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


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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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.

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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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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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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.


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).

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