The evolution of gene collectives: How natural selection drives chemical innovation

Fischbach, Michael A.; Walsh, Christopher T.; Clardy, Jon

doi:10.1073/pnas.0709132105

Cited by 255 publications

(239 citation statements)

References 113 publications

(79 reference statements)

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“…S2), resulting in two new insights into the nature and timing of this duplication in the context of bacterial evolution. First, type II PKS KSs appear more similar to primary metabolic FabF KS homologs from the fatty acid (FAS) pathway than to the KS of several secondary metabolic type II PKS relatives, such as aurachin and kedarcidin (1,3,4,(16)(17)(18). These other secondary metabolic gene clusters harbor tandem KSs that appear superficially similar to the tandem KSs of type II PKS gene clusters (SI Appendix, Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Elucidating the history of how gene clusters evolved to produce a powerhouse of structurally diverse and biologically active molecules could reveal how synthases can be engineered to produce new therapeutic agents. Phylogenetic analyses have revealed evolutionary histories of individual biosynthetic genes, but the mechanisms of evolution of entire gene clusters are not well understood (1)(2)(3)(4).…”

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confidence: 99%

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Evolution of chemical diversity by coordinated gene swaps in type II polyketide gene clusters

Hillenmeyer

Vandova

Berlew

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Natural product biosynthetic pathways generate molecules of enormous structural complexity and exquisitely tuned biological activities. Studies of natural products have led to the discovery of many pharmaceutical agents, particularly antibiotics. Attempts to harness the catalytic prowess of biosynthetic enzyme systems, for both compound discovery and engineering, have been limited by a poor understanding of the evolution of the underlying gene clusters. We developed an approach to study the evolution of biosynthetic genes on a cluster-wide scale, integrating pairwise gene coevolution information with large-scale phylogenetic analysis. We used this method to infer the evolution of type II polyketide gene clusters, tracing the path of evolution from the single ancestor to those gene clusters surviving today. We identified 10 key gene types in these clusters, most of which were swapped in from existing cellular processes and subsequently specialized. The ancestral type II polyketide gene cluster likely comprised a core set of five genes, a roster that expanded and contracted throughout evolution. A key C24 ancestor diversified into major classes of longer and shorter chain length systems, from which a C20 ancestor gave rise to the majority of characterized type II polyketide antibiotics. Our findings reveal that (i) type II polyketide structure is predictable from its gene roster, (ii) only certain gene combinations are compatible, and (iii) gene swaps were likely a key to evolution of chemical diversity. The lessons learned about how natural selection drives polyketide chemical innovation can be applied to the rational design and guided discovery of chemicals with desired structures and properties.evolution | polyketide | natural products | gene cluster

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Evolution of chemical diversity by coordinated gene swaps in type II polyketide gene clusters

Hillenmeyer

Vandova

Berlew

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Collinearity will be present, but will not be perfect. We would like to further constrain the relative contribution of different evolutionary modes, such as mutation and gene duplication, which have also been observed in PKS evolution (36). Further systematic phylogenetic analysis at the gene and protein domain level in modular PKSs will continue to be interesting and informative as to their evolutionary history, allowing better use of the predictions from models such as ours.…”

Section: Discussionmentioning

confidence: 99%

Emergent gene order in a model of modular polyketide synthases

Callahan

Thattai

Shraiman

2009

Proc. Natl. Acad. Sci. U.S.A.

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Polyketides are a class of biologically active heteropolymers produced by assembly line-like multiprotein complexes of modular polyketide synthases (PKS). The polyketide product is encoded in the order of the PKS proteins in the assembly line, suggesting that polyketide diversity derives from combinatorial rearrangement of these PKS complexes. Remarkably, the order of PKS genes on the chromosome follows the order of PKS proteins in the assembly line: This fact is commonly referred to as "collinearity". Here we propose an evolutionary origin for collinearity and demonstrate the mechanism by using a computational model of PKS evolution in a population. Assuming continuous evolutionary pressure for novel polyketides, and that new polyketide pathways are formed by horizontal transfer/recombination of PKS-encoding DNA, we demonstrate the existence of a broad range of parameters for which collinearity emerges spontaneously. Collinearity confers no fitness advantage in our model; it is established and maintained through a "secondary selection" mechanism, as a trait which increases the probability of forming long, novel PKS complexes through recombination. Consequently, collinearity hitchhikes on the successful genotypes which periodically sweep through the evolving population. In addition to computer simulation of a simplified model of PKS evolution, we provide a mathematical framework describing the secondary selection mechanism, which generalizes beyond the context of the present model. polyketides | horizontal transfer | evolution | collinearity | evolvability

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“…Secondary metabolites, such as toxins, can act as important models for the study of evolutionary processes, as they often consist of a measurable phenotype with known ecological impacts, produced by a specific group of genes (Fischbach et al, 2008). Processes such as gene duplication, selection and lateral transfer have been found to play a role in the evolution of ecologically significant traits in protists and in cyanobacteria (Murray et al, 2011b;Slamovits and Keeling, 2008;Waller et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Gene duplication, loss and selection in the evolution of saxitoxin biosynthesis in alveolates

Murray

Diwan

Orr

et al. 2015

Molecular Phylogenetics and Evolution

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a b s t r a c tA group of marine dinoflagellates (Alveolata, Eukaryota), consisting of $10 species of the genus Alexandrium, Gymnodinium catenatum and Pyrodinium bahamense, produce the toxin saxitoxin and its analogues (STX), which can accumulate in shellfish, leading to ecosystem and human health impacts. The genes, sxt, putatively involved in STX biosynthesis, have recently been identified, however, the evolution of these genes within dinoflagellates is not clear. There are two reasons for this: uncertainty over the phylogeny of dinoflagellates; and that the sxt genes of many species of Alexandrium and other dinoflagellate genera are not known. Here, we determined the phylogeny of STX-producing and other dinoflagellates based on a concatenated eight-gene alignment. We determined the presence, diversity and phylogeny of sxtA, domains A1 and A4 and sxtG in 52 strains of Alexandrium, and a further 43 species of dinoflagellates and thirteen other alveolates. We confirmed the presence and high sequence conservation of sxtA, domain A4, in 40 strains (35 Alexandrium, 1 Pyrodinium, 4 Gymnodinium) of 8 species of STX-producing dinoflagellates, and absence from non-producing species. We found three paralogs of sxtA, domain A1, and a widespread distribution of sxtA1 in non-STX producing dinoflagellates, indicating duplication events in the evolution of this gene. One paralog, clade 2, of sxtA1 may be particularly related to STX biosynthesis. Similarly, sxtG appears to be generally restricted to STX-producing species, while three amidinotransferase gene paralogs were found in dinoflagellates. We investigated the role of positive (diversifying) selection following duplication in sxtA1 and sxtG, and found negative selection in clades of sxtG and sxtA1, clade 2, suggesting they were functionally constrained. Significant episodic diversifying selection was found in some strains in clade 3 of sxtA1, a clade that may not be involved in STX biosynthesis, indicating pressure for diversification of function.

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The evolution of gene collectives: How natural selection drives chemical innovation

Cited by 255 publications

References 113 publications

Evolution of chemical diversity by coordinated gene swaps in type II polyketide gene clusters

Evolution of chemical diversity by coordinated gene swaps in type II polyketide gene clusters

Emergent gene order in a model of modular polyketide synthases

Gene duplication, loss and selection in the evolution of saxitoxin biosynthesis in alveolates

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