Publications by authors named "Ryan C Kennedy"

16 Publications

  • Page 1 of 1

Contrasting model mechanisms of alanine aminotransferase (ALT) release from damaged and necrotic hepatocytes as an example of general biomarker mechanisms.

PLoS Comput Biol 2020 06 2;16(6):e1007622. Epub 2020 Jun 2.

Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California, United States of America.

Interpretations of elevated blood levels of alanine aminotransferase (ALT) for drug-induced liver injury often assume that the biomarker is released passively from dying cells. However, the mechanisms driving that release have not been explored experimentally. The usefulness of ALT and related biomarkers will improve by developing mechanism-based explanations of elevated levels that can be expanded and elaborated incrementally. We provide the means to challenge the ability of closely related model mechanisms to generate patterns of simulated hepatic injury and ALT release that scale (or not) to be quantitatively similar to the wet-lab validation targets, which are elevated plasma ALT values following acetaminophen (APAP) exposure in mice. We build on a published model mechanism that helps explain the generation of characteristic spatiotemporal features of APAP hepatotoxicity within hepatic lobules. Discrete event and agent-oriented software methods are most prominent. We instantiate and leverage a small constellation of concrete model mechanisms. Their details during execution help bring into focus ways in which particular sources of uncertainty become entangled with cause-effect details within and across several levels. We scale ALT amounts in virtual mice directly to target plasma ALT values in individual mice. A virtual experiment comprises a set of Monte Carlo simulations. We challenge the sufficiency of four potentially explanatory theories for ALT release. The first of the tested model theories failed to achieve the initial validation target, but each of the three others succeeded. Results for one of the three model mechanisms matched all target ALT values quantitatively. It explains how ALT externalization is the combined consequence of lobular-location-dependent drug-induced cellular damage and hepatocyte death. Falsification of one (or more) of the model mechanisms provides new knowledge and incrementally shrinks the constellation of model mechanisms. The modularity and biomimicry of our explanatory models enable seamless transition from mice to humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pcbi.1007622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292418PMC
June 2020

Propagation of Pericentral Necrosis During Acetaminophen-Induced Liver Injury: Evidence for Early Interhepatocyte Communication and Information Exchange.

Toxicol Sci 2019 05;169(1):151-166

Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California.

Acetaminophen (APAP)-induced liver injury is clinically significant, and APAP overdose in mice often serves as a model for drug-induced liver injury in humans. By specifying that APAP metabolism, reactive metabolite formation, glutathione depletion, and mitigation of mitochondrial damage within individual hepatocytes are functions of intralobular location, an earlier virtual model mechanism provided the first concrete multiattribute explanation for how and why early necrosis occurs close to the central vein (CV). However, two characteristic features could not be simulated consistently: necrosis occurring first adjacent to the CV, and subsequent necrosis occurring primarily adjacent to hepatocytes that have already initiated necrosis. We sought parsimonious model mechanism enhancements that would manage spatiotemporal heterogeneity sufficiently to enable meeting two new target attributes and conducted virtual experiments to explore different ideas for model mechanism improvement at intrahepatocyte and multihepatocyte levels. For the latter, evidence supports intercellular communication via exosomes, gap junctions, and connexin hemichannels playing essential roles in the toxic effects of chemicals, including facilitating or counteracting cell death processes. Logic requiring hepatocytes to obtain current information about whether downstream and lateral neighbors have triggered necrosis enabled virtual hepatocytes to achieve both new target attributes. A virtual hepatocyte that is glutathione-depleted uses that information to determine if it will initiate necrosis. When a less-stressed hepatocyte is flanked by at least two neighbors that have triggered necrosis, it too will initiate necrosis. We hypothesize that the resulting intercellular communication-enabled model mechanism is analogous to the actual explanation for APAP-induced hepatotoxicity at comparable levels of granularity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/toxsci/kfz029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6484890PMC
May 2019

Simulation enabled search for explanatory mechanisms of the fracture healing process.

PLoS Comput Biol 2018 02 2;14(2):e1005980. Epub 2018 Feb 2.

Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California, United States of America.

