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1.  Identification of a candidate prognostic gene signature by transcriptome analysis of matched pre- and post-treatment prostatic biopsies from patients with advanced prostate cancer 
BMC Cancer  2014;14(1):977.
Background
Although chemotherapy for prostate cancer (PCa) can improve patient survival, some tumours are chemo-resistant. Tumour molecular profiles may help identify the mechanisms of drug action and identify potential prognostic biomarkers. We performed in vivo transcriptome profiling of pre- and post-treatment prostatic biopsies from patients with advanced hormone-naive prostate cancer treated with docetaxel chemotherapy and androgen deprivation therapy (ADT) with an aim to identify the mechanisms of drug action and identify prognostic biomarkers.
Methods
RNA sequencing (RNA-Seq) was performed on biopsies from four patients before and ~22 weeks after docetaxel and ADT initiation. Gene fusion products and differentially-regulated genes between treatment pairs were identified using TopHat and pathway enrichment analyses undertaken. Publically available datasets were interrogated to perform survival analyses on the gene signatures identified using cBioportal.
Results
A number of genomic rearrangements were identified including the TMPRSS2/ERG fusion and 3 novel gene fusions involving the ETS family of transcription factors in patients, both pre and post chemotherapy. In total, gene expression analyses showed differential expression of at least 2 fold in 575 genes in post-chemotherapy biopsies. Of these, pathway analyses identified a panel of 7 genes (ADAM7, FAM72B, BUB1B, CCNB1, CCNB2, TTK, CDK1), including a cell cycle-related geneset, that were differentially-regulated following treatment with docetaxel and ADT. Using cBioportal to interrogate the MSKCC-Prostate Oncogenome Project dataset we observed a statistically-significant reduction in disease-free survival of patients with tumours exhibiting alterations in gene expression of the above panel of 7 genes (p = 0.015).
Conclusions
Here we report on the first “real-time” in vivo RNA-Seq-based transcriptome analysis of clinical PCa from pre- and post-treatment TRUSS-guided biopsies of patients treated with docetaxel chemotherapy plus ADT. We identify a chemotherapy-driven PCa transcriptome profile which includes the down-regulation of important positive regulators of cell cycle progression. A 7 gene signature biomarker panel has also been identified in high-risk prostate cancer patients to be of prognostic value. Future prospective study is warranted to evaluate the clinical value of this panel.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2407-14-977) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2407-14-977
PMCID: PMC4301544  PMID: 25519703
Prostate cancer; Androgen deprivation therapy; Biomarkers; Docetaxel; Cell cycle
2.  Next-generation Sequencing of Advanced Prostate Cancer Treated with Androgen-deprivation Therapy 
European Urology  2014;66(1):32-39.
Background
Androgen-deprivation therapy (ADT) is standard treatment for locally advanced or metastatic prostate cancer (PCa). Many patients develop castration resistance (castration-resistant PCa [CRPC]) after approximately 2–3 yr, with a poor prognosis. The molecular mechanisms underlying CRPC progression are unclear.
Objective
To undertake quantitative tumour transcriptome profiling prior to and following ADT to identify functionally important androgen-regulated pathways or genes that may be reactivated in CRPC.
Design, setting, and participants
RNA sequencing (RNA-seq) was performed on tumour-rich, targeted prostatic biopsies from seven patients with locally advanced or metastatic PCa before and approximately 22 wk after ADT initiation. Differentially regulated genes were identified in treatment pairs and further investigated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) on cell lines and immunohistochemistry on a separate CRPC patient cohort. Functional assays were used to determine the effect of pathway modulation on cell phenotypes.
Outcome measurements and statistical analysis
We searched for gene expression changes affecting key cell signalling pathways that may be targeted as proof of principle in a CRPC in vitro cell line model.
Results and limitations
We identified ADT-regulated signalling pathways, including the Wnt/β-catenin signalling pathway, and observed overexpression of β-catenin in a subset of CRPC by immunohistochemistry. We validated 6 of 12 (50%) pathway members by qRT-PCR on LNCaP/LNCaP-AI cell RNAs, of which 4 (67%) demonstrated expression changes consistent with RNA-seq data. We show that the tankyrase inhibitor XAV939 (which promotes β-catenin degradation) reduced androgen-independent LNCaP-AI cell line growth compared with androgen-responsive LNCaP cells via an accumulation of cell proportions in the G0/G1 phase and reduction in the S and G2/M phases. Our biopsy protocol did not account for tumour heterogeneity, and pathway inhibition was limited to pharmacologic approaches.
