Publications by authors named "Richard Talbot"

44 Publications

A randomised trial of social support group intervention for people with aphasia: A Novel application of virtual reality.

PLoS One 2020 24;15(9):e0239715. Epub 2020 Sep 24.

Centre for Human Computer Interaction Design, City, University of London, London, United Kingdom.

About a third of strokes cause aphasia, or language loss, with profound consequences for the person's social participation and quality of life. These problems may be mitigated by group social support. But this intervention is not available to all individuals. This study investigated whether it is feasible to deliver group social support to people with aphasia via a multi-user, virtual reality platform. It also explored the indicative effects of intervention and the costs. Intervention aimed to promote wellbeing and communicative success. It enabled participants to form new social connections and share experiences of living with aphasia. It comprised 14 sessions delivered over 6 months and was led by community based co-ordinators and volunteers. Feasibility measures comprised: recruitment and retention rates, compliance with intervention and assessment of treatment fidelity. Effects of intervention were explored using a waitlist randomised controlled design, with outcome measures of wellbeing, communication, social connectedness and quality of life. Two intervention groups were randomised to an immediate condition and two were randomised to a delayed condition. The main analysis explored scores on the measures between two time points, between which those in the immediate condition had received intervention, but those in the delayed group had not (yet). A comprehensive approach to economic data collection ensured that all costs of treatment delivery were recorded. Feasibility findings showed that the recruitment target was met (N = 34) and 85.3% (29/34) of participants completed intervention. All groups ran the 14 sessions as planned, and participants attended a mean of 11.4 sessions (s.d. 2.8), which was 81.6% of the intended dose. Fidelity checking showed minimal drift from the manualised intervention. No significant change was observed on any of the outcome measures, although the study was not powered to detect these. Costs varied across the four groups, from £7,483 - £12,562 British Pounds Sterling ($10,972 - $18,419 US dollars), depending on travel costs, the relative contributions of volunteers and the number of hardware loans that were needed. The results suggest that a larger trial of remote group support, using virtual reality, would be merited. However the treatment content and regime, and the selection of outcome measures should be reviewed before conducting the trial. Trail registration: Study registered with ClinicalTrials.gov; Identifier: https://www.ncbi.nlm.nih.gov/NCT03115268.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239715PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7514104PMC
November 2020

Development of a single nucleotide polymorphism array for population genomic studies in four European pine species.

Mol Ecol Resour 2020 Nov 28;20(6):1697-1705. Epub 2020 Jul 28.

UK Centre for Ecology & Hydrology Edinburgh, Penicuik, UK.

Pines are some of the most ecologically and economically important tree species in the world, and many have enormous natural distributions or have been extensively planted. However, a lack of rapid genotyping capability is hampering progress in understanding the molecular basis of genetic variation in these species. Here, we deliver an efficient tool for genotyping thousands of single nucleotide polymorphism (SNP) markers across the genome that can be applied to genetic studies in pines. Polymorphisms from resequenced candidate genes and transcriptome sequences of P. sylvestris, P. mugo, P. uncinata, P. uliginosa and P. radiata were used to design a 49,829 SNP array (Axiom_PineGAP, Thermo Fisher). Over a third (34.68%) of the unigenes identified from the P. sylvestris transcriptome were represented on the array, which was used to screen samples of four pine species. The conversion rate for the array on all samples was 42% (N = 20,795 SNPs) and was similar for SNPs sourced from resequenced candidate gene and transcriptome sequences. The broad representation of gene ontology terms by unigenes containing converted SNPs reflected their coverage across the full transcriptome. Over a quarter of successfully converted SNPs were polymorphic among all species, and the data were successful in discriminating among the species and some individual populations. The SNP array provides a valuable new tool to advance genetic studies in these species and demonstrates the effectiveness of the technology for rapid genotyping in species with large and complex genomes.
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http://dx.doi.org/10.1111/1755-0998.13223DOI Listing
November 2020

An improved pig reference genome sequence to enable pig genetics and genomics research.

