Names are key to the big new biology

Author Posting. © The Author(s), 2010. This is the author's version of the work. It is posted here by permission of Elsevier B.V. for personal use, not for redistribution. The definitive version was published in Trends in Ecology & Evolution 25 (2010): 686-691, doi:10.1016/j.tree.2010.09.004.Those who seek answers to big, broad questions about biology, especially questions emphasizing the organism (taxonomy, evolution, ecology), will soon benefit from an emerging names-based infrastructure. It will draw on the almost universal association of organism names with biological information to index and interconnect information distributed across the Internet. The result will be a virtual data commons, expanding as further data are shared, allowing biology to become more of a “big science”. Informatics devices will exploit this ‘big new biology’, revitalizing comparative biology with a broad perspective to reveal previously inaccessible trends and discontinuities, so helping us to reveal unfamiliar biological truths. Here, we review the first components of this freely available, participatory, and semantic Global Names Architecture.DJP thanks the NSF for support through the Data Conservancy project and the Alfred P. Sloan and John D. and Catherine T. MacArthur foundations for their support

Deploying Big Data To Crack The Genotype To Phenotype Code

Mechanistically connecting genotypes to phenotypes is a longstanding and central mission of biology. Deciphering these connections will unite questions and datasets across all scales from molecules to ecosystems. Although high-throughput sequencing has provided a rich platform on which to launch this effort, tools for deciphering mechanisms further along the genome to phenome pipeline remain limited. Machine learning approaches and other emerging computational tools hold the promise of augmenting human efforts to overcome these obstacles. This vision paper is the result of a Reintegrating Biology Workshop, bringing together the perspectives of integrative and comparative biologists to survey challenges and opportunities in cracking the genotype to phenotype code and thereby generating predictive frameworks across biological scales. Key recommendations include: promoting the development of minimum “best practices” for the experimental design and collection of data; fostering sustained and long-term data repositories; promoting programs that recruit, train, and retain a diversity of talent and providing funding to effectively support these highly cross-disciplinary efforts. We follow this discussion by highlighting a few specific transformative research opportunities that will be advanced by these efforts

Centralising Labels to Distribute Data: The Regulatory Role of Genomic Consortia.

publication-status: Publishe

Emerging model spedies driven by transciptomics

This work is focused on 'emerging model species', i.e. question-driven model species which have sufficient molecular resources to investigate a specific phenomenon in molecular biology, developmental biology, molecular ecology and evolution or related molecular fields. This thesis shows how transcriptomic data can be generated, analyzed, and used to investigate such phenomena of interest even in species lacking a reference genome. The initial ButterflyBase resource has proven to be useful to researchers of species without a reference genome but is limited to the Lepidoptera and supports only the older Sanger sequencing technologies. Thanks to Next Generation Sequencing, transcriptome sequencing is more cost effective but the bottleneck of transcriptomic projects is now the bioinformatic analysis and data mining/dissemination. Therefore, this work continues with presenting novel and innovative approaches which effectively overcome this bottleneck. The est2assembly software produces deeply annotated reference transcriptomes stored in the Chado database. The Drupal Bioinformatic Server Framework and genes4all provide species-neutral and an innovative approach in building standardized online databases and associated web services. All public insect mRNA data were analyzed with est2assembly and genes4all to produce the InsectaCentral. With InsectaCentral, a powerful resource is now available to assist molecular biology in any question-driven model insect species. The software presented here was developed according to specifications of the General Model Organism Database (GMOD) community. All software specifications are species-neutral and can be seamlessly deployed to assist any research community. Further through a case studies chapter, it becomes apparent that the transcriptomic approach is more cost-effective than a genomic approach and therefore sequence-driven evolutionary biology will benefit faster with this field

Deciphering Chronometabolic Dynamics Through Metabolomics, Stable Isotope Tracers, And Genome-Scale Reaction Modeling