A significant portion of bone fractures fail to heal properly, increasing healthcare costs. Advances in fracture management have slowed because translation barriers have limited generation of mechanism-based explanations for the healing process. When uncertainties are numerous, analogical modeling can be an effective strategy for developing plausible explanations of complex phenomena. We demonstrate the feasibility of engineering analogical models in software to facilitate discovery of biomimetic explanations for how fracture healing may progress. Concrete analogical models-Callus Analogs-were created using the MASON simulation toolkit. We designated a Target Region initial state within a characteristic tissue section of mouse tibia fracture at day-7 and posited a corresponding day-10 Target Region final state. The goal was to discover a coarse-grain analog mechanism that would enable the discretized initial state to transform itself into the corresponding Target Region final state, thereby providing an alternative way to study the healing process. One of nine quasi-autonomous Tissue Unit types is assigned to each grid space, which maps to an 80×80 μm region of the tissue section. All Tissue Units have an opportunity each time step to act based on individualized logic, probabilities, and information about adjacent neighbors. Action causes transition from one Tissue Unit type to another, and simulation through several thousand time steps generates a coarse-grain analog-a theory-of the healing process. We prespecified a minimum measure of success: simulated and actual Target Region states achieve ≥ 70% Similarity. We used an iterative refinement protocol to explore many combinations of Tissue Unit logic and action constraints. Workflows progressed through four stages of analog mechanisms. Similarities of 73-90% were achieved for Mechanisms 2-4. The range of Upper-Level similarities increased to 83-94% when we allowed for uncertainty about two Tissue Unit designations. We have demonstrated how Callus Analog experiments provide domain experts with a fresh medium and tools for thinking about and understanding the fracture healing process.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pcbi.1005980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5812655PMC
February 2018

Competing Mechanistic Hypotheses of Acetaminophen-Induced Hepatotoxicity Challenged by Virtual Experiments.

PLoS Comput Biol 2016 12 16;12(12):e1005253. Epub 2016 Dec 16.

Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, United States of America.

Acetaminophen-induced liver injury in mice is a model for drug-induced liver injury in humans. A precondition for improved strategies to disrupt and/or reverse the damage is a credible explanatory mechanism for how toxicity phenomena emerge and converge to cause hepatic necrosis. The Target Phenomenon in mice is that necrosis begins adjacent to the lobule's central vein (CV) and progresses outward. An explanatory mechanism remains elusive. Evidence supports that location dependent differences in NAPQI (the reactive metabolite) formation within hepatic lobules (NAPQI zonation) are necessary and sufficient prerequisites to account for that phenomenon. We call that the NZ-mechanism hypothesis. Challenging that hypothesis in mice is infeasible because 1) influential variables cannot be controlled, and 2) it would require sequential intracellular measurements at different lobular locations within the same mouse. Virtual hepatocytes use independently configured periportal-to-CV gradients to exhibit lobule-location dependent behaviors. Employing NZ-mechanism achieved quantitative validation targets for acetaminophen clearance and metabolism but failed to achieve the Target Phenomenon. We posited that, in order to do so, at least one additional feature must exhibit zonation by decreasing in the CV direction. We instantiated and explored two alternatives: 1) a glutathione depletion threshold diminishes in the CV direction; and 2) ability to repair mitochondrial damage diminishes in the CV direction. Inclusion of one or the other feature into NZ-mechanism failed to achieve the Target Phenomenon. However, inclusion of both features enabled successfully achieving the Target Phenomenon. The merged mechanism provides a multilevel, multiscale causal explanation of key temporal features of acetaminophen hepatotoxicity in mice. We discovered that variants of the merged mechanism provide plausible quantitative explanations for the considerable variation in 24-hour necrosis scores among 37 genetically diverse mouse strains following a single toxic acetaminophen dose.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pcbi.1005253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161305PMC
December 2016

Genomic insights into the Ixodes scapularis tick vector of Lyme disease.

