Global Genetic Cartography of Urban Metagenomes and Anti-Microbial Resistance, bioRxiv, 2019-08-06

AbstractAlthough studies have shown that urban environments and mass-transit systems have distinct genetic profiles, there are no systematic studies of these dense, humanmicrobial ecosystems around the world. To address this gap in knowledge, we created a global metagenomic and antimicrobial resistance (AMR) atlas of urban mass transit systems from 58 cities, spanning 3,741 samples and 4,424 taxonomically-defined microorganisms collected for from 2015-2017. The map provides annotated, geospatial details about microbial strains, functional genetics, antimicrobial resistance, and novel genetic elements, including 10,928 novel predicted viral species. Urban microbiomes often resemble human commensal microbiomes from the skin and airways, but also contain a consistent “core” of 61 species which are predominantly not human commensal species. Conversely, samples may be accurately (91.4%) classified to their city-of-origin using a linear support vector machine over taxa. These data also show that AMR density across cities varies by several orders of magnitude, including many AMRs present on plasmids with specific cosmopolitan distributions. Together, these results constitute a high-resolution global metagenomic atlas, which enables the discovery of new genetic components of the built human environment, highlights potential forensic applications, and provides an essential first draft of the global AMR burden of the world’s cities.

biorxiv microbiology 100-200-users 2019

Non-antibiotic pharmaceuticals can enhance the spread of antibiotic resistance via conjugation, bioRxiv, 2019-08-06

AbstractAntibiotic resistance is a global threat for public health. It is widely acknowledged that antibiotics at sub-inhibitory concentrations are important in disseminating antibiotic resistance via horizontal gene transfer. While there is high use of non-antibiotic human-targeted pharmaceuticals in our societies, the potential contribution of these on the spread of antibiotic resistance has been overlooked so far. Here, we report that commonly consumed non-antibiotic pharmaceuticals, including nonsteroidal anti-inflammatories (ibuprofen, naproxen, diclofenac), a lipid-lowering drug (gemfibrozil), and a β-blocker (propanolol), at clinically and environmentally relevant concentrations, significantly accelerated the conjugation of plasmid-borne antibiotic resistance genes. We looked at the response to these drugs by the bacteria involved in the gene transfer through various analyses that included monitoring reactive oxygen species (ROS) and cell membrane permeability by flow cytometry, cell arrangement, and whole-genome RNA and protein sequencing. We found the enhanced conjugation correlated well with increased production of ROS and cell membrane permeability. We also detected closer cell-to-cell contact and upregulated conjugal genes. Additionally, these non-antibiotic pharmaceuticals caused the bacteria to have responses similar to those detected when exposed to antibiotics, such as inducing the SOS response, and enhancing efflux pumps. The findings advance our understanding of the bacterial transfer of antibiotic resistance genes, and importantly emphasize concerns of non-antibiotic human-targeted pharmaceuticals for enhancing the spread of antibiotic resistance.

biorxiv microbiology 100-200-users 2019

The Integrator complex terminates promoter-proximal transcription at protein-coding genes, bioRxiv, 2019-08-06

SUMMARYThe transition of RNA polymerase II (Pol II) from initiation to productive elongation is a central, regulated step in metazoan gene expression. At many genes, Pol II pauses stably in early elongation, remaining engaged with the 25-60 nucleotide-long nascent RNA for many minutes while awaiting signals for release into the gene body. However, a number of genes display highly unstable promoter Pol II, suggesting that paused polymerase might dissociate from template DNA at these promoters and release a short, non-productive mRNA. Here, we report that paused Pol II can be actively destabilized by the Integrator complex. Specifically, Integrator utilizes its RNA endonuclease activity to cleave nascent RNA and drive termination of paused Pol II. These findings uncover a previously unappreciated mechanism of metazoan gene repression, akin to bacterial transcription attenuation, wherein promoter-proximal Pol II is prevented from entering productive elongation through factor-regulated termination.Highlights<jatslist list-type=bullet><jatslist-item>The Integrator complex inhibits transcription elongation at ∼15% of mRNA genes<jatslist-item><jatslist-item>Integrator targets promoter-proximally paused Pol II for termination<jatslist-item><jatslist-item>The RNA endonuclease of Integrator subunit 11 is critical for gene attenuation<jatslist-item><jatslist-item>Integrator-repressed genes are enriched in signaling and growth-responsive pathways<jatslist-item>

biorxiv genomics 100-200-users 2019

 

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