Conclusions
RNA-seq of paired PCa samples revealed ADT-regulated signalling pathways. Proof-of-principle inhibition of the Wnt/β-catenin signalling pathway specifically delays androgen-independent PCa cell cycle progression and proliferation and warrants further investigation as a potential target for therapy for CRPC.
Take Home Message
A comprehensive RNA sequencing analysis of the prostate cancer (PCa) transcriptome during androgen-deprivation therapy identifies gene expression changes within several cell-signalling pathways, including the Wnt/β-catenin signalling pathway, which has a potential role in androgen-independent PCa cell growth.
doi:10.1016/j.eururo.2013.08.011
PMCID: PMC4062940  PMID: 24054872
Prostate cancer; Androgen-deprivation therapy; Castration resistant; Wnt; β-catenin
3.  CGAT: computational genomics analysis toolkit 
Bioinformatics  2014;30(9):1290-1291.
Summary: Computational genomics seeks to draw biological inferences from genomic datasets, often by integrating and contextualizing next-generation sequencing data. CGAT provides an extensive suite of tools designed to assist in the analysis of genome scale data from a range of standard file formats. The toolkit enables filtering, comparison, conversion, summarization and annotation of genomic intervals, gene sets and sequences. The tools can both be run from the Unix command line and installed into visual workflow builders, such as Galaxy.
Availability: The toolkit is freely available from http://github.com/CGATOxford/cgat
Contact: andreas.heger@dpag.ox.ac.uk
doi:10.1093/bioinformatics/btt756
PMCID: PMC3998125  PMID: 24395753
4.  Epigenetic conservation at gene regulatory elements revealed by non-methylated DNA profiling in seven vertebrates 
eLife  2013;2:e00348.
Two-thirds of gene promoters in mammals are associated with regions of non-methylated DNA, called CpG islands (CGIs), which counteract the repressive effects of DNA methylation on chromatin. In cold-blooded vertebrates, computational CGI predictions often reside away from gene promoters, suggesting a major divergence in gene promoter architecture across vertebrates. By experimentally identifying non-methylated DNA in the genomes of seven diverse vertebrates, we instead reveal that non-methylated islands (NMIs) of DNA are a central feature of vertebrate gene promoters. Furthermore, NMIs are present at orthologous genes across vast evolutionary distances, revealing a surprising level of conservation in this epigenetic feature. By profiling NMIs in different tissues and developmental stages we uncover a unifying set of features that are central to the function of NMIs in vertebrates. Together these findings demonstrate an ancient logic for NMI usage at gene promoters and reveal an unprecedented level of epigenetic conservation across vertebrate evolution.
DOI: http://dx.doi.org/10.7554/eLife.00348.001
eLife digest
DNA methylation—the addition of a methyl group to cytosine, one of the four bases found in DNA—is a central process in genetics. By preventing genes from being expressed as proteins, DNA methylation is one of a number of epigenetic mechanisms that can determine which proteins are made in different cell types without changing the underlying DNA sequence.
In warm-blooded vertebrates such as mammals most of the genome is methylated, however short regions of non-methylated DNA are known to be associated with gene promoters (regions of DNA that act as binding sites for the enzymes and transcription factors that transcribe the DNA in the gene into RNA). Much of our current understanding of the role of these islands of non-methylated DNA is based on computational predictions rather than experimental data. In cold-blooded vertebrates, for example, computer models often predict that non-methylated islands are not associated with gene promoters, which potentially suggests an evolutionary divergence in the role of methylation amongst vertebrates. However, this idea has not been confirmed by experimental data.
Long et al. have performed experiments to compare the location of non-methylated islands in seven different vertebrate species. In general they find that computational models are not a reliable method for identifying non-methylated islands. Moreover they find that non-methylated islands are a central epigenetic feature of gene promoters in all vertebrates analysed–including three mammals, a bird, a lizard, a frog and a fish—and not just in warm-blooded vertebrates as suggested by computational models. This shows that the epigenetic function of these non-methylated islands has been conserved over more than 450 million years of evolution.
In addition to the non-methylated islands associated with gene promoters, Long et al. identify two other types: intergenic non-methylated islands that are found away from gene promoters and are said to be ‘plastic’ because the DNA in these islands can acquire methyl groups, and ‘broad’ non-methylated islands that span many of the genes that are involved in embryonic development.
By showing that the epigenetic role of non-methylated islands has been conserved over time, and identifying three specific types of island, the work of Long et al. marks an important change in our understanding of epigenetics in vertebrates.