Synchrony across environmental cues, endogenous genetic clocks, sleep/wake cycles, and metabolism evoke physiological harmony for organismal health. Perturbation of this synchrony has been recently correlated with a growing list of pathologies, which is alarming given the ubiquity of sleep deprivation, mistimed light exposure, and altered eating schedules in modern society. Deeper insights into clocks, sleep, and metabolism are necessary to understand these outcomes. In this work, extensive metabolic profiles of circadian systems were obtained from the development of new liquid chromatography mass spectrometry (LC-MS) metabolomics methods. These methods were applied to Drosophila melanogaster to discern relative influences of environmental and genetic drivers of metabolic cycles. Unique sets of metabolites oscillated with 24-hour circadian periods under light:dark (LD) and constant darkness (DD) conditions, and ultradian rhythms were noted for clock mutant flies under LD, suggesting clock-independent metabolic cycles driven by environmental inputs. However, this metabolomic analysis does not fully capture the inherently dynamic nature of circadian metabolism. These LC-MS methods were adapted to analyze isotope enrichments from a novel 13C6 glucose injection platform in Drosophila. Metabolic flux cycles were noted from glucose carbons into serine, glutamine and reduced glutathione biosynthesis, and altered under sleep deprivation, demonstrating unique energy and redox demands in perturbed sleep/wake cycles. Global isotopolome shifts were most notable in WT flies after lights-on, suggesting a catabolic rush from glucose oxidation early in the active phase. As the scope of these isotope tracer-based metabolomic analyses expand, attributing labeling patterns to specific reactions requires consideration of genome-scale metabolic networks. A new computational approach was developed, called the IsoPathFinder, which uncovered biosynthetic paths from glucose to serine, and extends to glycine and glutathione production. Carbon flux into glutamine was predicted to occur through the TCA cycle, supported by enzyme thermodynamics and circadian expression datasets. This tool is presented as a new mechanism to simulate additional isotope tracer experiments, with broad applicability beyond circadian research. Collectively, a new set of analytical and computational tools are developed to both produce dynamic metabolomic data and improve data interpretability, with applications to uncover new chronometabolic connections

Rapid Evolution of cis-Regulatory Architecture and Activity in the Drosophila Yellow Gene.

In the last 10 years, an increasing number of case studies showed that changes in cis-regulatory elements, mainly enhancers, are one of the main causes of altered phenotypes, but the mechanisms underlying enhancer evolution remain to be elucidated. More specifically, what is the relationship between changes in enhancer sequence, transcription factor binding and activity? In this thesis, I used evolution of yellow enhancers among Drosophila species as a model to shed light onto how cis-regulatory architecture and activity change over time. I first identified the enhancer activities lying in the 5’ intergenic and intronic regions of yellow from six Drosophila species spanning the Drosophila evolutionary history, using a reporter gene assay. I found that yellow epidermal-cell and wing-vein, but not bristle enhancers, have different positions, with respect to the coding sequence, in different Drosophila species. This was the first systematic demonstration of altered enhancer position between species and suggested that enhancer position can be labile. Sequence comparisons failed to show any indication of translocation or duplication suggesting gradual compensatory changes in the transcription factor binding profiles of yellow enhancers is the likely mechanism underlying altered enhancer position. Subsequent subdivision of yellow 5’ intergenic and intronic regions showed a complex distribution of enhancer activities among sub-elements, where some drove expression in patterns that were not part of the expression pattern driven by the full region. Existence of such “cryptic” epidermal-cell enhancer activities suggests that yellow cis-regulatory regions were primed for facilitating the rapid evolutionary changes in the position and activities of this enhancer. Lastly, for the first time, I identified a large set of candidate transcription factors binding to yellow enhancers. This thesis shows that position and activity of yellow enhancers diverged rapidly among species, perhaps by taking advantage of the cryptic activities lying in the yellow cis-regulatory sequences. Further in vitro and in vivo tests validating the direct binding of the identified transcription factors on yellow enhancers and characterizing their functional effects on yellow expression among species can elucidate the evolutionary changes underlying altered position and activity of the particular yellow enhancers.Ph.D.Molecular, Cellular, and Developmental BiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/91435/1/gizemkly_1.pd