Authors:
Monika Gulia-Nuss Andrew B Nuss Jason M Meyer Daniel E Sonenshine R Michael Roe Robert M Waterhouse David B Sattelle José de la Fuente Jose M Ribeiro Karine Megy Jyothi Thimmapuram Jason R Miller Brian P Walenz Sergey Koren Jessica B Hostetler Mathangi Thiagarajan Vinita S Joardar Linda I Hannick Shelby Bidwell Martin P Hammond Sarah Young Qiandong Zeng Jenica L Abrudan Francisca C Almeida Nieves Ayllón Ketaki Bhide Brooke W Bissinger Elena Bonzon-Kulichenko Steven D Buckingham Daniel R Caffrey Melissa J Caimano Vincent Croset Timothy Driscoll Don Gilbert Joseph J Gillespie Gloria I Giraldo-Calderón Jeffrey M Grabowski David Jiang Sayed M S Khalil Donghun Kim Katherine M Kocan Juraj Koči Richard J Kuhn Timothy J Kurtti Kristin Lees Emma G Lang Ryan C Kennedy Hyeogsun Kwon Rushika Perera Yumin Qi Justin D Radolf Joyce M Sakamoto Alejandro Sánchez-Gracia Maiara S Severo Neal Silverman Ladislav Šimo Marta Tojo Cristian Tornador Janice P Van Zee Jesús Vázquez Filipe G Vieira Margarita Villar Adam R Wespiser Yunlong Yang Jiwei Zhu Peter Arensburger Patricia V Pietrantonio Stephen C Barker Renfu Shao Evgeny M Zdobnov Frank Hauser Cornelis J P Grimmelikhuijzen Yoonseong Park Julio Rozas Richard Benton Joao H F Pedra David R Nelson Maria F Unger Jose M C Tubio Zhijian Tu Hugh M Robertson Martin Shumway Granger Sutton Jennifer R Wortman Daniel Lawson Stephen K Wikel Vishvanath M Nene Claire M Fraser Frank H Collins Bruce Birren Karen E Nelson Elisabet Caler Catherine A Hill

Nat Commun 2016 Feb 9;7:10507. Epub 2016 Feb 9.

Department of Entomology, Purdue University, West Lafayette, Indiana 47907, USA.

Ticks transmit more pathogens to humans and animals than any other arthropod. We describe the 2.1 Gbp nuclear genome of the tick, Ixodes scapularis (Say), which vectors pathogens that cause Lyme disease, human granulocytic anaplasmosis, babesiosis and other diseases. The large genome reflects accumulation of repetitive DNA, new lineages of retro-transposons, and gene architecture patterns resembling ancient metazoans rather than pancrustaceans. Annotation of scaffolds representing ∼57% of the genome, reveals 20,486 protein-coding genes and expansions of gene families associated with tick-host interactions. We report insights from genome analyses into parasitic processes unique to ticks, including host 'questing', prolonged feeding, cuticle synthesis, blood meal concentration, novel methods of haemoglobin digestion, haem detoxification, vitellogenesis and prolonged off-host survival. We identify proteins associated with the agent of human granulocytic anaplasmosis, an emerging disease, and the encephalitis-causing Langat virus, and a population structure correlated to life-history traits and transmission of the Lyme disease agent.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncomms10507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4748124PMC
February 2016

A cell-centered, agent-based framework that enables flexible environment granularities.

Theor Biol Med Model 2016 Feb 2;13. Epub 2016 Feb 2.

Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA.

Background: Mechanistic explanations of cell-level phenomena typically adopt an observer perspective. Explanations developed from a cell's perspective may offer new insights. Agent-based models lend themselves to model from an individual perspective, and existing agent-based models generally utilize a regular lattice-based environment. A framework which utilizes a cell's perspective in an off-lattice environment could improve the overall understanding of biological phenomena.

Results: We present an agent-based, discrete event framework, with a demonstrative focus on biomimetic agents. The framework was first developed in 2-dimensions and then extended, with a subset of behaviors, to 3-dimensions. The framework is expected to facilitate studies of more complex biological phenomena through exploitation of a dynamic Delaunay and Voronoi off-lattice environment. We used the framework to model biological cells and to specifically demonstrate basic biological cell behaviors in two- and three-dimensional space. Potential use cases are highlighted, suggesting the utility of the framework in various scenarios.

Conclusions: The framework presented in this manuscript expands on existing cell- and agent-centered methods by offering a new perspective in an off-lattice environment. As the demand for biomimetic models grows, the demand for new methods, such as the presented Delaunay and Voronoi framework, is expected to increase.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12976-016-0030-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4736144PMC
February 2016

Mosquito genomics. Highly evolvable malaria vectors: the genomes of 16 Anopheles mosquitoes.

