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Search Results: 1 - 10 of 179335 matches for " Jonathan E Allen "
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A phylogenetic generalized hidden Markov model for predicting alternatively spliced exons
Jonathan E Allen, Steven L Salzberg
Algorithms for Molecular Biology , 2006, DOI: 10.1186/1748-7188-1-14
Abstract: A non-expression based statistical method is presented to annotate alternatively spliced exons using a single genome sequence and evidence from cross-species sequence conservation. The computational method is implemented in the program ExAlt and an analysis of prediction accuracy is given for Drosophila melanogaster.ExAlt identifies the structure of most alternatively spliced exons in the test set and cross-species sequence conservation is shown to improve the precision of predictions. The software package is available to run on Drosophila genomes to search for new cases of alternative splicing.High-throughput sequencing of expression data provides compelling evidence that the long held hypothesis "one gene produces one protein" is far less common than previously thought. Surveys from the human genome estimate that as many as 70% of human genes produce more than one transcribed form [1]. Examples are found in a variety of metazoan organisms confirming that a significant number of genes produce multiple distinct transcripts [2,3]. Alternative splicing is an important biological mechanism for producing multiple distinct transcripts from a single gene locus. Exon intron junctions are pieced together to produce differing mRNAs. In some cases alternative exon splicing leads to different functional proteins thereby increasing protein diversity. In other cases an alternatively spliced exon leads to non-functional mRNA, effectively regulating gene expression [3].Given an input genomic sequence and the locations of gene regions, our goal is to find the functional exons originating from each gene locus, identifying their respective amino acid codons and splice sites. Figure 1 shows examples of alternatively spliced exons examined in this study: intron retention (IR), cassette exon (CE), and multiple splice sites (MS). Also considered are constitutive exons (CS), defined to be an exon included with the same splice site boundaries in all functional mRNA forms.Gene expression pr
DNA signatures for detecting genetic engineering in bacteria
Jonathan E Allen, Shea N Gardner, Tom R Slezak
Genome Biology , 2008, DOI: 10.1186/gb-2008-9-3-r56
Abstract: Synthetic vector sequences are of fundamental importance in molecular biology. Cloning and expression vectors are among a multitude of synthetic sequence types commonly used as part of a basic tool set for DNA amplification and protein production [1]. As the emerging maturity of synthetic biology research fast approaches [2], it is reasonable to imagine in the not too distant future the broad-scale manufacture of sophisticated synthetic plasmids to modify existing bacteria and possibly the construction of new functioning synthetic genomes [3]. The potential exists to address challenges in many areas, from food production [4] to drug discovery [5]. However, along with the potential benefit comes the increased risk of engineered pathogens [6,7]. Thus, with improvements in genetic manipulation comes the need for tools to detect genetically modified bacteria in the environment.Large-scale computational pipelines have advanced bio-defense by efficiently finding polymerase chain reaction (PCR) assay-based primers that are able to accurately identify dangerous bacterial and viral pathogens [8-10]. The development of random DNA amplification methods have highlighted microarrays as a potentially practical multiplexing complement to PCR [11] with DNA signatures on microarrays [12]. Recent progress has made DNA signature design tools widely available to pathogen research through the development of a publicly available computational pipeline for designing PCR-based signatures [13]. These advances demonstrate the utility of DNA signature pipelines, but the question remains whether such an approach could be used to detect genetically engineered bacteria.A computational analysis was performed on the available synthetic vector sequences, which form an important basis for current tools in genetic engineering [14]. One of the results of this work is a report on the presence of DNA signatures found to differentiate the vector sequences from the sequenced naturally occurring plasmid an
JIGSAW, GeneZilla, and GlimmerHMM: puzzling out the features of human genes in the ENCODE regions
Jonathan E Allen, William H Majoros, Mihaela Pertea, Steven L Salzberg
Genome Biology , 2006, DOI: 10.1186/gb-2006-7-s1-s9