New Assembly, Reannotation and Analysis of the Entamoeba histolytica Genome Reveal New Genomic Features and Protein Content Information

Entamoeba histolytica is an anaerobic parasitic protozoan that causes amoebic dysentery. The parasites colonize the large intestine, but under some circumstances may invade the intestinal mucosa, enter the bloodstream and lead to the formation of abscesses such amoebic liver abscesses. The draft genome of E. histolytica, published in 2005, provided the scientific community with the first comprehensive view of the gene set for this parasite and important tools for elucidating the genetic basis of Entamoeba pathogenicity. Because complete genetic knowledge is critical for drug discovery and potential vaccine development for amoebiases, we have re-examined the original draft genome for E. histolytica. We have corrected the sequence assembly, improved the gene predictions and refreshed the functional gene assignments. As a result, this effort has led to a more accurate gene annotation, and the discovery of novel features, such as the presence of genome segmental duplications and the close association of some gene families with transposable elements. We believe that continuing efforts to improve genomic data will undoubtedly help to identify and characterize potential targets for amoebiasis control, as well as to contribute to a better understanding of genome evolution and pathogenesis for this parasite

The computational analysis of post-translational modifications

The post-translational modification (PTMs) of proteins presents a means to increase the proteome size and diversity of an organism through the inclusion of structural elements not encoded at the sequence-level alone. Their erroneous inclusion or exclusion has been linked to a variety of diseases and disorders thus their characterisation has the potential to present viable drug targets. The proliferation of newer high-throughput methods, such as mass spectrometry, to identify such modifications has led to a rapid increase in the number of databases and tools to display and analyse such vast amounts of data effectively. This study covers the development of one such tool; PTM Browser, and the construction of the underlying database that it is based upon. This new database was initially seeded with annotations from the Swiss-Prot and Phospho.ELM resources. The initial database of PTMs was then expanded to include a large repertoire of previously unannotated proteins for a selection of topical species (e.g. Danio rerio and Tetraodon nigroviridis). Orthologue assignments have also been added to the database – to allow for queries to be performed regarding the conservation of modifications between homologous proteins. The PTM Browser tool allows for a full exploration of this new database of PTMs – with a special focus on allowing users to identify modifications that are both shared between and are specific to particular species. This tool is freely available for non-commercial use at the following URL: http://www.ptmbrowser.org. An analysis is presented on the conservation of modifications between members of the tumour suppressor family, p53, using this new tool. This tool has also been used to analysis the conservation of modifications between super-kingdoms and Eukaryote species

Scientific Agency and Social Scaffolding in Contemporary Data-Intensive Biology

This is the author accepted manuscript. The final version is available from University of Minnesota Press via the link in this recordIt is widely recognised that social scaffolding is crucial to the entrenchment of new technologies and related standards and practices in scientific research, as well as to its manifestations and results. At the same time, there is little understanding of the circumstances under which, and the reasons why, some forms of sociality are effective in promoting particular types of scientific work. This chapter explores these questions by focusing on two forms of social scaffolding involved in the development of practices of data dissemination through digital means – and particularly infrastructures such as online databases – within the contemporary life sciences: (1) ontology consortia, which have recently emerged as de facto regulatory bodies for data curation in the US and Europe, and (2) steering committees for model organism communities, which play significant roles in the governance of biological research in the UK. I discuss the successful transformation of these initially ad hoc groups into scientific institutions with political and epistemic visibility and power. Drawing on political theory, I then argue that viewing these organisations as social movements is a fruitful strategy to understand their development from informal gatherings into well-recognised regulatory bodies, and how this process of institutionalisation builds on highly entrenched forms of group socialisation. This in turn facilitates an analysis of the interrelation between institutional and infrastructural scaffolding involved in the evolution of scientific knowledge-making activities.This research was funded by the European Research Council grant award 335925