Authors:
Daniel E Neafsey Robert M Waterhouse Mohammad R Abai Sergey S Aganezov Max A Alekseyev James E Allen James Amon Bruno Arcà Peter Arensburger Gleb Artemov Lauren A Assour Hamidreza Basseri Aaron Berlin Bruce W Birren Stephanie A Blandin Andrew I Brockman Thomas R Burkot Austin Burt Clara S Chan Cedric Chauve Joanna C Chiu Mikkel Christensen Carlo Costantini Victoria L M Davidson Elena Deligianni Tania Dottorini Vicky Dritsou Stacey B Gabriel Wamdaogo M Guelbeogo Andrew B Hall Mira V Han Thaung Hlaing Daniel S T Hughes Adam M Jenkins Xiaofang Jiang Irwin Jungreis Evdoxia G Kakani Maryam Kamali Petri Kemppainen Ryan C Kennedy Ioannis K Kirmitzoglou Lizette L Koekemoer Njoroge Laban Nicholas Langridge Mara K N Lawniczak Manolis Lirakis Neil F Lobo Ernesto Lowy Robert M MacCallum Chunhong Mao Gareth Maslen Charles Mbogo Jenny McCarthy Kristin Michel Sara N Mitchell Wendy Moore Katherine A Murphy Anastasia N Naumenko Tony Nolan Eva M Novoa Samantha O'Loughlin Chioma Oringanje Mohammad A Oshaghi Nazzy Pakpour Philippos A Papathanos Ashley N Peery Michael Povelones Anil Prakash David P Price Ashok Rajaraman Lisa J Reimer David C Rinker Antonis Rokas Tanya L Russell N'Fale Sagnon Maria V Sharakhova Terrance Shea Felipe A Simão Frederic Simard Michel A Slotman Pradya Somboon Vladimir Stegniy Claudio J Struchiner Gregg W C Thomas Marta Tojo Pantelis Topalis José M C Tubio Maria F Unger John Vontas Catherine Walton Craig S Wilding Judith H Willis Yi-Chieh Wu Guiyun Yan Evgeny M Zdobnov Xiaofan Zhou Flaminia Catteruccia George K Christophides Frank H Collins Robert S Cornman Andrea Crisanti Martin J Donnelly Scott J Emrich Michael C Fontaine William Gelbart Matthew W Hahn Immo A Hansen Paul I Howell Fotis C Kafatos Manolis Kellis Daniel Lawson Christos Louis Shirley Luckhart Marc A T Muskavitch José M Ribeiro Michael A Riehle Igor V Sharakhov Zhijian Tu Laurence J Zwiebel Nora J Besansky

Science 2015 Jan 27;347(6217):1258522. Epub 2014 Nov 27.

Eck Institute for Global Health and Department of Biological Sciences, University of Notre Dame, 317 Galvin Life Sciences Building, Notre Dame, IN 46556, USA.

Variation in vectorial capacity for human malaria among Anopheles mosquito species is determined by many factors, including behavior, immunity, and life history. To investigate the genomic basis of vectorial capacity and explore new avenues for vector control, we sequenced the genomes of 16 anopheline mosquito species from diverse locations spanning ~100 million years of evolution. Comparative analyses show faster rates of gene gain and loss, elevated gene shuffling on the X chromosome, and more intron losses, relative to Drosophila. Some determinants of vectorial capacity, such as chemosensory genes, do not show elevated turnover but instead diversify through protein-sequence changes. This dynamism of anopheline genes and genomes may contribute to their flexible capacity to take advantage of new ecological niches, including adapting to humans as primary hosts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.1258522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4380271PMC
January 2015

Genome analysis of a major urban malaria vector mosquito, Anopheles stephensi.

Genome Biol 2014 Sep 23;15(9):459. Epub 2014 Sep 23.

Background: Anopheles stephensi is the key vector of malaria throughout the Indian subcontinent and Middle East and an emerging model for molecular and genetic studies of mosquito-parasite interactions. The type form of the species is responsible for the majority of urban malaria transmission across its range.

