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Special Issue Perspective | Host-Microbe Biology

The Who, Why, and How of Small-Molecule Production in Invertebrate Microbiomes: Basic Insights Fueling Drug Discovery

Jason C. Kwan
Jason C. Kwan
aDivision of Pharmaceutical Sciences, School of Pharmacy, University of Wisconsin—Madison, Madison, Wisconsin, USA
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DOI: 10.1128/mSystems.00186-17
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    FIG 1

    Investigating microbiome function with shotgun metagenomics and metatranscriptomics. The effects of different environmental conditions, for example, dysbioses in marine sponges, can be studied through a combination of metagenomics and metatranscriptomics. Individual bacterial genomes can be extracted through metagenomic assembly, followed by binning (who is there and what they can potentially do). Integrating metatranscriptomics with binned genomes allows transcripts to be normalized on a per-genome basis, reducing the effects of genome copy number changes on relative expression quantification. This allows us to determine who is responding to the environmental change and how. DNAseq, DNA sequencing; RNAseq, RNA sequencing.

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    (A) Model for the transition from biosynthetic pathway duplication shortly after establishment of symbiosis to pathway fragmentation frequently observed in older symbionts (18). Early in the symbiosis, selection pressure for increased compound production could lead to pathway duplication. However, loss of DNA repair pathways and facile fixation of mutations due to frequent population bottlenecks give rise to sequence drift and proliferation of pseudogenes. All but lethal mutations accumulate, lowering the gene dosage of each repeated gene in the pathway. Eventually, one copy of each pathway gene will remain because further loss would impact the survival of the host. The remaining copies will not necessarily originate from the same repeat, leaving a single fragmented pathway. (B) Bioactive, and presumably defensive, compounds are produced by symbionts on a continuous spectrum of genome reduction, including the bryostatins (19), mandelalides (15), patellazoles (13), and diaphorin (25). In the early stages of genome reduction, coding density decreases, and at least in the case of “Ca. Didemnitutus mandela,” biosynthetic gene cluster copy number increases. Intergenic sequences are progressively deleted, as more and more functional genes are also degraded and deleted, until symbionts possess dense, tiny genomes. IC50, 50% inhibitory concentration.

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The Who, Why, and How of Small-Molecule Production in Invertebrate Microbiomes: Basic Insights Fueling Drug Discovery
Jason C. Kwan
mSystems Mar 2018, 3 (2) e00186-17; DOI: 10.1128/mSystems.00186-17

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The Who, Why, and How of Small-Molecule Production in Invertebrate Microbiomes: Basic Insights Fueling Drug Discovery
Jason C. Kwan
mSystems Mar 2018, 3 (2) e00186-17; DOI: 10.1128/mSystems.00186-17
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KEYWORDS

genome reduction
metagenomics
metatranscriptomics
natural products/secondary metabolites
symbiosis
synthetic biology

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