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  • Journals
  • Articles  (6,595)
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  • Oxford University Press  (6,595)
  • American Chemical Society
  • American Chemical Society (ACS)
  • Frontiers Media
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  • 1
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    Gene Loss Dominates As a Source of Genetic Variation within Clonal Pathogenic Bacterial Species (2015)
    Oxford University Press
    Details
    Publication Date: 2015-08-12
    Description: Some of the most dangerous pathogens such as Mycobacterium tuberculosis and Yersinia pestis evolve clonally . This means that little or no recombination occurs between strains belonging to these species. Paradoxically, although different members of these species show extreme sequence similarity of orthologous genes, some show considerable intraspecies phenotypic variation, the source of which remains elusive. To examine the possible sources of phenotypic variation within clonal pathogenic bacterial species, we carried out an extensive genomic and pan-genomic analysis of the sources of genetic variation available to a large collection of clonal and nonclonal pathogenic bacterial species. We show that while nonclonal species diversify through a combination of changes to gene sequences, gene loss and gene gain, gene loss completely dominates as a source of genetic variation within clonal species. Indeed, gene loss is so prevalent within clonal species as to lead to levels of gene content variation comparable to those found in some nonclonal species that are much more diverged in their gene sequences and that acquire a substantial number of genes horizontally. Gene loss therefore needs to be taken into account as a potential dominant source of phenotypic variation within clonal bacterial species.
    Electronic ISSN: 1759-6653
    Topics: Biology
    Published by Oxford University Press
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  • 2
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    Draft Genomes, Phylogenetic Reconstruction, and Comparative Genomics of Two Novel Cohabiting Bacterial Symbionts Isolated from Frankliniella occidentalis (2015)
    Oxford University Press
    Details
    Publication Date: 2015-08-12
    Description: Obligate bacterial symbionts are widespread in many invertebrates, where they are often confined to specialized host cells and are transmitted directly from mother to progeny. Increasing numbers of these bacteria are being characterized but questions remain about their population structure and evolution. Here we take a comparative genomics approach to investigate two prominent bacterial symbionts (BFo1 and BFo2) isolated from geographically separated populations of western flower thrips, Frankliniella occidentalis. Our multifaceted approach to classifying these symbionts includes concatenated multilocus sequence analysis (MLSA) phylogenies, ribosomal multilocus sequence typing (rMLST), construction of whole-genome phylogenies, and in-depth genomic comparisons. We showed that the BFo1 genome clusters more closely to species in the genus Erwinia, and is a putative close relative to Erwinia aphidicola . BFo1 is also likely to have shared a common ancestor with Erwinia pyrifoliae/Erwinia amylovora and the nonpathogenic Erwinia tasmaniensis and genetic traits similar to Erwinia billingiae . The BFo1 genome contained virulence factors found in the genus Erwinia but represented a divergent lineage. In contrast, we showed that BFo2 belongs within the Enterobacteriales but does not group closely with any currently known bacterial species. Concatenated MLSA phylogenies indicate that it may have shared a common ancestor to the Erwinia and Pantoea genera, and based on the clustering of rMLST genes, it was most closely related to Pantoea ananatis but represented a divergent lineage. We reconstructed a core genome of a putative common ancestor of Erwinia and Pantoea and compared this with the genomes of BFo bacteria. BFo2 possessed none of the virulence determinants that were omnipresent in the Erwinia and Pantoea genera. Taken together, these data are consistent with BFo2 representing a highly novel species that maybe related to known Pantoea .
    Electronic ISSN: 1759-6653
    Topics: Biology
    Published by Oxford University Press
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  • 3
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    Gains and Losses of Transcription Factor Binding Sites in Saccharomyces cerevisiae and Saccharomyces paradoxus (2015)
    Oxford University Press
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    Publication Date: 2015-08-16
    Description: Gene expression evolution occurs through changes in cis - or trans -regulatory elements or both. Interactions between transcription factors (TFs) and their binding sites (TFBSs) constitute one of the most important points where these two regulatory components intersect. In this study, we investigated the evolution of TFBSs in the promoter regions of different Saccharomyces strains and species. We divided the promoter of a gene into the proximal region and the distal region, which are defined, respectively, as the 200-bp region upstream of the transcription starting site and as the 200-bp region upstream of the proximal region. We found that the predicted TFBSs in the proximal promoter regions tend to be evolutionarily more conserved than those in the distal promoter regions. Additionally, Saccharomyces cerevisiae strains used in the fermentation of alcoholic drinks have experienced more TFBS losses than gains compared with strains from other environments (wild strains, laboratory strains, and clinical strains). We also showed that differences in TFBSs correlate with the cis component of gene expression evolution between species (comparing S. cerevisiae and its sister species Saccharomyces paradoxus ) and within species (comparing two closely related S. cerevisiae strains).
