Public health officials have raised concerns that plasmid transfer between Enterobacteriaceae species may spread resistance to carbapenems, an antibiotic class of last resort, thereby rendering common healthcare-associated infections nearly impossible to treat. We performed comprehensive surveillance and genomic sequencing to identify carbapenem-resistant Enterobacteriaceae in the NIH Clinical Center patient population and hospital environment in order to to articulate the diversity of carbapenemase-encoding plasmids and survey the mobility of and assess the mobility of these plasmids between bacterial species. We isolated a repertoire of carbapenemase-encoding Enterobacteriaceae, including multiple strains of Klebsiella pneumoniae, Klebsiella oxytoca, Escherichia coli, Enterobacter cloacae, Citrobacter freundii, and Pantoea species. Long-read genome sequencing with full end-to-end assembly revealed that these organisms carry the carbapenem-resistance genes on a wide array of plasmids. Klebsiella pneumoniae and Enterobacter cloacae isolated simultaneously from a single patient harbored two different carbapenemase-encoding plasmids, overriding the epidemiological scenario of plasmid transfer between organisms within this patient. We did, however, find evidence supporting horizontal transfer of carbapenemase-encoding plasmids between Klebsiella pneumoniae, Enterobacter cloacae and Citrobacter freundii in the hospital environment. Our comprehensive sequence data, with full plasmid identification, challenges assumptions about horizontal gene transfer events within patients and identified wider possible connections between patients and the hospital environment. In addition, we identified a new carbapenemase-encoding plasmid of potentially high clinical impact carried by Klebsiella pneumoniae, Escherichia coli, Enterobacter cloacae and Pantoea species, from unrelated patients and the hospital environment.
Substitution of specific terminal subunits within septin complexes and septin phosphorylation drive the formation of distinct higher-order septin assemblies in budding yeast.
Genetic mapping of complex diseases to date depends on variations inside or close to the genes that perturb their activities. A strong body of evidence suggests that changes in gene expression play a key role in complex diseases and that numerous loci perturb gene expression in trans. The information in trans variants, however, has largely been ignored in the current analysis paradigm. Here we present a statistical framework for genetic mapping by utilizing collective information in both cis and trans variants. We reason that for a disease-associated gene, any genetic variation that perturbs its expression is also likely to influence the disease risk. Thus, the expression quantitative trait loci (eQTL) of the gene, which constitute a unique "genetic signature," should overlap significantly with the set of loci associated with the disease. We translate this idea into a computational algorithm (named Sherlock) to search for gene-disease associations from GWASs, taking advantage of independent eQTL data. Application of this strategy to Crohn disease and type 2 diabetes predicts a number of genes with possible disease roles, including several predictions supported by solid experimental evidence. Importantly, predicted genes are often implicated by multiple trans eQTL with moderate associations. These genes are far from any GWAS association signals and thus cannot be identified from the GWAS alone. Our approach allows analysis of association data from a new perspective and is applicable to any complex phenotype. It is readily generalizable to molecular traits other than gene expression, such as metabolites, noncoding RNAs, and epigenetic modifications.
Bacterial phosphorothioate (PT) DNA modifications are incorporated by Dnd proteins A-E and often function with DndF-H as a restriction-modification (R-M) system, as in Escherichia coli B7A. However, bacteria such as Vibrio cyclitrophicus FF75 lack dndF-H, which points to other PT functions. To better understand PT biology, we report two novel, orthogonal technologies to map PTs across the genomes of B7A and FF75 with >90% agreement: real-time (SMRT) sequencing and deep sequencing of iodine-induced cleavage at PT (ICDS). In B7A, we detect PT on both strands of GpsAAC/GpsTTC motifs, but with only 18% of 40,701 possible sites modified. In contrast, PT in FF75 occurs as a single-strand modification at CpsCA, again with only 14% of 160,541 sites modified. Single-molecule analysis indicates that modification could be partial at any particular genomic site even with active restriction by DndF-H, with direct interaction of modification proteins with GAAC/GTTC sites demonstrated with oligonucleotides. These results point to highly unusual target selection by PT modification proteins and rule out known R-M mechanisms.
Sequences of the internal transcribed spacers (ITS) of nuclear ribosomal DNA were acquired for 112 species of Balsaminaceae worldwide and five species of its closest relatives Marcgraviaceae and Tetrameristaceae. Phylogenetic analyses applying parsimony and distance estimates confirmed the monophyly of Balsaminaceae and suggest the monophyly of Impatiens. Within Impatiens, a few clades are recognized with strong support. Two of the most important clades are the spurless Madagascan endemic group, and the one comprising species with broadly fusiform fruits and the basic chromosome number x = 8, that shows a Southeast Asia, southern India, Africa, and Madagascar connection. Despite recognition of several strongly supported small lineages, ITS data alone could not resolve relationships among most of the lineages with confident support values. ITS phylogenies are therefore of limited taxonomic value for Impatiens. However, ITS phylogenies do reveal that extant Impatiens species are of Southeast Asian origin, from where dispersals to boreal Eurasia and North America, to central Asia and eastern Europe via the Himalayas, and to India and Africa have occurred. The Madagascan Impatiens show an African origin. Molecular phylogenies suggest the ancestral basic chromosome number to be x = 10, and the spurred flowers and elongated linear fruits to be plesiomorphic states in Impatiens. A predominantly descending dysploid chromosome evolution, following dispersal of the clade with broadly fusiform fruits from Southeast Asia to India, Africa, and Madagascar, is also suggested.
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