu gene cluster determines three key players in a beta-diketone synthase polyketide pathway synthesizing aliphatics in epicuticular waxes. J. Exp. Bot. 67, 2715–2730 (2016).

    CAS  PubMed Central  PubMed  Google Scholar 

  138. Olsen, K. M. & Small, L. L. Micro- and macroevolutionary adaptation through repeated loss of a complete metabolic pathway. New Phytol. 219, 757–766 (2018).

    CAS  PubMed  Google Scholar 

  139. Takos, A. M. et al. Genomic clustering of cyanogenic glucoside biosynthetic genes aids their identification in Lotus japonicus and suggests the repeated evolution of this chemical defence pathway. Plant J. 68, 273–286 (2011).

    CAS  PubMed  Google Scholar 

  140. Winzer, T. et al. A Papaver somniferum 10-gene cluster for synthesis of the anticancer alkaloid noscapine. Science 336, 1704–1708 (2012).

    CAS  PubMed  Google Scholar 

  141. Itkin, M. et al. Biosynthesis of antinutritional alkaloids in solanaceous crops is mediated by clustered genes. Science 341, 175–179 (2013).

    CAS  PubMed  Google Scholar 

  142. Qi, X. et al. 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 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Shimura, K. et al. Identification of a biosynthetic gene cluster in rice for momilactones. J. Biol. Chem. 282, 34013–34018 (2007).

    CAS  PubMed  Google Scholar 

  144. Field, B. & Osbourn, A. E. Metabolic diversification — independent assembly of operon-like gene clusters in different plants. Science 320, 543–547 (2008).

    CAS  PubMed  Google Scholar 

  145. Swaminathan, S., Morrone, D., Wang, Q., Fulton, D. B. & Peters, R. J. CYP76M7 is an ent-cassadiene C11alpha-hydroxylase defining a second multifunctional diterpenoid biosynthetic gene cluster in rice. Plant Cell 21, 3315–3325 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Field, B. et al. Formation of plant metabolic gene clusters within dynamic chromosomal regions. Proc. Natl Acad. Sci. USA 108, 16116–16121 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Krokida, A. et al. A metabolic gene cluster in Lotus japonicus discloses novel enzyme functions and products in triterpene biosynthesis. New Phytol. 200, 675–690 (2013).

    CAS  PubMed  Google Scholar 

  148. Matsuba, Y. et al. Evolution of a complex locus for terpene biosynthesis in Solanum. Plant Cell 25, 2022–2036 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. King, A. J., Brown, G. D., Gilday, A. D., Larson, T. R. & Graham, I. A. Production of bioactive diterpenoids in the Euphorbiaceae depends on evolutionarily conserved gene clusters. Plant Cell 26, 3286–3298 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Shang, Y. et al. Biosynthesis, regulation, and domestication of bitterness in cucumber. Science 346, 1084–1088 (2014).

    CAS  PubMed  Google Scholar 

  151. Chu, H. Y., Wegel, E. & Osbourn, A. From hormones to secondary metabolism: the emergence of metabolic gene clusters in plants. Plant J. 66, 66–79 (2011).

    CAS  PubMed  Google Scholar 

  152. Boutanaev, A. M. et al. Investigation of terpene diversification across multiple sequenced plant genomes. Proc. Natl Acad. Sci. USA 112, E81–E88 (2015).

    CAS  PubMed  Google Scholar 

  153. Schlapfer, P. et al. Genome-wide prediction of metabolic enzymes, pathways, and gene clusters in plants. Plant Physiol. 173, 2041–2059 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Topfer, N., Fuchs, L. M. & Aharoni, A. The PhytoClust tool for metabolic gene clusters discovery in plant genomes. Nucleic Acids Res. 45, 7049–7063 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Kautsar, S. A., Suarez Duran, H. G., Blin, K., Osbourn, A. & Medema, M. H. plantiSMASH: automated identification, annotation and expression analysis of plant biosynthetic gene clusters. Nucleic Acids Res. 45, W55–W63 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Kliebenstein, D. J. & Osbourn, A. Making new molecules — evolution of pathways for novel metabolites in plants. Curr. Opin. Plant Biol. 15, 415–423 (2012).

    CAS  PubMed  Google Scholar 

  157. Itkin, M. et al. The biosynthetic pathway of the nonsugar, high-intensity sweetener mogroside V from Siraitia grosvenorii. Proc. Natl Acad. Sci. USA 113, E7619–E7628 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Klein, A. P. & Sattely, E. S. Biosynthesis of cabbage phytoalexins from indole glucosinolate. Proc. Natl Acad. Sci. USA 114, 1910–1915 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Gladyshev, E. A., Meselson, M. & Arkhipova, I. R. Massive horizontal gene transfer in bdelloid rotifers. Science 320, 1210–1213 (2008).