    Electronic ISSN: 1759-6653
    Topics: Biology
    Published by Oxford University Press
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  • 4
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    A Genome-Wide Landscape of Retrocopies in Primate Genomes (2015)
    Oxford University Press
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    Publication Date: 2015-08-16
    Description: Gene duplication is a key factor contributing to phenotype diversity across and within species. Although the availability of complete genomes has led to the extensive study of genomic duplications, the dynamics and variability of gene duplications mediated by retrotransposition are not well understood. Here, we predict mRNA retrotransposition and use comparative genomics to investigate their origin and variability across primates. Analyzing seven anthropoid primate genomes, we found a similar number of mRNA retrotranspositions (~7,500 retrocopies) in Catarrhini (Old Word Monkeys, including humans), but a surprising large number of retrocopies (~10,000) in Platyrrhini (New World Monkeys), which may be a by-product of higher long interspersed nuclear element 1 activity in these genomes. By inferring retrocopy orthology, we dated most of the primate retrocopy origins, and estimated a decrease in the fixation rate in recent primate history, implying a smaller number of species-specific retrocopies. Moreover, using RNA-Seq data, we identified approximately 3,600 expressed retrocopies. As expected, most of these retrocopies are located near or within known genes, present tissue-specific and even species-specific expression patterns, and no expression correlation to their parental genes. Taken together, our results provide further evidence that mRNA retrotransposition is an active mechanism in primate evolution and suggest that retrocopies may not only introduce great genetic variability between lineages but also create a large reservoir of potentially functional new genomic loci in primate genomes.
    Electronic ISSN: 1759-6653
    Topics: Biology
    Published by Oxford University Press
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  • 5
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    Cancer, Warts, or Asymptomatic Infections: Clinical Presentation Matches Codon Usage Preferences in Human Papillomaviruses (2015)
    Oxford University Press
    Details
    Publication Date: 2015-08-06
    Description: Viruses rely completely on the hosts’ machinery for translation of viral transcripts. However, for most viruses infecting humans, codon usage preferences (CUPrefs) do not match those of the host. Human papillomaviruses (HPVs) are a showcase to tackle this paradox: they present a large genotypic diversity and a broad range of phenotypic presentations, from asymptomatic infections to productive lesions and cancer. By applying phylogenetic inference and dimensionality reduction methods, we demonstrate first that genes in HPVs are poorly adapted to the average human CUPrefs, the only exception being capsid genes in viruses causing productive lesions. Phylogenetic relationships between HPVs explained only a small proportion of CUPrefs variation. Instead, the most important explanatory factor for viral CUPrefs was infection phenotype, as orthologous genes in viruses with similar clinical presentation displayed similar CUPrefs. Moreover, viral genes with similar spatiotemporal expression patterns also showed similar CUPrefs. Our results suggest that CUPrefs in HPVs reflect either variations in the mutation bias or differential selection pressures depending on the clinical presentation and expression timing. We propose that poor viral CUPrefs may be central to a trade-off between strong viral gene expression and the potential for eliciting protective immune response.
    Electronic ISSN: 1759-6653
    Topics: Biology
    Published by Oxford University Press
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  • 6
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    Tree-based methods for individualized treatment regimes (2015)
    Oxford University Press
    Details
    Publication Date: 2015-08-21
    Description: Individualized treatment rules recommend treatments on the basis of individual patient characteristics. A high-quality treatment rule can produce better patient outcomes, lower costs and less treatment burden. If a treatment rule learned from data is to be used to inform clinical practice or provide scientific insight, it is crucial that it be interpretable; clinicians may be unwilling to implement models they do not understand, and black-box models may not be useful for guiding future research. The canonical example of an interpretable prediction model is a decision tree. We propose a method for estimating an optimal individualized treatment rule within the class of rules that are representable as decision trees. The class of rules we consider is interpretable but expressive. A novel feature of this problem is that the learning task is unsupervised, as the optimal treatment for each patient is unknown and must be estimated. The proposed method applies to both categorical and continuous treatments and produces favourable marginal mean outcomes in simulation experiments. We illustrate it using data from a study of major depressive disorder.