Gigascience 2020 06;9(6)

The Roslin Institute and Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Easter Bush Campus, Midlothian EH25 9RG, UK.

Background: The domestic pig (Sus scrofa) is important both as a food source and as a biomedical model given its similarity in size, anatomy, physiology, metabolism, pathology, and pharmacology to humans. The draft reference genome (Sscrofa10.2) of a purebred Duroc female pig established using older clone-based sequencing methods was incomplete, and unresolved redundancies, short-range order and orientation errors, and associated misassembled genes limited its utility.

Results: We present 2 annotated highly contiguous chromosome-level genome assemblies created with more recent long-read technologies and a whole-genome shotgun strategy, 1 for the same Duroc female (Sscrofa11.1) and 1 for an outbred, composite-breed male (USMARCv1.0). Both assemblies are of substantially higher (>90-fold) continuity and accuracy than Sscrofa10.2.

Conclusions: These highly contiguous assemblies plus annotation of a further 11 short-read assemblies provide an unprecedented view of the genetic make-up of this important agricultural and biomedical model species. We propose that the improved Duroc assembly (Sscrofa11.1) become the reference genome for genomic research in pigs.
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http://dx.doi.org/10.1093/gigascience/giaa051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448572PMC
June 2020

Functional Annotation of the Transcriptome of the Pig, , Based Upon Network Analysis of an RNAseq Transcriptional Atlas.

Front Genet 2019 14;10:1355. Epub 2020 Feb 14.

Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, QLD, Australia.

The domestic pig () is both an economically important livestock species and a model for biomedical research. Two highly contiguous pig reference genomes have recently been released. To support functional annotation of the pig genomes and comparative analysis with large human transcriptomic data sets, we aimed to create a pig gene expression atlas. To achieve this objective, we extended a previous approach developed for the chicken. We downloaded RNAseq data sets from public repositories, down-sampled to a common depth, and quantified expression against a reference transcriptome using the mRNA quantitation tool, Kallisto. We then used the network analysis tool Graphia to identify clusters of transcripts that were coexpressed across the merged data set. Consistent with the principle of guilt-by-association, we identified coexpression clusters that were highly tissue or cell-type restricted and contained transcription factors that have previously been implicated in lineage determination. Other clusters were enriched for transcripts associated with biological processes, such as the cell cycle and oxidative phosphorylation. The same approach was used to identify coexpression clusters within RNAseq data from multiple individual liver and brain samples, highlighting cell type, process, and region-specific gene expression. Evidence of conserved expression can add confidence to assignment of orthology between pig and human genes. Many transcripts currently identified as novel genes with ENSSSCG or LOC IDs were found to be coexpressed with annotated neighbouring transcripts in the same orientation, indicating they may be products of the same transcriptional unit. The meta-analytic approach to utilising public RNAseq data is extendable to include new data sets and new species and provides a framework to support the Functional Annotation of Animals Genomes (FAANG) initiative.
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http://dx.doi.org/10.3389/fgene.2019.01355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7034361PMC
February 2020

Author Correction: The Beta-adrenergic agonist, Ractopamine, increases skeletal muscle expression of Asparagine Synthetase as part of an integrated stress response gene program.

Sci Rep 2019 Oct 28;9(1):15412. Epub 2019 Oct 28.

School of Biosciences, University of Nottingham, Sutton Bonington Campus, Loughborough, LE12 5RD, UK.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-019-43807-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817859PMC
October 2019

The Beta-adrenergic agonist, Ractopamine, increases skeletal muscle expression of Asparagine Synthetase as part of an integrated stress response gene program.

Sci Rep 2018 10 29;8(1):15915. Epub 2018 Oct 29.

School of Biosciences, University of Nottingham, Sutton Bonington Campus, Loughborough, LE12 5RD, UK.