DOI: http://dx.doi.org/10.7554/eLife.00348.002
doi:10.7554/eLife.00348
PMCID: PMC3583005  PMID: 23467541
CpG islands; DNA methylation; Epigenetics; Chromatin; Evolutionary conservation; Chicken; Human; Mouse; Xenopus; Zebrafish
5.  High activity and Lévy searches: jellyfish can search the water column like fish 
Over-fishing may lead to a decrease in fish abundance and a proliferation of jellyfish. Active movements and prey search might be thought to provide a competitive advantage for fish, but here we use data-loggers to show that the frequently occurring coastal jellyfish (Rhizostoma octopus) does not simply passively drift to encounter prey. Jellyfish (327 days of data from 25 jellyfish with depth collected every 1 min) showed very dynamic vertical movements, with their integrated vertical movement averaging 619.2 m d−1, more than 60 times the water depth where they were tagged. The majority of movement patterns were best approximated by exponential models describing normal random walks. However, jellyfish also showed switching behaviour from exponential patterns to patterns best fitted by a truncated Lévy distribution with exponents (mean μ = 1.96, range 1.2–2.9) close to the theoretical optimum for searching for sparse prey (μopt ≈ 2.0). Complex movements in these ‘simple’ animals may help jellyfish to compete effectively with fish for plankton prey, which may enhance their ability to increase in dominance in perturbed ocean systems.
doi:10.1098/rspb.2011.0978
PMCID: PMC3234559  PMID: 21752825
plankton thin layers; Lasker's stable ocean hypothesis; zooplankton; superdiffusion; biologging
6.  KDM2B links the Polycomb Repressive Complex 1 (PRC1) to recognition of CpG islands 
eLife  2012;1:e00205.
CpG islands (CGIs) are associated with most mammalian gene promoters. A subset of CGIs act as polycomb response elements (PREs) and are recognized by the polycomb silencing systems to regulate expression of genes involved in early development. How CGIs function mechanistically as nucleation sites for polycomb repressive complexes remains unknown. Here we discover that KDM2B (FBXL10) specifically recognizes non-methylated DNA in CGIs and recruits the polycomb repressive complex 1 (PRC1). This contributes to histone H2A lysine 119 ubiquitylation (H2AK119ub1) and gene repression. Unexpectedly, we also find that CGIs are occupied by low levels of PRC1 throughout the genome, suggesting that the KDM2B-PRC1 complex may sample CGI-associated genes for susceptibility to polycomb-mediated silencing. These observations demonstrate an unexpected and direct link between recognition of CGIs by KDM2B and targeting of the polycomb repressive system. This provides the basis for a new model describing the functionality of CGIs as mammalian PREs.
DOI: http://dx.doi.org/10.7554/eLife.00205.001
eLife digest
Gene expression in eukaryotic cells can be controlled in a number of different ways, including various epigenetic mechanisms that do not involve making changes to DNA sequences that define the genes themselves. A well-known epigenetic mechanism for silencing genes in vertebrates is DNA methylation—the addition of a methyl group (CH3) to cytosine, which is one of the four bases found in the DNA. Methylation is thought to silence genes by preventing transcription factors from binding to the DNA, and also by recruiting proteins that inhibit the transcription of DNA.
DNA methylation occurs naturally throughout the genome, mostly at positions where cytosine is bonded to guanine to form a CpG dinucleotide. While the cytosine bases in most CpG dinucleotides are methylated, there are short stretches of DNA known as CpG islands that contain a high proportion of unmethylated CpG dinucleotides. These islands contain a large number of cytosine and guanine bases, and they are often found at or near transcription start sites.
The lack of methylation at CpG islands has long been assumed to have a passive role in gene expression, leaving the DNA easily accessible and available for transcription factors to bind and initiate transcription. However, recent work suggests that CpG islands may have a more active role. In particular, it has been shown that specific proteins bind to CpG islands to create chromatin environments that are more favourable for the initiation of gene expression. Moreover, a subset of CpG islands can also bind polycomb-group proteins, including the polycomb repressive complex 1 (PRC1) that silence gene expression. These complexes have an important role in the regulation of genes during early development in animals, but the mechanism by which PRC1 recognizes CpG islands in mammals has remained enigmatic.