Results: Here, we report the genome sequence and annotation of the Indian strain of the type form of An. stephensi. The 221 Mb genome assembly represents more than 92% of the entire genome and was produced using a combination of 454, Illumina, and PacBio sequencing. Physical mapping assigned 62% of the genome onto chromosomes, enabling chromosome-based analysis. Comparisons between An. stephensi and An. gambiae reveal that the rate of gene order reshuffling on the X chromosome was three times higher than that on the autosomes. An. stephensi has more heterochromatin in pericentric regions but less repetitive DNA in chromosome arms than An. gambiae. We also identify a number of Y-chromosome contigs and BACs. Interspersed repeats constitute 7.1% of the assembled genome while LTR retrotransposons alone comprise more than 49% of the Y contigs. RNA-seq analyses provide new insights into mosquito innate immunity, development, and sexual dimorphism.

Conclusions: The genome analysis described in this manuscript provides a resource and platform for fundamental and translational research into a major urban malaria vector. Chromosome-based investigations provide unique perspectives on Anopheles chromosome evolution. RNA-seq analysis and studies of immunity genes offer new insights into mosquito biology and mosquito-parasite interactions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13059-014-0459-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4195908PMC
September 2014

A test of agent-based models as a tool for predicting patterns of pathogen transmission in complex landscapes.

BMC Ecol 2013 Sep 25;13:35. Epub 2013 Sep 25.

Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA.

Background: Landscape complexity can mitigate or facilitate host dispersal, influencing patterns of pathogen transmission. Spatial transmission of pathogens through landscapes, therefore, presents an important but not fully elucidated aspect of transmission dynamics. Using an agent-based model (LiNK) that incorporates GIS data, we examined the effects of landscape information on the spatial patterns of host movement and pathogen transmission in a system of long-tailed macaques and their gut parasites. We first examined the role of the landscape to identify any individual or additive effects on host movement. We then compared modeled dispersal distance to patterns of actual macaque gene flow to both confirm our model's predictions and to understand the role of individual land uses on dispersal. Finally, we compared the rate and the spread of two gastrointestinal parasites, Entamoeba histolytica and E. dispar, to understand how landscape complexity influences spatial patterns of pathogen transmission.

Results: LiNK captured emergent properties of the landscape, finding that interaction effects between landscape layers could mitigate the rate of infection in a non-additive way. We also found that the inclusion of landscape information facilitated an accurate prediction of macaque dispersal patterns across a complex landscape, as confirmed by Mantel tests comparing genetic and simulated dispersed distances. Finally, we demonstrated that landscape heterogeneity proved a significant barrier for a highly virulent pathogen, limiting the dispersal ability of hosts and thus its own transmission into distant populations.

Conclusions: Landscape complexity plays a significant role in determining the path of host dispersal and patterns of pathogen transmission. Incorporating landscape heterogeneity and host behavior into disease management decisions can be important in targeting response efforts, identifying cryptic transmission opportunities, and reducing or understanding potential for unintended ecological and evolutionary consequences. The inclusion of these data into models of pathogen transmission patterns improves our understanding of these dynamics, ultimately proving beneficial for sound public health policy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1472-6785-13-35DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3850893PMC
September 2013

Agent-based modeling: a systematic assessment of use cases and requirements for enhancing pharmaceutical research and development productivity.

Wiley Interdiscip Rev Syst Biol Med 2013 Jul-Aug;5(4):461-80. Epub 2013 Jun 4.

Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA.

A crisis continues to brew within the pharmaceutical research and development (R&D) enterprise: productivity continues declining as costs rise, despite ongoing, often dramatic scientific and technical advances. To reverse this trend, we offer various suggestions for both the expansion and broader adoption of modeling and simulation (M&S) methods. We suggest strategies and scenarios intended to enable new M&S use cases that directly engage R&D knowledge generation and build actionable mechanistic insight, thereby opening the door to enhanced productivity. What M&S requirements must be satisfied to access and open the door, and begin reversing the productivity decline? Can current methods and tools fulfill the requirements, or are new methods necessary? We draw on the relevant, recent literature to provide and explore answers. In so doing, we identify essential, key roles for agent-based and other methods. We assemble a list of requirements necessary for M&S to meet the diverse needs distilled from a collection of research, review, and opinion articles. We argue that to realize its full potential, M&S should be actualized within a larger information technology framework--a dynamic knowledge repository--wherein models of various types execute, evolve, and increase in accuracy over time. We offer some details of the issues that must be addressed for such a repository to accrue the capabilities needed to reverse the productivity decline.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/wsbm.1222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3739932PMC
January 2014

Combination of bendamustine, lenalidomide, and dexamethasone (BLD) in patients with relapsed or refractory multiple myeloma is feasible and highly effective: results of phase 1/2 open-label, dose escalation study.