Synthetic beta-adrenergic agonists (BA) have broad biomedical and agricultural application for increasing lean body mass, yet a poor understanding of the biology underpinning these agents is limiting further drug discovery potential. Growing female pigs (77 ± 7 kg) were administered the BA, Ractopamine (20 ppm in feed), or the recombinant growth hormone (GH), Reporcin (10 mg/48 hrs injected) for 1, 3, 7, 13 (n = 10 per treatment, per time point) or 27 days (n = 15 per treatment). Using RNA-sequencing and inferred pathway analysis, we examined temporal changes to the Longissimus Dorsi skeletal muscle transcriptome (n = 3 per treatment, per time point) relative to a feed-only control cohort. Gene expression changes were affirmed by quantitative-PCR on all samples (n = 164). RNA-sequencing analysis revealed that BA treatment had greater effects than GH, and that asparagine synthetase (Asns) was the 5 most significantly increased gene by BA at day 3. ASNS protein expression was dramatically increased by BA treatment at day 7 (p < 0.05). The most significantly increased gene at day 3 was activating transcription factor 5 (Atf5), a transcription factor known to regulate ASNS gene expression. Gene and protein expression of Atf4, another known regulator of Asns expression, was not changed by BA treatment. Expression of more than 20 known Atf4 target genes were increased by BA treatment, suggesting that BA treatment induces an integrated stress response (ISR) in skeletal muscle of pigs. In support of this, mRNA expression of sestrin-2 (Sesn2) and cyclin-dependant kinase 1 alpha (Cdkn1a), two key stress-responsive genes and negative regulators of cellular growth, were also strongly increased from day 3 of BA treatment. Finally, tRNA charging was the most significantly enriched pathway induced by BA treatment, suggesting alterations to the translational capacity/efficiency of the muscle. BA-mediated changes to the skeletal muscle transcriptome are highly indicative of an integrated stress response (ISR), particularly genes relating to amino acid biosynthesis and protein translational capacity.
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http://dx.doi.org/10.1038/s41598-018-34315-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6206132PMC
October 2018

Chicken anaemia virus evades host immune responses in transformed lymphocytes.

J Gen Virol 2018 Mar;99(3):321-327

Institute for Animal Health, Compton, UK.

Chicken anaemia virus (CAV) is a lymphotropic virus that causes anaemia and immunosuppression in chickens. Previously, we proposed that CAV evades host antiviral responses by disrupting T-cell signalling, but the precise cellular targets and modes of action remain elusive. In this study, we examined gene expression in Marek's disease virus-transformed chicken T-cell line MSB-1 after infection with CAV using both a custom 5K immune-focused microarray and quantitative real-time PCR at 24, 48 and 72 h post-infection. The data demonstrate an intricate equilibrium between CAV and the host gene expression, displaying subtle but significant modulation of transcripts involved in the T-cell, inflammation and NF-κB signalling cascades. CAV efficiently blocked the induction of type-I interferons and interferon-stimulated genes at 72 h. The cell expression pattern implies that CAV subverts host antiviral responses and that the transformed environment of MSB-1 cells offers an opportunistic advantage for virus growth.
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http://dx.doi.org/10.1099/jgv.0.001011DOI Listing
March 2018

Development of a Medium Density Combined-Species SNP Array for Pacific and European Oysters ( and ).

G3 (Bethesda) 2017 07 5;7(7):2209-2218. Epub 2017 Jul 5.