Farcas et al. now reveal that a protein, KDM2B (FBXL10), can recognize CpG islands and recruit PRC1 to them. To achieve this, KDM2B encodes a DNA binding domain that specifically recognizes non-methylated CpG dinucleotides. By interacting biochemically with a variant PRC1 complex, KDM2B then nucleates PRC1 at CpG islands, and PRC1 activity silences certain polycomb target genes in embryonic stem cells. Surprisingly, Farcas et al. also find low but appreciable levels of PRC1 at most CpG islands genome-wide, in addition to the high levels of PRC1 at selected islands: this suggests that KDM2B may sample the whole genome to find CpG islands where PRC1 can establish silencing. An improved understanding of the polycomb repressive system, and the role of CpG islands within it, could lead to new insights into the role of epigenetic mechanisms in mammalian development.
DOI: http://dx.doi.org/10.7554/eLife.00205.002
doi:10.7554/eLife.00205
PMCID: PMC3524939  PMID: 23256043
CpG island; Chromatin; Epigenetics; Transcription; Methylation; Demethylase; Chicken; Human; Mouse; Xenopus; Zebrafish
7.  Synthesis and Development of Poly(N-Hydroxyethyl Acrylamide)-Ran-3-Acrylamidophenylboronic Acid Polymer Fluid for Potential Application in Affinity Sensing of Glucose 
Background
In previous work, we described viscosity and permittivity microelectromechanical systems (MEMS) sensors for continuous glucose monitoring (CGM) using poly[acrylamide-ran-3-acrylamidophenylboronic acid (PAA-ran-PAAPBA). In order to enhance our MEMS device antifouling properties, a novel, more hydrophilic polymer-sensing fluid was developed.
Method
To optimize sensing performance, we synthesized biocompatible copolymers poly(N-hydroxyethyl acrylamide)-ran-3-acrylamidophenylboronic acid (PHEAA-ran-PAAPBA) and developed its sensing fluid for viscosity-based glucose sensing. Key factors such as polymer composition and molecular weight were investigated in order to optimize viscometric responses.
Results
Compared with PAA-ran-PAAPBA fluid of a similar binding moiety percentage, PHEAA-ran-PAAPBA showed comparable high binding specificity to glucose in a reversible manner and even better performance in glucose sensing in terms of glucose sensing range (27–468 mg/ml) and sensitivity (within 3% standard error of estimate). Preliminary experiment on a MEMS viscometer demonstrated that the polymer fluid was able to sense the glucose concentration.
Conclusions
Our MEMS systems using PHEAA-ran-PAAPBA will possess enhanced implantable traits necessary to enable CGM in subcutaneous tissues.
PMCID: PMC3208861  PMID: 22027298
antifouling; boronic acid; continuous glucose monitoring; microelectromechanical systems; poly(acrylamide-ran-3-acrylamidophenylboronic acid); poly(N-hydroxyethyl acrylamide)-ran-3-acrylamidophenylboronic acid)
8.  Complete genome sequence of Thauera aminoaromatica strain MZ1T 
Standards in Genomic Sciences  2012;6(3):325-335.
Thauera aminoaromatica strain MZ1T, an isolate belonging to genus Thauera, of the family Rhodocyclaceae and the class the Betaproteobacteria, has been characterized for its ability to produce abundant exopolysaccharide and degrade various aromatic compounds with nitrate as an electron acceptor. These properties, if fully understood at the genome-sequence level, can aid in environmental processing of organic matter in anaerobic cycles by short-circuiting a central anaerobic metabolite, acetate, from microbiological conversion to methane, a critical greenhouse gas. Strain MZ1T is the first strain from the genus Thauera with a completely sequenced genome. The 4,496,212 bp chromosome and 78,374 bp plasmid contain 4,071 protein-coding and 71 RNA genes, and were sequenced as part of the DOE Community Sequencing Program CSP_776774.
doi:10.4056/sigs.2696029
PMCID: PMC3558969  PMID: 23407619
Thauera aminoaromatica; MZ1T; genome
9.  Antipodean white sharks on a Mediterranean walkabout? Historical dispersal leads to genetic discontinuity and an endangered anomalous population 
The provenance of white sharks (Carcharodon carcharias) in the Mediterranean is both a conundrum and an important conservation issue. Considering this species's propensity for natal philopatry, any evidence that the Mediterranean stock has little or no contemporary immigration from the Atlantic would suggest that it is extraordinarily vulnerable. To address this issue we sequenced the mitochondrial control region of four rare Mediterranean white sharks. Unexpectedly, the juvenile sequences were identical although collected at different locations and times, showing little genetic differentiation from Indo-Pacific lineages, but strong separation from geographically closer Atlantic/western Indian Ocean haplotypes. Historical long-distance dispersal (probably a consequence of navigational error during past climatic oscillations) and potential founder effects are invoked to explain the anomalous relationships of this isolated ‘sink’ population, highlighting the present vulnerability of its nursery grounds.
doi:10.1098/rspb.2010.1856
PMCID: PMC3081765  PMID: 21084352
Mediterranean; white shark; mitochondrial DNA; conservation; climate change; migration
10.  Comparative RNAi screening identifies a conserved core metazoan actinome by phenotype 
The Journal of Cell Biology  2011;194(5):789-805.
