Complex evolutionary dynamics govern the diversity and distribution of biosynthetic gene clusters and their encoded specialized metabolites

ABSTRACTWhile specialized metabolites are thought to mediate ecological interactions, the evolutionary processes driving their distributions, particularly among closely related lineages, remain poorly understood. Here, we examine the evolutionary dynamics governing the diversity and distribution of biosynthetic gene clusters (BGCs) in 118 strains across nine described species within the marine actinomycete genus Salinispora. While previous evidence indicated that horizontal gene transfer largely contributed to BGC diversity, we find that a majority of BGCs in Salinispora genomes are maintained by processes of vertical descent. In particular, we identified species-specific signatures that were associated with both BGC distributions and the production of their encoded specialized metabolites. By analyzing nine experimentally characterized BGCs that range in conservation from species to genus specific, we find that the distribution of BGCs among Salinispora species is maintained by selection, while BGC diversification is constrained by recombination among closely related strains and strengthened by gain/loss events between species. Notably, the evolutionary processes driving BGC diversification had direct consequences for compound production, elucidating the mechanisms that lead to chemical diversification. These results support the concept that specialized metabolites, and their cognate BGCs, represent functional traits associated with ecological differentiation among Salinispora species.GRAPHICAL ABSTRACT

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Vertical Inheritance Facilitates Interspecies Diversification in Biosynthetic Gene Clusters and Specialized Metabolites

mBio ◽

10.1128/mbio.02700-21 ◽

2021 ◽

Author(s):

Alexander B. Chase ◽

Douglas Sweeney ◽

Mitchell N. Muskat ◽

Dulce G. Guillén-Matus ◽

Paul R. Jensen

Keyword(s):

Natural Products ◽

Gene Clusters ◽

Species Level ◽

Biosynthetic Gene ◽

Biosynthetic Gene Clusters ◽

Evolutionary Processes ◽

Vertical Inheritance ◽

Metabolite Production ◽

Specialized Metabolites ◽

Microbial Natural Products

Microbial natural products are traditionally exploited for their pharmaceutical potential, yet our understanding of the evolutionary processes driving BGC evolution and compound diversification remains poorly developed. While HGT is recognized as an integral driver of BGC distributions, we find that the effects of vertical inheritance on BGC diversification had direct implications for species-level specialized metabolite production.

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Transporter genes in biosynthetic gene clusters predict metabolite characteristics and siderophore activity

10.1101/2020.06.24.170084 ◽

2020 ◽

Author(s):

Alexander Crits-Christoph ◽

Nicholas Bhattacharya ◽

Matthew R. Olm ◽

Yun S. Song ◽

Jillian F. Banfield

Keyword(s):

Gut Microbiome ◽

Gene Clusters ◽

Biosynthetic Gene ◽

Biosynthetic Gene Clusters ◽

Gene Frequencies ◽

Specialized Metabolites ◽

Molecular Weights ◽

And Function ◽

Extracellular Environment ◽

Siderophore Activity

AbstractBiosynthetic gene clusters (BGCs) are operonic sets of microbial genes that synthesize specialized metabolites with diverse functions, including siderophores and antibiotics, which often require export to the extracellular environment. For this reason, genes for transport across cellular membranes are essential for the production of specialized metabolites, and are often genomically co-localized with BGCs. Here we conducted a comprehensive computational analysis of transporters associated with characterized BGCs. In addition to known exporters, in BGCs we found many importer-specific transmembrane domains that co-occur with substrate binding proteins possibly for uptake of siderophores or metabolic precursors. Machine learning models using transporter gene frequencies were predictive of known siderophore activity, molecular weights, and a measure of lipophilicity (log P) for corresponding BGC-synthesized metabolites. Transporter genes associated with BGCs were often equally or more predictive of metabolite features than biosynthetic genes. Given the importance of siderophores as pathogenicity factors, we used transporters specific for siderophore BGCs to identify both known and uncharacterized siderophore-like BGCs in genomes from metagenomes from the infant and adult gut microbiome. We find that 23% of microbial genomes from the infant gut have siderophore-like BGCs, but only 3% of those assembled from adult gut microbiomes do. While siderophore-like BGCs from the infant gut are predominantly associated with Enterobactericaee and Staphylococcus, siderophore-like BGCs can be identified from taxa in the adult gut microbiome that have rarely been recognized for siderophore production. Taken together, these results show that consideration of BGC-associated transporter genes can inform predictions of specialized metabolite structure and function.