The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian EH25 9RG, United Kingdom

SNP arrays are enabling tools for high-resolution studies of the genetic basis of complex traits in farmed and wild animals. Oysters are of critical importance in many regions from both an ecological and economic perspective, and oyster aquaculture forms a key component of global food security. The aim of our study was to design a combined-species, medium density SNP array for Pacific oyster () and European flat oyster (), and to test the performance of this array on farmed and wild populations from multiple locations, with a focus on European populations. SNP discovery was carried out by whole-genome sequencing (WGS) of pooled genomic DNA samples from eight populations, and restriction site-associated DNA sequencing (RAD-Seq) of 11 geographically diverse populations. Nearly 12 million candidate SNPs were discovered and filtered based on several criteria, including preference for SNPs segregating in multiple populations and SNPs with monomorphic flanking regions. An Affymetrix Axiom Custom Array was created and tested on a diverse set of samples ( = 219) showing ∼27 K high quality SNPs for and ∼11 K high quality SNPs for segregating in these populations. A high proportion of SNPs were segregating in each of the populations, and the array was used to detect population structure and levels of linkage disequilibrium (LD). Further testing of the array on three nuclear families ( = 165) revealed that the array can be used to clearly distinguish between both families based on identity-by-state (IBS) clustering parental assignment software. This medium density, combined-species array will be publicly available through Affymetrix, and will be applied for genome-wide association and evolutionary genetic studies, and for genomic selection in oyster breeding programs.
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http://dx.doi.org/10.1534/g3.117.041780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5499128PMC
July 2017

FOXO1, PXK, PYCARD and SAMD9L are differentially expressed by fibroblast-like cells in equine synovial membrane compared to joint capsule.

BMC Vet Res 2017 Apr 14;13(1):106. Epub 2017 Apr 14.

Department of Veterinary Clinical Sciences, University of Copenhagen, Hoejbakkegaards alle 5, 2630, Taastrup, Denmark.

Background: The synovial membrane lines the luminal side of the joint capsule in synovial joints. It maintains joint homeostasis and plays a crucial role in equine joint pathology. When trauma or inflammation is induced in a joint, the synovial membrane influences progression of joint damage. Equine synovial membrane research is hampered by a lack of markers of fibroblast-like synoviocytes (FLS) to distinguish FLS from other fibroblast-like cells in musculoskeletal connective tissues. The aim of this study is to identify potential FLS markers of the equine synovial membrane using microarray to compare between gene expression in equine synovial membrane and the joint capsule in metacarpophalangeal joints.

Results: Microarray analysis of tissues from 6 horses resulted in 1167 up-regulated genes in synovial membrane compared with joint capsule. Pathway analysis resulted in 241 candidate genes. Of these, 15 genes were selected for further confirmation as genes potentially expressed by fibroblast-like synoviocytes. Four genes: FOXO1, PXK, PYCARD and SAMD9L were confirmed in 9 horses by qPCR as differentially expressed in synovial membrane compared to joint capsule.

Conclusions: In conclusion, FOXO1, PXK, PYCARD and SAMD9L were confirmed as differentially expressed in synovial membrane compared to joint capsule. These four genes are potential markers of fibroblast-like synoviocytes of the synovial membrane. As these genes are overexpressed in synovial membrane compared to joint capsule, these genes could shed light on synovial membrane physiology and its role in joint disease.
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http://dx.doi.org/10.1186/s12917-017-1003-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5391632PMC
April 2017

Rapid Diagnosis of Rhabdomyolysis with Point-of-Care Ultrasound.

West J Emerg Med 2016 Nov 2;17(6):801-804. Epub 2016 Nov 2.

University of South Florida, Division of Emergency Medicine, Tampa, Florida.

It is important to rapidly diagnosis and treat rhabdomyolysis in order to decrease morbidity and mortality. To date there are no reports in the emergency medicine literature on the use of point-of-care ultrasound in the diagnosis of rhabdomyolysis. This unique case describes how ultrasound was used in the emergency department (ED) to quickly diagnose and treat rhabdomyolysis prior to confirmation with an elevated serum creatine kinase. When coupled with a high index of suspicion, ultrasound can be one of the most portable, readily available, low cost, and minimally invasive techniques for making a rapid diagnosis of rhabdomyolysis in the ED.
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http://dx.doi.org/10.5811/westjem.2016.8.31255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5102611PMC
November 2016

Evaluating the Benefits of Aphasia Intervention Delivered in Virtual Reality: Results of a Quasi-Randomised Study.