Blood 2012 May 26;119(20):4608-13. Epub 2012 Mar 26.

Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh School of Medicine and Cancer Institute, Pittsburgh, PA, USA.

This multicenter phase 1/2 trial investigated the combination of bendamustine, lenalidomide, and dexamethasone in repeating 4-week cycles as treatment for relapsed refractory multiple myeloma (MM). Phase 1 established maximum tolerated dose (MTD). Phase 2 assessed overall response rate at the MTD. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). A total of 29 evaluable patients were enrolled. Median age was 63 years (range, 38-80 years). Median number of prior therapies was 3 (range, 1-6). MTD was bendamustine 75 mg/m(2) (days 1 and 2), lenalidomide 10 mg (days 1-21), and dexamethasone 40 mg (weekly) of a 28-day cycle. Partial response rate was 52%, with very good partial response achieved in 24%, and minimal response in an additional 24% of patients. Median follow-up was 13 months; median OS has not been reached. One-year OS is 93% (95% confidence interval [CI], 59%-99%). Median PFS is 6.1 months (95% CI, 3.7-9.4 months) with one-year PFS of 20% (95% CI, 6%-41%). Grade 3/4 adverse events included neutropenia, thrombocytopenia, anemia, hyperglycemia, and fatigue. This first phase 1/2 trial testing bendamustine, lenalidomide, and dexamethasone as treatment of relapsed refractory MM was feasible and highly active. This study is registered at www.clinicaltrials.gov as #NCT01042704.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2011-12-395715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3392072PMC
May 2012

An automated homology-based approach for identifying transposable elements.

BMC Bioinformatics 2011 May 3;12:130. Epub 2011 May 3.

Department of Computer Science and Engineering, University of Notre Dame, Notre Dame, IN, USA.

Background: Transposable elements (TEs) are mobile sequences found in nearly all eukaryotic genomes. They have the ability to move and replicate within a genome, often influencing genome evolution and gene expression. The identification of TEs is an important part of every genome project. The number of sequenced genomes is rapidly rising, and the need to identify TEs within them is also growing. The ability to do this automatically and effectively in a manner similar to the methods used for genes is of increasing importance. There exist many difficulties in identifying TEs, including their tendency to degrade over time and that many do not adhere to a conserved structure. In this work, we describe a homology-based approach for the automatic identification of high-quality consensus TEs, aimed for use in the analysis of newly sequenced genomes.

Results: We describe a homology-based approach for the automatic identification of TEs in genomes. Our modular approach is dependent on a thorough and high-quality library of representative TEs. The implementation of the approach, named TESeeker, is BLAST-based, but also makes use of the CAP3 assembly program and the ClustalW2 multiple sequence alignment tool, as well as numerous BioPerl scripts. We apply our approach to newly sequenced genomes and successfully identify consensus TEs that are up to 99% identical to manually annotated TEs.

Conclusions: While TEs are known to be a major force in the evolution of genomes, the automatic identification of TEs in genomes is far from mature. In particular, there is a lack of automated homology-based approaches that produce high-quality TEs. Our approach is able to generate high-quality consensus TE sequences automatically, requiring the user to only provide a few basic parameters. This approach is intentionally modular, allowing researchers to use components separately or iteratively. Our approach is most effective for TEs with intact reading frames. The implementation, TESeeker, is available for download as a virtual appliance, while the library of representative TEs is available as a separate download.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1471-2105-12-130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107183PMC
May 2011

Sequencing of Culex quinquefasciatus establishes a platform for mosquito comparative genomics.

Science 2010 Oct;330(6000):86-8

Center for Disease Vector Research, University of California Riverside, Riverside, CA 92521, USA.