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Dynamics of the compartmentalized Streptomyces chromosome during metabolic differentiation

Nature Communications ◽

10.1038/s41467-021-25462-1 ◽

2021 ◽

Vol 12 (1) ◽

Cited By ~ 1

Author(s):

Virginia S. Lioy ◽

Jean-Noël Lorenzi ◽

Soumaya Najah ◽

Thibault Poinsignon ◽

Hervé Leh ◽

...

Keyword(s):

Chromosome Structure ◽

Gene Clusters ◽

Structural Features ◽

Biosynthetic Gene ◽

Biosynthetic Gene Clusters ◽

Linear Chromosome ◽

Chromosome Architecture ◽

Specialized Metabolites ◽

Streptomyces Ambofaciens ◽

Core Genes

AbstractBacteria of the genus Streptomyces are prolific producers of specialized metabolites, including antibiotics. The linear chromosome includes a central region harboring core genes, as well as extremities enriched in specialized metabolite biosynthetic gene clusters. Here, we show that chromosome structure in Streptomyces ambofaciens correlates with genetic compartmentalization during exponential phase. Conserved, large and highly transcribed genes form boundaries that segment the central part of the chromosome into domains, whereas the terminal ends tend to be transcriptionally quiescent compartments with different structural features. The onset of metabolic differentiation is accompanied by a rearrangement of chromosome architecture, from a rather ‘open’ to a ‘closed’ conformation, in which highly expressed specialized metabolite biosynthetic genes form new boundaries. Thus, our results indicate that the linear chromosome of S. ambofaciens is partitioned into structurally distinct entities, suggesting a link between chromosome folding, gene expression and genome evolution.

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Formation and diversification of a paradigm biosynthetic gene cluster in plants

Nature Communications ◽

10.1038/s41467-020-19153-6 ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Zhenhua Liu ◽

Jitender Cheema ◽

Marielle Vigouroux ◽

Lionel Hill ◽

James Reed ◽

...

Keyword(s):

Complex Traits ◽

Common Ancestor ◽

Low Frequency ◽

Gene Clusters ◽

Biosynthetic Gene Cluster ◽

Species Level ◽

Biosynthetic Gene ◽

Biosynthetic Gene Clusters ◽

Life And Death ◽

Species Specific

Abstract Numerous examples of biosynthetic gene clusters (BGCs), including for compounds of agricultural and medicinal importance, have now been discovered in plant genomes. However, little is known about how these complex traits are assembled and diversified. Here, we examine a large number of variants within and between species for a paradigm BGC (the thalianol cluster), which has evolved recently in a common ancestor of the Arabidopsis genus. Comparisons at the species level reveal differences in BGC organization and involvement of auxiliary genes, resulting in production of species-specific triterpenes. Within species, the thalianol cluster is primarily fixed, showing a low frequency of deleterious haplotypes. We further identify chromosomal inversion as a molecular mechanism that may shuffle more distant genes into the cluster, so enabling cluster compaction. Antagonistic natural selection pressures are likely involved in shaping the occurrence and maintenance of this BGC. Our work sheds light on the birth, life and death of complex genetic and metabolic traits in plants.

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Sequencing rare marine actinomycete genomes reveals high density of unique natural product biosynthetic gene clusters

Microbiology ◽

10.1099/mic.0.000386 ◽

2016 ◽

Vol 162 (12) ◽

pp. 2075-2086 ◽

Cited By ~ 28

Author(s):

Michelle A. Schorn ◽

Mohammad M. Alanjary ◽

Kristen Aguinaldo ◽

Anton Korobeynikov ◽

Sheila Podell ◽

...