Abstract: Here we describe our general-purpose eukaryotic gene finding pipeline and its major components, as well as the methodological adaptations that we found necessary in accommodating human DNA in our pipeline, noting that a similar level of effort may be necessary by ourselves and others with similar pipelines whenever a new class of genomes is presented to the community for analysis. We also describe a number of controlled experiments involving the differential inclusion of various types of evidence and feature states into our models and the resulting impact these variations have had on predictive accuracy.While in the case of the non-comparative gene finders we found that adding model states to represent specific biological features did little to enhance predictive accuracy, for our evidence-based 'combiner' program the incorporation of additional evidence tracks tended to produce significant gains in accuracy for most evidence types, suggesting that improved modeling efforts at the hidden Markov model level are of relatively little value. We relate these findings to our current plans for future research.Predicting complete protein-coding genes in human DNA remains a significant challenge, as the results of the ENCODE Genome Annotation Assessment Project (EGASP) workshop clearly demonstrate. Although much progress has been made of late in the use of increasingly sophisticated models of gene structure, particularly those that utilize homology evidence within a phylogenetic framework (for example, [1,2]), it is clear that there is yet much room for improvement. In the wake of the most recent spate of advances in gene structure modeling, we additionally observe that the sophistication in modeling techniques has to some degree outstripped our ability to ascribe, with high confidence, specific reasons for the difference in performance between competing gene finding systems, particularly those that utilize similar underlying models and/or forms of evidence, but that differ
Conserved amino acid markers from past influenza pandemic strains
Jonathan E Allen, Shea N Gardner, Elizabeth A Vitalis, Tom R Slezak
BMC Microbiology , 2009, DOI: 10.1186/1471-2180-9-77
Abstract: Thirty-four amino acid markers associated with host specificity and high mortality rate were found. Some markers had little impact on distinguishing the functional classes by themselves, however in combination with other mutations they improved class prediction. Pairwise combinations of influenza genomes were checked for reassortment and mutation events needed to acquire the pandemic conserved markers. Evolutionary pathways involving H1N1 human and swine strains mixed with avian strains show the potential to acquire the pandemic markers with a double reassortment and one or two amino acid mutations.The small mutation combinations found at multiple protein positions associated with viral phenotype indicate that surveillance tools could monitor genetic variation beyond single point mutations to track influenza strains. Finding that certain strain combinations have the potential to acquire pandemic conserved markers through a limited number of reassortment and mutation events illustrates the potential for reassortment and mutation events to lead to new circulating influenza strains.Influenza A has evolved toward host specific mechanisms of infection leading to genetic divergence between human and avian strains. Sequence divergence is so striking that single nucleotide counts are sufficient for classifying the host type for most influenza strains when analyzing whole segment or whole genome data [1]. A notable exception is the H5N1 avian strain that crosses the species barrier and can lead to deadly human infection. The H5 surface protein, hemagglutinin (HA), in some cases is able to recognize human cell receptors [2,3] along with mutations that allow the virus to better survive in the upper respiratory tract [4]. To date, however, there are relatively low numbers of human H5N1 infections compared to the more human persistent subtypes, which may be in part due to inefficient human to human transmission [5,6]. In this study the influenza viruses from the pandemics of 191
Bioavailability of Oil-Based and β-Lactoglobulin-Complexed Vitamin A in a Rat Model
Ying Liu,Ju-Jean Shaw,Harold E. Swaisgood,Jonathan C. Allen
ISRN Nutrition , 2013, DOI: 10.5402/2013/270580
Abstract: β-Lactoglobulin is capable of binding fat-soluble compounds including vitamin A palmitate and is suggested to specifically enhance intestinal uptake of retinol. In this study, bioavailability of a vitamin-A-retinyl palmitate complex in skim milk and in water-based liquids was investigated in vitamin-A-depleted rats. First, rats were fed a vitamin-A-free pellet diet for 6?wk and were thereafter gavage-fed with vitamin A in oil, vitamin-A-β-lactoglobulin complex, vitamin A in oil + skim milk, and vitamin-A-β-lactoglobulin + skim milk for 2?wk and 42?wk. Vitamin A repletion, as judged by vitamin A accumulation in serum and liver, occurred in all the treatments. Vitamin-A-β-lactoglobulin complex treatments had statistical equivalence with oil-based vitamin A treatments. In a second experiment, vitamin-A-depleted rats were fed UHT-processed skim milk fortified with either oil-based or freeze-dried β-lactoglobulin-complexed retinyl palmitate. Liver and serum vitamin A were analyzed by HPLC to indicate vitamin A status in the rats. Results showed no significant difference in bioavailability of retinyl palmitate from milk made with either regular oil-based or β-lactoglobulin-complexed fortifiers. The vitamin-A-β-lactoglobulin complex, being water soluble, may be useful for fortification of nonfat products. 