RNAi Screens in Drosophila and human cells for novel actin regulators revealed conserved roles for proteins involved in nuclear actin export, RNA splicing, and ubiquitination.
Although a large number of actin-binding proteins and their regulators have been identified through classical approaches, gaps in our knowledge remain. Here, we used genome-wide RNA interference as a systematic method to define metazoan actin regulators based on visual phenotype. Using comparative screens in cultured Drosophila and human cells, we generated phenotypic profiles for annotated actin regulators together with proteins bearing predicted actin-binding domains. These phenotypic clusters for the known metazoan “actinome” were used to identify putative new core actin regulators, together with a number of genes with conserved but poorly studied roles in the regulation of the actin cytoskeleton, several of which we studied in detail. This work suggests that although our search for new components of the core actin machinery is nearing saturation, regulation at the level of nuclear actin export, RNA splicing, ubiquitination, and other upstream processes remains an important but unexplored frontier of actin biology.
doi:10.1083/jcb.201103168
PMCID: PMC3171124  PMID: 21893601
11.  Spatial Dynamics and Expanded Vertical Niche of Blue Sharks in Oceanographic Fronts Reveal Habitat Targets for Conservation 
PLoS ONE  2012;7(2):e32374.
Dramatic population declines among species of pelagic shark as a result of overfishing have been reported, with some species now at a fraction of their historical biomass. Advanced telemetry techniques enable tracking of spatial dynamics and behaviour, providing fundamental information on habitat preferences of threatened species to aid conservation. We tracked movements of the highest pelagic fisheries by-catch species, the blue shark Prionace glauca, in the North-east Atlantic using pop-off satellite-linked archival tags to determine the degree of space use linked to habitat and to examine vertical niche. Overall, blue sharks moved south-west of tagging sites (English Channel; southern Portugal), exhibiting pronounced site fidelity correlated with localized productive frontal areas, with estimated space-use patterns being significantly different from that of random walks. Tracked female sharks displayed behavioural variability in diel depth preferences, both within and between individuals. Diel depth use ranged from normal DVM (nDVM; dawn descent, dusk ascent), to reverse DVM (rDVM; dawn ascent, dusk descent), to behavioural patterns where no diel differences were apparent. Results showed that blue sharks occupy some of the most productive marine zones for extended periods and structure diel activity patterns across multiple spatio-temporal scales in response to particular habitat types. In so doing, sharks occupied an extraordinarily broad vertical depth range for their size (1.0–2.0 m fork length), from the surface into the bathypelagic realm (max. dive depth, 1160 m). The space-use patterns of blue sharks indicated they spend much of the time in areas where pelagic longlining activities are often highest, and in depth zones where these fisheries particularly target other species, which could account for the rapid declines recently reported for blue sharks in many parts of the world's oceans. Our results provide habitat targets for blue shark conservation that may also be relevant to other pelagic species.
doi:10.1371/journal.pone.0032374
PMCID: PMC3290575  PMID: 22393403
12.  Functional Viability Profiles of Breast Cancer 
Cancer discovery  2011;1(3):260-273.
The design of targeted therapeutic strategies for cancer has been driven by the identification of tumor specific genetic changes. However, the large number of genetic alterations present in tumor cells means that it is difficult to discriminate between genes that are critical for maintenance of the disease state from those that are merely coincidental. Even when critical genes can be identified, directly targeting these is often challenging, meaning that alternative strategies such as exploiting synthetic lethality may be beneficial. To address these issues, we have carried out a functional genetic screen in over 30 commonly used models of breast cancer to identify genes that are critical for the growth of specific breast cancer subtypes. In particular, we describe potential new therapeutic targets for PTEN mutated cancers and for ER+ve breast cancers. We also show that large-scale functional profiling allows the classification of breast cancers into subgroups distinct from established subtypes.
doi:10.1158/2159-8290.CD-11-0107
PMCID: PMC3188379  PMID: 21984977
13.  Genome Sequence of Victivallis vadensis ATCC BAA-548, an Anaerobic Bacterium from the Phylum Lentisphaerae, Isolated from the Human Gastrointestinal Tract▿ 
Journal of Bacteriology  2011;193(9):2373-2374.