PLoS One 2016 12;11(8):e0160381. Epub 2016 Aug 12.

Division of Language and Communication Science, City University London, London, United Kingdom.

Introduction: This study evaluated an intervention for people with aphasia delivered in a novel virtual reality platform called EVA Park. EVA Park contains a number of functional and fantastic locations and allows for interactive communication between multiple users. Twenty people with aphasia had 5 weeks' intervention, during which they received daily language stimulation sessions in EVA Park from a support worker. The study employed a quasi randomised design, which compared a group that received immediate intervention with a waitlist control group. Outcome measures explored the effects of intervention on communication and language skills, communicative confidence and feelings of social isolation. Compliance with the intervention was also explored through attrition and usage data.

Results: There was excellent compliance with the intervention, with no participants lost to follow up and most (18/20) receiving at least 88% of the intended treatment dose. Intervention brought about significant gains on a measure of functional communication. Gains were achieved by both groups of participants, once intervention was received, and were well maintained. Changes on the measures of communicative confidence and feelings of social isolation were not achieved. Results are discussed with reference to previous aphasia therapy findings.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0160381PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4982664PMC
July 2017

Genetic loci inherited from hens lacking maternal behaviour both inhibit and paradoxically promote this behaviour.

Genet Sel Evol 2015 Dec 30;47:100. Epub 2015 Dec 30.

Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh Easter Bush, Midlothian, EH25 9RG, Scotland, UK.

Background: A major step towards the success of chickens as a domesticated species was the separation between maternal care and reproduction. Artificial incubation replaced the natural maternal behaviour of incubation and, thus, in certain breeds, it became possible to breed chickens with persistent egg production and no incubation behaviour; a typical example is the White Leghorn strain. Conversely, some strains, such as the Silkie breed, are prized for their maternal behaviour and their willingness to incubate eggs. This is often colloquially known as broodiness.

Results: Using an F2 linkage mapping approach and a cross between White Leghorn and Silkie chicken breeds, we have mapped, for the first time, genetic loci that affect maternal behaviour on chromosomes 1, 5, 8, 13, 18 and 19 and linkage group E22C19W28. Paradoxically, heterozygous and White Leghorn homozygous genotypes were associated with an increased incidence of incubation behaviour, which exceeded that of the Silkie homozygotes for most loci. In such cases, it is likely that the loci involved are associated with increased egg production. Increased egg production increases the probability of incubation behaviour occurring because egg laying must precede incubation. For the loci on chromosomes 8 and 1, alleles from the Silkie breed promote incubation behaviour and influence maternal behaviour (these explain 12 and 26% of the phenotypic difference between the two founder breeds, respectively).

Conclusions: The over-dominant locus on chromosome 5 coincides with the strongest selective sweep reported in chickens and together with the loci on chromosomes 1 and 8, they include genes of the thyrotrophic axis. This suggests that thyroid hormones may play a critical role in the loss of incubation behaviour and the improved egg laying behaviour of the White Leghorn breed. Our findings support the view that loss of maternal incubation behaviour in the White Leghorn breed is the result of selection for fertility and egg laying persistency and against maternal incubation behaviour.
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http://dx.doi.org/10.1186/s12711-015-0180-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4697313PMC
December 2015

Using Targeted Resequencing for Identification of Candidate Genes and SNPs for a QTL Affecting the pH Value of Chicken Meat.

G3 (Bethesda) 2015 Aug 14;5(10):2085-9. Epub 2015 Aug 14.