    Print ISSN: 0006-3444
    Electronic ISSN: 1464-3510
    Topics: Biology , Mathematics , Medicine
    Published by Oxford University Press
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  • 7
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    Diagnostic studies in sufficient dimension reduction (2015)
    Oxford University Press
    Details
    Publication Date: 2015-08-21
    Description: Sufficient dimension reduction in regression aims to reduce the predictor dimension by replacing the original predictors with some set of linear combinations of them without loss of information. Numerous dimension reduction methods have been developed based on this paradigm. However, little effort has been devoted to diagnostic studies within the context of dimension reduction. In this paper we introduce methods to check goodness-of-fit for a given dimension reduction subspace. The key idea is to extend the so-called distance correlation to measure the conditional dependence relationship between the covariates and the response given a reduction subspace. Our methods require minimal assumptions, which are usually much less restrictive than the conditions needed to justify the original methods. Asymptotic properties of the test statistic are studied. Numerical examples demonstrate the effectiveness of the proposed approach.
    Print ISSN: 0006-3444
    Electronic ISSN: 1464-3510
    Topics: Biology , Mathematics , Medicine
    Published by Oxford University Press
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  • 8
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    Bayesian sensitivity analysis with the Fisher-Rao metric (2015)
    Oxford University Press
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    Publication Date: 2015-08-21
    Description: We propose a geometric framework to assess sensitivity of Bayesian procedures to modelling assumptions based on the nonparametric Fisher–Rao metric. While the framework is general, the focus of this article is on assessing local and global robustness in Bayesian procedures with respect to perturbations of the likelihood and prior, and on the identification of influential observations. The approach is based on a square-root representation of densities, which enables analytical computation of geodesic paths and distances, facilitating the definition of naturally calibrated local and global discrepancy measures. An important feature of our approach is the definition of a geometric $\epsilon$ -contamination class of sampling distributions and priors via intrinsic analysis on the space of probability density functions. We demonstrate the applicability of our framework to generalized mixed-effects models and to directional and shape data.
    Print ISSN: 0006-3444
    Electronic ISSN: 1464-3510
    Topics: Biology , Mathematics , Medicine
    Published by Oxford University Press
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  • 9
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    Efficient estimation of nonparametric genetic risk function with censored data (2015)
    Oxford University Press
    Details
    Publication Date: 2015-08-21
    Description: With the discovery of an increasing number of causal genes for complex human disorders, it is crucial to assess the genetic risk of disease onset for individuals who are carriers of these causal mutations and to compare the distribution of the age-at-onset for such individuals with the distribution for noncarriers. In many genetic epidemiological studies that aim to estimate causal gene effect on disease, the age-at-onset of disease is subject to censoring. In addition, the mutation carrier or noncarrier status of some individuals may be unknown, due to the high cost of in-person ascertainment by collecting DNA samples or because of the death of older individuals. Instead, the probability of such individuals’ mutation status can be obtained from various other sources. When mutation status is missing, the available data take the form of censored mixture data. Recently, various methods have been proposed for risk estimation using such data, but none is efficient for estimating a nonparametric distribution. We propose a fully efficient sieve maximum likelihood estimation method, in which we estimate the logarithm of the hazard ratio between genetic mutation groups using B-splines, while applying nonparametric maximum likelihood estimation to the reference baseline hazard function. Our estimator can be calculated via an expectation-maximization algorithm which is much faster than existing methods. We show that our estimator is consistent and semiparametrically efficient and establish its asymptotic distribution. Simulation studies demonstrate the superior performance of the proposed method, which is used to estimate the distribution of the age-at-onset of Parkinson's disease for carriers of mutations in the leucine-rich repeat kinase 2, LRRK2, gene.
    Print ISSN: 0006-3444
    Electronic ISSN: 1464-3510
    Topics: Biology , Mathematics , Medicine
    Published by Oxford University Press
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  • 10
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    Efficient computation of smoothing splines via adaptive basis sampling (2015)
    Oxford University Press
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    Publication Date: 2015-08-21
    Description: Smoothing splines provide flexible nonparametric regression estimators. However, the high computational cost of smoothing splines for large datasets has hindered their wide application. In this article, we develop a new method, named adaptive basis sampling, for efficient computation of smoothing splines in super-large samples. Except for the univariate case where the Reinsch algorithm is applicable, a smoothing spline for a regression problem with sample size n can be expressed as a linear combination of n basis functions and its computational complexity is generally O ( n 3 ). We achieve a more scalable computation in the multivariate case by evaluating the smoothing spline using a smaller set of basis functions, obtained by an adaptive sampling scheme that uses values of the response variable. Our asymptotic analysis shows that smoothing splines computed via adaptive basis sampling converge to the true function at the same rate as full basis smoothing splines. Using simulation studies and a large-scale deep earth core-mantle boundary imaging study, we show that the proposed method outperforms a sampling method that does not use the values of response variables.
    Print ISSN: 0006-3444
    Electronic ISSN: 1464-3510
    Topics: Biology , Mathematics , Medicine
    Published by Oxford University Press
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