Victivallis vadensis ATCC BAA-548 represents the first cultured representative from the novel phylum Lentisphaerae, a deep-branching bacterial lineage. Few cultured bacteria from this phylum are known, and V. vadensis therefore represents an important organism for evolutionary studies. V. vadensis is a strictly anaerobic sugar-fermenting isolate from the human gastrointestinal tract.
doi:10.1128/JB.00271-11
PMCID: PMC3133096  PMID: 21398537
14.  High-throughput RNA interference screening using pooled shRNA libraries and next generation sequencing 
Genome Biology  2011;12(10):R104.
RNA interference (RNAi) screening is a state-of-the-art technology that enables the dissection of biological processes and disease-related phenotypes. The commercial availability of genome-wide, short hairpin RNA (shRNA) libraries has fueled interest in this area but the generation and analysis of these complex data remain a challenge. Here, we describe complete experimental protocols and novel open source computational methodologies, shALIGN and shRNAseq, that allow RNAi screens to be rapidly deconvoluted using next generation sequencing. Our computational pipeline offers efficient screen analysis and the flexibility and scalability to quickly incorporate future developments in shRNA library technology.
doi:10.1186/gb-2011-12-10-r104
PMCID: PMC3333774  PMID: 22018332
15.  Comprehensive Genomic Analysis of a BRCA2 Deficient Human Pancreatic Cancer 
PLoS ONE  2011;6(7):e21639.
Capan-1 is a well-characterised BRCA2-deficient human cell line isolated from a liver metastasis of a pancreatic adenocarcinoma. Here we report a genome-wide assessment of structural variations and high-depth exome characterization of single nucleotide variants and small insertion/deletions in Capan-1. To identify potential somatic and tumour-associated variations in the absence of a matched-normal cell line, we devised a novel method based on the analysis of HapMap samples. We demonstrate that Capan-1 has one of the most rearranged genomes sequenced to date. Furthermore, small insertions and deletions are detected more frequently in the context of short sequence repeats than in other genomes. We also identify a number of novel mutations that may represent genetic changes that have contributed to tumour progression. These data provide insight into the genomic effects of loss of BRCA2 function.
doi:10.1371/journal.pone.0021639
PMCID: PMC3130048  PMID: 21750719
16.  Molecular markers reveal spatially segregated cryptic species in a critically endangered fish, the common skate (Dipturus batis) 
Many sharks and skates are particularly vulnerable to overfishing because of their large size, slow growth, late maturity and low fecundity. In Europe dramatic population declines have taken place in common skate (Dipturus batis L.), one of the largest demersal fish in regional shelf seas, leading to extirpations from substantial parts of its former range. Here we report the discovery of cryptic species in common skate collected from the northeast Atlantic continental shelf. Data from nuclear microsatellite markers indicated two clearly distinct clades and phylogenetic analysis of mitochondrial DNA sequences demonstrated monophyly of each one of them. Capture locations showed evidence of strong spatial segregation, with one taxon occurring mainly in waters off the southern British Isles and around Rockall, while the other was restricted to more northerly shelf waters. These apparently cryptic species showed overlapping substrate and depth preferences, but distributional limits were closely related to temperature gradients, potentially indicating thermal limits to their distributions. This discovery of hidden diversity within a large, critically endangered marine vertebrate demonstrates how marine biodiversity can be underestimated, even in such a relatively well-studied and heavily exploited region.
doi:10.1098/rspb.2009.2111
PMCID: PMC2871835  PMID: 20106849
elasmobranch; marine fishes; biodiversity; fisheries; genetic differences; extinction
17.  Complete genome sequence of Sulfurimonas autotrophica type strain (OK10T) 
Standards in Genomic Sciences  2010;3(2):194-202.
Sulfurimonas autotrophica Inagaki et al. 2003 is the type species of the genus Sulfurimonas. This genus is of interest because of its significant contribution to the global sulfur cycle as it oxidizes sulfur compounds to sulfate and by its apparent habitation of deep-sea hydrothermal and marine sulfidic environments as potential ecological niche. Here we describe the features of this organism, together with the complete genome sequence and annotation. This is the second complete genome sequence of the genus Sulfurimonas and the 15th genome in the family Helicobacteraceae. The 2,153,198 bp long genome with its 2,165 protein-coding and 55 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project.
doi:10.4056/sigs.1173118
PMCID: PMC3035374  PMID: 21304749
mesophilic; facultatively anaerobic; sulfur metabolism; deep-sea hydrothermal vents; spermidine; Gram-negative; Helicobacteriaceae; Epsilonproteobacteria; GEBA
18.  The FLIGHT Drosophila RNAi database 
Fly  2010;4(4):344-348.