    CAS  PubMed  Google Scholar 

  160. Moran, N. A. & Jarvik, T. Lateral transfer of genes from fungi underlies carotenoid production in aphids. Science 328, 624–627 (2010).

    CAS  PubMed  Google Scholar 

  161. Derelle, E. et al. Genome analysis of the smallest free-living eukaryote Ostreococcus tauri unveils many unique features. Proc. Natl Acad. Sci. USA 103, 11647–11652 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Fernandez, E. & Galvan, A. Inorganic nitrogen assimilation in Chlamydomonas. J. Exp. Bot. 58, 2279–2287 (2007).

    CAS  PubMed  Google Scholar 

  163. McDonald, S. M., Plant, J. N. & Worden, A. Z. The mixed lineage nature of nitrogen transport and assimilation in marine eukaryotic phytoplankton: a case study of Micromonas. Mol. Biol. Evol. 27, 2268–2283 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Foflonker, F. et al. The unexpected extremophile: tolerance to fluctuating salinity in the green alga Picochlorum. Algal Res. 16, 465–472 (2016).

    Google Scholar 

  165. Vallon, O. & Spalding, M. H. in The Chlamydomonas Sourcebook Vol. 2 (ed. Stern, D.) 115–158 (Academic Press, 2009).

  166. Foflonker, F. et al. Genome of the halotolerant green alga Picochlorum sp. reveals strategies for thriving under fluctuating environmental conditions. Environ. Microbiol. 17, 412–426 (2015).

    CAS  PubMed  Google Scholar 

  167. Medema, M. H. et al. antiSMASH: rapid identification, annotation and analysis of secondary metabolite biosynthesis gene clusters in bacterial and fungal genome sequences. Nucleic Acids Res. 39, W339–W346 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank past and present members of the Rokas laboratory, particularly J. Slot, J. Gibbons, M. Mead, K. McGary and J. Steenwyk, as well as long-time collaborator C. T. Hittinger for discussions over the years on the evolution of metabolic gene clusters in fungi. Research in the Rokas laboratory has been supported by the National Science Foundation, the Searle Scholars Program, the Guggenheim Foundation, the Burroughs Wellcome Trust, the National Institutes of Health, the Beckman Scholars Program and the March of Dimes.

Reviewer information

Nature Reviews Microbiology thanks B. McDonald and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Authors and Affiliations

  1. Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA

    Antonis Rokas & Jennifer H. Wisecaver

  2. Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN, USA

    Antonis Rokas & Abigail L. Lind

  3. Department of Biochemistry, Purdue University, West Lafayette, IN, USA

    Jennifer H. Wisecaver

  4. Gladstone Institutes, San Francisco, CA, USA

    Abigail L. Lind

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  1. Antonis Rokas
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A.R., J.H.W. and A.L.L. wrote the article, researched data for the article, made substantial contributions to discussions of the content and reviewed and/or edited the manuscript before submission.

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Correspondence to Antonis Rokas.

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Glossary

Primary metabolism

The part of metabolism involving pathways associated with growth, such as those for macronutrients (for example, carbohydrates, fat and proteins).

Secondary metabolism

(Or specialized metabolism). The part of metabolism involving pathways associated with the production of small, bioactive molecules, such as mycotoxins, pigments and antibiotics.

Metabolic gene clusters

(MGCs) A set of genes from the same metabolic pathway that is physically linked and occupies the same genetic locus in the chromosome; in other organisms, similarly organized co-adapted gene complexes are associated with non-metabolic traits and have come to be known as supergenes.

Pangenome

The full complement of genes present in a population or species, which includes genes present in all individuals as well as genes that are present in only some individuals (or even in a single individual).

Idiomorph alleles

The non-homologous alleles that determine the fungal mating type of an isolate.

Regulatory rewiring

The same metabolic pathway (or other biological process) is regulated by different (non-homologous) transcriptional factors (and circuits) in different species.

Horizontal gene transfer

(HGT; also known as lateral gene transfer). The transfer of genetic material from one organism to another through a process other than reproduction.

Convergent evolution

The independent evolution of similar traits or features in organisms belonging to different, unrelated lineages.

Black queen hypothesis

The idea that the loss of genes whose functions are associated with public goods (for example, the production of an antitoxin) may be individually advantageous (up to the point at which the cost associated with loss of public goods exceeds the benefit of loss).

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Rokas, A., Wisecaver, J.H. & Lind, A.L. The birth, evolution and death of metabolic gene clusters in fungi. Nat Rev Microbiol 16, 731–744 (2018). https://doi.org/10.1038/s41579-018-0075-3

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