Culex quinquefasciatus (the southern house mosquito) is an important mosquito vector of viruses such as West Nile virus and St. Louis encephalitis virus, as well as of nematodes that cause lymphatic filariasis. C. quinquefasciatus is one species within the Culex pipiens species complex and can be found throughout tropical and temperate climates of the world. The ability of C. quinquefasciatus to take blood meals from birds, livestock, and humans contributes to its ability to vector pathogens between species. Here, we describe the genomic sequence of C. quinquefasciatus: Its repertoire of 18,883 protein-coding genes is 22% larger than that of Aedes aegypti and 52% larger than that of Anopheles gambiae with multiple gene-family expansions, including olfactory and gustatory receptors, salivary gland genes, and genes associated with xenobiotic detoxification.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.1191864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3740384PMC
October 2010

Genome sequences of the human body louse and its primary endosymbiont provide insights into the permanent parasitic lifestyle.

Proc Natl Acad Sci U S A 2010 Jul 21;107(27):12168-73. Epub 2010 Jun 21.

J Craig Venter Institute, Rockville, MD 20850, USA.

As an obligatory parasite of humans, the body louse (Pediculus humanus humanus) is an important vector for human diseases, including epidemic typhus, relapsing fever, and trench fever. Here, we present genome sequences of the body louse and its primary bacterial endosymbiont Candidatus Riesia pediculicola. The body louse has the smallest known insect genome, spanning 108 Mb. Despite its status as an obligate parasite, it retains a remarkably complete basal insect repertoire of 10,773 protein-coding genes and 57 microRNAs. Representing hemimetabolous insects, the genome of the body louse thus provides a reference for studies of holometabolous insects. Compared with other insect genomes, the body louse genome contains significantly fewer genes associated with environmental sensing and response, including odorant and gustatory receptors and detoxifying enzymes. The unique architecture of the 18 minicircular mitochondrial chromosomes of the body louse may be linked to the loss of the gene encoding the mitochondrial single-stranded DNA binding protein. The genome of the obligatory louse endosymbiont Candidatus Riesia pediculicola encodes less than 600 genes on a short, linear chromosome and a circular plasmid. The plasmid harbors a unique arrangement of genes required for the synthesis of pantothenate, an essential vitamin deficient in the louse diet. The human body louse, its primary endosymbiont, and the bacterial pathogens that it vectors all possess genomes reduced in size compared with their free-living close relatives. Thus, the body louse genome project offers unique information and tools to use in advancing understanding of coevolution among vectors, symbionts, and pathogens.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1003379107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2901460PMC
July 2010

Genome sequence of Aedes aegypti, a major arbovirus vector.

Science 2007 Jun 17;316(5832):1718-23. Epub 2007 May 17.

Institute for Genomic Research, 9712 Medical Center Drive, Rockville, MD 20850, USA.

We present a draft sequence of the genome of Aedes aegypti, the primary vector for yellow fever and dengue fever, which at approximately 1376 million base pairs is about 5 times the size of the genome of the malaria vector Anopheles gambiae. Nearly 50% of the Ae. aegypti genome consists of transposable elements. These contribute to a factor of approximately 4 to 6 increase in average gene length and in sizes of intergenic regions relative to An. gambiae and Drosophila melanogaster. Nonetheless, chromosomal synteny is generally maintained among all three insects, although conservation of orthologous gene order is higher (by a factor of approximately 2) between the mosquito species than between either of them and the fruit fly. An increase in genes encoding odorant binding, cytochrome P450, and cuticle domains relative to An. gambiae suggests that members of these protein families underpin some of the biological differences between the two mosquito species.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.1138878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2868357PMC
June 2007

VectorBase: a home for invertebrate vectors of human pathogens.

Nucleic Acids Res 2007 Jan 1;35(Database issue):D503-5. Epub 2006 Dec 1.

European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK.

VectorBase (http://www.vectorbase.org/) is a web-accessible data repository for information about invertebrate vectors of human pathogens. VectorBase annotates and maintains vector genomes providing an integrated resource for the research community. Currently, VectorBase contains genome information for two organisms: Anopheles gambiae, a vector for the Plasmodium protozoan agent causing malaria, and Aedes aegypti, a vector for the flaviviral agents causing Yellow fever and Dengue fever.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/nar/gkl960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1751530PMC
January 2007