FLIGHT (http://flight.icr.ac.uk/) is an online resource compiling data from high-throughput Drosophila in vivo and in vitro RNAi screens. FLIGHT includes details of RNAi reagents and their predicted off-target effects, alongside RNAi screen hits, scores and phenotypes, including images from high-content screens. The latest release of FLIGHT is designed to enable users to upload, analyze, integrate and share their own RNAi screens. Users can perform multiple normalizations, view quality control plots, detect and assign screen hits and compare hits from multiple screens using a variety of methods including hierarchical clustering. FLIGHT integrates RNAi screen data with microarray gene expression as well as genomic annotations and genetic/physical interaction datasets to provide a single interface for RNAi screen analysis and datamining in Drosophila.
doi:10.4161/fly.4.4.13303
PMCID: PMC3174485  PMID: 20855970
RNAi; database; integration; bioinformatics; phenotype
19.  Genomic distance entrained clustering and regression modelling highlights interacting genomic regions contributing to proliferation in breast cancer 
BMC Systems Biology  2010;4:127.
Background
Genomic copy number changes and regional alterations in epigenetic states have been linked to grade in breast cancer. However, the relative contribution of specific alterations to the pathology of different breast cancer subtypes remains unclear. The heterogeneity and interplay of genomic and epigenetic variations means that large datasets and statistical data mining methods are required to uncover recurrent patterns that are likely to be important in cancer progression.
Results
We employed ridge regression to model the relationship between regional changes in gene expression and proliferation. Regional features were extracted from tumour gene expression data using a novel clustering method, called genomic distance entrained agglomerative (GDEC) clustering. Using gene expression data in this way provides a simple means of integrating the phenotypic effects of both copy number aberrations and alterations in chromatin state. We show that regional metagenes derived from GDEC clustering are representative of recurrent regions of epigenetic regulation or copy number aberrations in breast cancer. Furthermore, detected patterns of genomic alterations are conserved across independent oestrogen receptor positive breast cancer datasets. Sequential competitive metagene selection was used to reveal the relative importance of genomic regions in predicting proliferation rate. The predictive model suggested additive interactions between the most informative regions such as 8p22-12 and 8q13-22.
Conclusions
Data-mining of large-scale microarray gene expression datasets can reveal regional clusters of co-ordinate gene expression, independent of cause. By correlating these clusters with tumour proliferation we have identified a number of genomic regions that act together to promote proliferation in ER+ breast cancer. Identification of such regions should enable prioritisation of genomic regions for combinatorial functional studies to pinpoint the key genes and interactions contributing to tumourigenicity.
doi:10.1186/1752-0509-4-127
PMCID: PMC2946304  PMID: 20825665
20.  Sexual segregation of pelagic sharks and the potential threat from fisheries 
Biology Letters  2009;5(2):156-159.
Large pelagic sharks are declining in abundance in many oceans owing to fisheries exploitation. What is not known however is whether within-species geographical segregation of the sexes exacerbates this as a consequence of differential exploitation by spatially focused fisheries. Here we show striking sexual segregation in the fastest swimming shark, the shortfin mako Isurus oxyrinchus, across the South Pacific Ocean. The novel finding of a sexual ‘line in the sea’ spans a historical longline-fishing intensity gradient, suggesting that differential exploitation of the sexes is possible, a phenomenon which may underlie changes in the shark populations observed elsewhere.
doi:10.1098/rsbl.2008.0761
PMCID: PMC2665836  PMID: 19324655
distribution; behaviour; sex ratio; sexual harassment; overfishing; conservation
21.  Complete genome sequence of Nakamurella multipartita type strain (Y-104T) 
Standards in Genomic Sciences  2010;2(2):168-175.
Nakamurella multipartita (Yoshimi et al. 1996) Tao et al. 2004 is the type species of the monospecific genus Nakamurella in the actinobacterial suborder Frankineae. The nonmotile, coccus-shaped strain was isolated from activated sludge acclimated with sugar-containing synthetic wastewater, and is capable of accumulating large amounts of polysaccharides in its cells. Here we describe the features of the organism, together with the complete genome sequence and annotation. This is the first complete genome sequence of a member of the family Nakamurellaceae. The 6,060,298 bp long single replicon genome with its 5415 protein-coding and 56 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project.
doi:10.4056/sigs.721316
PMCID: PMC3035273  PMID: 21304699
polysaccharide-accumulating; septa-forming; nonmotile; Gram-positive; MK-8 (H4); ‘Microsphaeraceae’; Frankineae; GEBA
22.  Complete genome sequence of Conexibacter woesei type strain (ID131577T) 
Standards in Genomic Sciences  2010;2(2):212-219.