1. Introduction Vitamin A has long been known to be crucial to normal vision and control of differentiation of epithelial cells in the digestive tract, respiratory system, skin, and bone [1]. It is also important in cell replication, growth, and maturation of the nervous and immune systems. Because of the important role of vitamin A, fluid milk products have been fortified with vitamin A (along with vitamin D) since the 1930s to reduce the incidence of disorders caused by vitamin deficiency in the USA. Vitamin A addition to whole milk is optional, but low fat and nonfat milk must be fortified with vitamin A so that each quart contains >2000?IU [2]. Vitamin-A-fortified skim milk is either prepared with oil-based carriers or water-based emulsions. Currently, the acceptable deviation range of vitamin A is 100% to 150% of the FDA-specified concentration [3]. However, nonfat or low-fat milk products often do not comply with nutrition labeling requirements over their entire shelf life. This may be due to analytical methods and loss of vitamin during processing and storage [4, 5]. Furthermore, the degradation of vitamin A generally parallels the oxidative degradation of unsaturated lipids. β-Lactoglobulin is a major whey protein (7 to 12% of skim milk total
Ultra-Deep Sequencing of Intra-host Rabies Virus Populations during Cross-species Transmission
Monica K. Borucki ,Haiyin Chen-Harris,Victoria Lao,Gilda Vanier,Debra A. Wadford,Sharon Messenger,Jonathan E. Allen
PLOS Neglected Tropical Diseases , 2013, DOI: 10.1371/journal.pntd.0002555
Abstract: One of the hurdles to understanding the role of viral quasispecies in RNA virus cross-species transmission (CST) events is the need to analyze a densely sampled outbreak using deep sequencing in order to measure the amount of mutation occurring on a small time scale. In 2009, the California Department of Public Health reported a dramatic increase (350) in the number of gray foxes infected with a rabies virus variant for which striped skunks serve as a reservoir host in Humboldt County. To better understand the evolution of rabies, deep-sequencing was applied to 40 unpassaged rabies virus samples from the Humboldt outbreak. For each sample, approximately 11 kb of the 12 kb genome was amplified and sequenced using the Illumina platform. Average coverage was 17,448 and this allowed characterization of the rabies virus population present in each sample at unprecedented depths. Phylogenetic analysis of the consensus sequence data demonstrated that samples clustered according to date (1995 vs. 2009) and geographic location (northern vs. southern). A single amino acid change in the G protein distinguished a subset of northern foxes from a haplotype present in both foxes and skunks, suggesting this mutation may have played a role in the observed increased transmission among foxes in this region. Deep-sequencing data indicated that many genetic changes associated with the CST event occurred prior to 2009 since several nonsynonymous mutations that were present in the consensus sequences of skunk and fox rabies samples obtained from 20032010 were present at the sub-consensus level (as rare variants in the viral population) in skunk and fox samples from 1995. These results suggest that analysis of rare variants within a viral population may yield clues to ancestral genomes and identify rare variants that have the potential to be selected for if environment conditions change.
The Melanopic Sensitivity Function Accounts for Melanopsin-Driven Responses in Mice under Diverse Lighting Conditions
Timothy M. Brown, Annette E. Allen, Jazi al-Enezi, Jonathan Wynne, Luc Schlangen, Vanja Hommes, Robert J. Lucas
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0053583
Abstract: In addition to rods and cones, photoreception in mammals extends to a third retinal cell type expressing the photopigment melanopsin. The influences of this novel opsin are widespread, ranging from pupillary and circadian responses to brightness perception, yet established approaches to quantifying the biological effects of light do not adequately account for melanopsin sensitivity. We have recently proposed a novel metric, the melanopic sensitivity function (VZλ), to address this deficiency. Here, we further validate this new measure with a variety of tests based on potential barriers to its applicability identified in the literature or relating to obvious practical benefits. Using electrophysiogical approaches and pupillometry, initially in rodless+coneless mice, our data demonstrate that under a very wide range of different conditions (including switching between stimuli with highly divergent spectral content) the VZλ function provides an accurate prediction of the sensitivity of melanopsin-dependent responses. We further show that VZλ provides the best available description of the spectral sensitivity of at least one aspect of the visual response in mice with functional rods and cones: tonic firing activity in the lateral geniculate nuclei. Together, these data establish VZλ as an important new approach for light measurement with widespread practical utility.