Keyword(s):

Natural Product ◽

Gene Clusters ◽

High Density ◽

Biosynthetic Gene ◽

Biosynthetic Gene Clusters ◽

Marine Actinomycete

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Bagremycin Antibiotics and Ferroverdin iron-chelators are synthetized by the Same Gene Cluster

10.1101/631242 ◽

2019 ◽

Author(s):

Loïc Martinet ◽

Aymeric Naômé ◽

Benoit Deflandre ◽

Marta Maciejewska ◽

Déborah Tellatin ◽

...

Keyword(s):

Environmental Conditions ◽

Biosynthetic Pathway ◽

Gene Clusters ◽

Iron Chelators ◽

Hydroxybenzoic Acid ◽

Iron Availability ◽

Biosynthetic Gene ◽

Single Family ◽

Biosynthetic Gene Clusters ◽

Specialized Metabolites

AbstractBiosynthetic gene clusters (BGCs) are organized groups of genes involved in the production of specialized metabolites. Typically, one BGC is responsible for the production of one or several similar compounds with bioactivities that usually only vary in terms of strength and/or specificity. Here we show that the previously described ferroverdins and bagremycins, which are families of metabolites with different bioactivities, are produced from the same BGC, whereby the fate of the biosynthetic pathway depends on iron availability. Under conditions of iron depletion, the monomeric bagremycins are formed, which are amino-aromatic antibiotics resulting from the condensation of 3-amino-4-hydroxybenzoic acid with p-vinylphenol. Conversely, when iron is abundantly available, the biosynthetic pathway additionally produces a molecule based on p-vinylphenyl-3-nitroso-4-hydroxybenzoate, which complexes iron to form the trimeric ferroverdins that have anticholesterol activity. Thus our work challenges the concept that BGCs should produce a single family of molecules with one type of bioactivity, the occurrence of the different metabolites being triggered by the environmental conditions.

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Phylogenetic analysis of the salinipostin γ-butyrolactone gene cluster uncovers new potential for bacterial signaling-molecule diversity

10.1101/2020.10.16.342204 ◽

2020 ◽

Author(s):

Kaitlin E. Creamer ◽

Yuta Kudo ◽

Bradley S. Moore ◽

Paul R. Jensen

Keyword(s):

Gene Cluster ◽

Species Interactions ◽

Gene Clusters ◽

Biosynthetic Gene Cluster ◽

Signaling Molecules ◽

Biosynthetic Gene ◽

Biosynthetic Gene Clusters ◽

Specialized Metabolism ◽

Bacterial Phyla ◽

Marine Actinomycete

AbstractBacteria communicate by small-molecule chemicals that facilitate intra- and inter-species interactions. These extracellular signaling molecules mediate diverse processes including virulence, bioluminescence, biofilm formation, motility, and specialized metabolism. The signaling molecules produced by members of the phylum Actinobacteria are generally comprised of γ-butyrolactones, γ-butenolides, and furans. The best known actinomycete γ-butyrolactone is A-factor, which triggers specialized metabolism and morphological differentiation in the genus Streptomyces. Salinipostins A-K are unique γ-butyrolactone molecules with rare phosphotriester moieties that were recently characterized from the marine actinomycete genus Salinispora. The production of these compounds has been linked to the 9-gene biosynthetic gene cluster spt. Critical to salinipostin assembly is the γ-butyrolactone synthase encoded by spt9. Here, we report the global distribution of spt9 among sequenced bacterial genomes, revealing a surprising diversity of gene homologs across 12 bacterial phyla, the majority of which are not known to produce γ-butyrolactones. Further analyses uncovered a large group of spt-like gene clusters outside of the genus Salinispora, suggesting the production of new salinipostin-like diversity. These gene clusters show evidence of horizontal transfer between many bacterial taxa and location specific homologous recombination exchange among Salinispora strains. The results suggest that γ-butyrolactone production may be more widespread than previously recognized. The identification of new γ-butyrolactone biosynthetic gene clusters is the first step towards understanding the regulatory roles of the encoded small molecules in Actinobacteria.ImportanceSignaling molecules orchestrate a wide variety of bacterial behaviors. Among Actinobacteria, γ-butyrolactones mediate morphological changes and regulate specialized metabolism. Despite their importance, few γ-butyrolactones have been linked to their cognate biosynthetic gene clusters. A new series of γ-butyrolactones called the salinipostins was recently identified from the marine actinomycete genus Salinispora and linked to the spt biosynthetic gene cluster. Here we report the detection of spt-like gene clusters in diverse bacterial families not known for the production of this class of compounds. This finding expands the taxonomic range of bacteria that may employ this class of compounds and provides opportunities to discover new compounds associated with chemical communication.