The genus Conexibacter (Monciardini et al. 2003) represents the type genus of the family Conexibacteraceae (Stackebrandt 2005, emend. Zhi et al. 2009) with Conexibacter woesei as the type species of the genus. C. woesei is a representative of a deep evolutionary line of descent within the class Actinobacteria. Strain ID131577T was originally isolated from temperate forest soil in Gerenzano (Italy). Cells are small, short rods that are motile by peritrichous flagella. They may form aggregates after a longer period of growth and, then as a typical characteristic, an undulate structure is formed by self-aggregation of flagella with entangled bacterial cells. Here we describe the features of the organism, together with the complete sequence and annotation. The 6,359,369 bp long genome of C. woesei contains 5,950 protein-coding and 48 RNA genes and is part of the Genomic Encyclopedia of Bacteria and Archaea project.
doi:10.4056/sigs.751339
PMCID: PMC3035278  PMID: 21304704
aerobic; short rods; forest soil; Solirubrobacterales; Conexibacteraceae; GEBA
23.  Novel Acoustic Technology for Studying Free-Ranging Shark Social Behaviour by Recording Individuals' Interactions 
PLoS ONE  2010;5(2):e9324.
Group behaviours are widespread among fish but comparatively little is known about the interactions between free-ranging individuals and how these might change across different spatio-temporal scales. This is largely due to the difficulty of observing wild fish groups directly underwater over long enough time periods to quantify group structure and individual associations. Here we describe the use of a novel technology, an animal-borne acoustic proximity receiver that records close-spatial associations between free-ranging fish by detection of acoustic signals emitted from transmitters on other individuals. Validation trials, held within enclosures in the natural environment, on juvenile lemon sharks Negaprion brevirostris fitted with external receivers and transmitters, showed receivers logged interactions between individuals regularly when sharks were within 4 m (∼4 body lengths) of each other, but rarely when at 10 m distance. A field trial lasting 17 days with 5 juvenile lemon sharks implanted with proximity receivers showed one receiver successfully recorded association data, demonstrating this shark associated with 9 other juvenile lemon sharks on 128 occasions. This study describes the use of acoustic underwater proximity receivers to quantify interactions among wild sharks, setting the scene for new advances in understanding the social behaviours of marine animals.
doi:10.1371/journal.pone.0009324
PMCID: PMC2824825  PMID: 20174465
24.  Complete genome sequence of Alicyclobacillus acidocaldarius type strain (104-IAT) 
Alicyclobacillus acidocaldarius (Darland and Brock 1971) is the type species of the larger of the two genera in the bacillal family ‘Alicyclobacillaceae’. A. acidocaldarius is a free-living and non-pathogenic organism, but may also be associated with food and fruit spoilage. Due to its acidophilic nature, several enzymes from this species have since long been subjected to detailed molecular and biochemical studies. Here we describe the features of this organism, together with the complete genome sequence and annotation. This is the first completed genome sequence of the family ‘Alicyclobacillaceae’. The 3,205,686 bp long genome (chromosome and three plasmids) with its 3,153 protein-coding and 82 RNA genes is part of the Genomic Encyclopedia of Bacteria and Archaea project.
doi:10.4056/sigs.591104
PMCID: PMC3035248  PMID: 21304673
thermophile; acidophilic; aerobic; non-pathogenic; food spoilage; non-motile but encodes flagellar genes; GEBA
25.  Complete genome sequence of Streptosporangium roseum type strain (NI 9100T) 
Standards in Genomic Sciences  2010;2(1):29-37.
Streptosporangium roseum Crauch 1955 is the type strain of the species which is the type species of the genus Streptosporangium. The ‘pinkish coiled Streptomyces-like organism with a spore case’ was isolated from vegetable garden soil in 1955. Here we describe the features of this organism, together with the complete genome sequence and annotation. This is the first completed genome sequence of a member of the family Streptosporangiaceae, and the second largest microbial genome sequence ever deciphered. The 10,369,518 bp long genome with its 9421 protein-coding and 80 RNA genes is a part of the Genomic Encyclopedia of Bacteria and Archaea project.
doi:10.4056/sigs.631049
PMCID: PMC3035251  PMID: 21304675
Sporangia; vegetative and aerial mycelia; aerobic; non-motile; non-motile spores; Gram-positive; Streptosporangiaceae; S. cloviforme

Results 1-25 (42)