The High Resolution X-Ray Imaging Detector Planes for the MIRAX Mission
Barbara H. G. Rodrigues,Jonathan E. Grindlay,Branden Allen,Jaesub Hong,Scott Barthelmy,Joao Braga,Flavio D'Amico,Richard E. Rothschild
Physics , 2013, DOI: 10.1088/1748-0221/8/09/P09010
Abstract: The MIRAX X-ray observatory, the first Brazilian-led astrophysics space mission, is designed to perform an unprecedented wide-field, wide-band hard X-ray (5-200 keV) survey of Galactic X-ray transient sources. In the current configuration, MIRAX will carry a set of four coded-mask telescopes with high spatial resolution Cadmium Zinc Telluride (CZT) detector planes, each one consisting of an array of 64 closely tiled CZT pixelated detectors. Taken together, the four telescopes will have a total detection area of 959 cm^2, a large field of view (60x60 degrees FWHM), high angular resolution for this energy range (6 arcmin) and very good spectral resolution (~2 keV @ 60 keV). A stratospheric balloon-borne prototype of one of the MIRAX telescopes has been developed, tested and flown by the Harvard-Smithsonian Center for Astrophysics (CfA) as part of the ProtoEXIST program. In this paper we show results of validation and calibration tests with individual CZT detectors of the ProtoEXIST second generation experiment (P2). Each one of 64 detector units of the P2 detector plane consists of an ASIC, developed by Caltech for the NuSTAR telescope, hybridized to a CZT crystal with 0.6 mm pixel size. The performance of each detector was evaluated using radioactive sources in the laboratory. The calibration results show that the P2 detectors have average energy resolution of ~2.1 keV @ 60 keV and ~2.3 keV @ 122 keV. P2 was also successfully tested on near-space environment on a balloon flight, demonstrating the detector unit readiness for integration on a space mission telescope, as well as satisfying all MIRAX mission requirements.
The Dictyostelium Kinome—Analysis of the Protein Kinases from a Simple Model Organism
Jonathan M Goldberg equal contributor,Gerard Manning equal contributor,Allen Liu,Petra Fey,Karen E Pilcher,Yanji Xu,Janet L Smith
PLOS Genetics , 2006, DOI: 10.1371/journal.pgen.0020038
Abstract: Dictyostelium discoideum is a widely studied model organism with both unicellular and multicellular forms in its developmental cycle. The Dictyostelium genome encodes 285 predicted protein kinases, similar to the count of the much more advanced Drosophila. It contains members of most kinase classes shared by fungi and metazoans, as well as many previously thought to be metazoan specific, indicating that they have been secondarily lost from the fungal lineage. This includes the entire tyrosine kinase–like (TKL) group, which is expanded in Dictyostelium and includes several novel receptor kinases. Dictyostelium lacks tyrosine kinase group kinases, and most tyrosine phosphorylation appears to be mediated by TKL kinases. About half of Dictyostelium kinases occur in subfamilies not present in yeast or metazoa, suggesting that protein kinases have played key roles in the adaptation of Dictyostelium to its habitat. This study offers insights into kinase evolution and provides a focus for signaling analysis in this system.
Automated eukaryotic gene structure annotation using EVidenceModeler and the Program to Assemble Spliced Alignments
Brian J Haas, Steven L Salzberg, Wei Zhu, Mihaela Pertea, Jonathan E Allen, Joshua Orvis, Owen White, C Robin Buell, Jennifer R Wortman
Genome Biology , 2008, DOI: 10.1186/gb-2008-9-1-r7
Abstract: Accurate and comprehensive gene discovery in eukaryotic genome sequences requires multiple independent and complementary analysis methods including, at the very least, the application of ab initio gene prediction software and sequence alignment tools. The problem is technically challenging, and despite many years of research no single method has yet been able to solve it, although numerous tools have been developed to target specialized and diverse variations on the gene finding problem (for review [1,2]). Conventional gene finding software employs probabilistic techniques such as hidden Markov models (HMMs). These models are employed to find the most likely partitioning of a nucleotide sequence into introns, exons, and intergenic states according to a prior set of probabilities for the states in the model. Such gene finding programs, including GENSCAN [3], GlimmerHMM [4], Fgenesh [5], and GeneMark.hmm [6], are effective at identifying individual exons and regions that correspond to protein-coding genes, but nevertheless they are far from perfect at correctly predicting complete gene structures, differing from correct gene structures in exon content or position [7-10].The correct gene structures, or individual components including introns and exons, are often apparent from spliced alignments of homologous transcript or protein sequences. Many software tools are available that perform these alignment tasks. Tools used to align expressed sequence tags (ESTs) and full-length cDNAs (FL-cDNAs) to genomic sequence include EST_GENOME [11], AAT [12], sim4 [13], geneseqer [14], BLAT [15], and GMAP [16], among numerous others. The list of programs that perform spliced alignments of protein sequences to DNA are much fewer, including the multifunctional AAT, exonerate [17], and PMAP (derived from GMAP). An extension of spliced protein alignment that includes a probabilistic model of eukaryotic gene structure is implemented in GeneWise [18], a popular homology-based gene predict
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