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Expansion of gamma-butyrolactone signaling molecule biosynthesis to phosphotriester natural products

10.1101/2020.10.11.335315 ◽

2020 ◽

Cited By ~ 1

Author(s):

Yuta Kudo ◽

Takayoshi Awakawa ◽

Yi-Ling Du ◽

Peter A. Jordan ◽

Kaitlin E. Creamer ◽

...

Keyword(s):

Natural Products ◽

Gene Clusters ◽

Biosynthetic Gene Clusters ◽

Physiological Processes ◽

Marine Actinomycete ◽

Structural Differences ◽

Species Specific ◽

Gamma Butyrolactone

AbstractBacterial hormones, such as the iconic gamma-butyrolactone A-factor, are essential signaling molecules that regulate diverse physiological processes, including specialized metabolism. These low molecular weight compounds are common in Streptomyces species and display species-specific structural differences. Recently, unusual gamma-butyrolactone natural products called salinipostins were isolated from the marine actinomycete genus Salinispora based on their anti-malarial properties. As the salinipostins possess a rare phosphotriester motif of unknown biosynthetic origin, we set out to explore its construction by the widely conserved 9-gene spt operon in Salinispora species. We show through a series of in vivo and in vitro studies that the spt gene cluster dually encodes the saliniphostins and newly identified A-factor-like gamma-butyrolactones (Sal-GBLs). Remarkably, homologous biosynthetic gene clusters are widely distributed amongst many actinomycete genera, including Streptomyces, suggesting the significance of this operon in bacteria.

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Biosynthetic gene clusters and the evolution of fungal chemodiversity

Natural Product Reports ◽

10.1039/c9np00045c ◽

2020 ◽

Vol 37 (7) ◽

pp. 868-878 ◽

Cited By ~ 9

Author(s):

Antonis Rokas ◽

Matthew E. Mead ◽

Jacob L. Steenwyk ◽

Huzefa A. Raja ◽

Nicholas H. Oberlies

Keyword(s):

Gene Cluster ◽

Horizontal Transfer ◽

De Novo ◽

Functional Divergence ◽

Gene Clusters ◽

Biosynthetic Gene Cluster ◽

Biosynthetic Gene ◽

Biosynthetic Gene Clusters ◽

Evolutionary Processes

This highlight synthesizes knowledge of the molecular evolutionary processes – functional divergence, horizontal transfer, and de novo assembly – that govern biosynthetic gene cluster diversification and the generation of chemodiversity in fungi.

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Mining and unearthing hidden biosynthetic potential

Nature Communications ◽

10.1038/s41467-021-24133-5 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Kirstin Scherlach ◽

Christian Hertweck

Keyword(s):

Small Molecules ◽

Genome Mining ◽

Gene Clusters ◽

Ecological Interactions ◽

Biosynthetic Gene ◽

Biosynthetic Gene Clusters ◽

Metabolic Potential ◽

Analytical Tools ◽

Drug Leads ◽

Chemical Mediators

AbstractGenetically encoded small molecules (secondary metabolites) play eminent roles in ecological interactions, as pathogenicity factors and as drug leads. Yet, these chemical mediators often evade detection, and the discovery of novel entities is hampered by low production and high rediscovery rates. These limitations may be addressed by genome mining for biosynthetic gene clusters, thereby unveiling cryptic metabolic potential. The development of sophisticated data mining methods and genetic and analytical tools has enabled the discovery of an impressive array of previously overlooked natural products. This review shows the newest developments in the field, highlighting compound discovery from unconventional sources and microbiomes.

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