Swedish University of Agricultural Sciences, SE-750 07 Uppsala, Sweden, Roslin Institute and R(D)SVS, University of Edinburgh, Midlothian, EH25 9RG, United Kingdom

Using targeted genetical genomics, a quantitative trait locus (QTL) affecting the initial postmortem pH value of chicken breast muscle (Pectoralis major) on chromosome 1 (GGA1) recently was fine-mapped. Thirteen genes were present in the QTL region of approximately 1 Mb. In this study, 10 birds that were inferred to be homozygous for either the high (QQ) or low (qq) QTL allele were selected for resequencing. After enrichment for 1 Mb around the QTL region, >500 × coverage for the QTL region in each of the 10 birds was obtained. In total 5056 single-nucleotide polymorphisms (SNPs) were identified for which the genotypes were consistent with one of the QTL genotypes. We used custom tools to identify putative causal mutations in the mapped QTL region from these SNPs. Four nonsynonymous SNPs differentiating the two QTL genotype groups were identified within four local genes (PRDX4, EIF2S3, PCYT1B, and E1BTD2). Although these are likely candidate SNPs to explain the QTL effect, 54 additional consensus SNPs were detected within gene-related regions (untranslated regions, splicing sites CpG island, and promoter regions) for the QQ birds and 71 for the qq birds. These could also play a role explaining the observed QTL effect. The results provide an important step for prioritizing among a large amount of candidate mutations and significantly contribute to the understanding of the genetic mechanisms affecting the initial postmortem pH value of chicken muscle.
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http://dx.doi.org/10.1534/g3.115.020552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4592991PMC
August 2015

Transcriptomic Profiling of Virus-Host Cell Interactions following Chicken Anaemia Virus (CAV) Infection in an In Vivo Model.

PLoS One 2015 5;10(8):e0134866. Epub 2015 Aug 5.

Institute for Animal Health, Compton, United Kingdom.

Chicken Anaemia Virus (CAV) is an economically important virus that targets lymphoid and erythroblastoid progenitor cells leading to immunosuppression. This study aimed to investigate the interplay between viral infection and the host's immune response to better understand the pathways that lead to CAV-induced immunosuppression. To mimic vertical transmission of CAV in the absence of maternally-derived antibody, day-old chicks were infected and their responses measured at various time-points post-infection by qRT-PCR and gene expression microarrays. The kinetics of mRNA expression levels of signature cytokines of innate and adaptive immune responses were determined by qRT-PCR. The global gene expression profiles of mock-infected (control) and CAV-infected chickens at 14 dpi were also compared using a chicken immune-related 5K microarray. Although in the thymus there was evidence of induction of an innate immune response following CAV infection, this was limited in magnitude. There was little evidence of a Th1 adaptive immune response in any lymphoid tissue, as would normally be expected in response to viral infection. Most cytokines associated with Th1, Th2 or Treg subsets were down-regulated, except IL-2, IL-13, IL-10 and IFNγ, which were all up-regulated in thymus and bone marrow. From the microarray studies, genes that exhibited significant (greater than 1.5-fold, false discovery rate <0.05) changes in expression in thymus and bone marrow on CAV infection were mainly associated with T-cell receptor signalling, immune response, transcriptional regulation, intracellular signalling and regulation of apoptosis. Expression levels of a number of adaptor proteins, such as src-like adaptor protein (SLA), a negative regulator of T-cell receptor signalling and the transcription factor Special AT-rich Binding Protein 1 (SATB1), were significantly down-regulated by CAV infection, suggesting potential roles for these genes as regulators of viral infection or cell defence. These results extend our understanding of CAV-induced immunosuppression and suggest a global immune dysregulation following CAV infection.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0134866PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526643PMC
May 2016

Central and systemic inflammatory responses to thoracotomy - potential implications for acute and chronic postsurgical pain.

J Neuroimmunol 2015 Aug 21;285:147-9. Epub 2015 Jun 21.

Department of Pain Medicine, St. James's Hospital, Dublin, Ireland; Trinity College Institute of Neuroscience, Trinity College Dublin, Ireland.

Chronic postsurgical pain (CPSP) may affect up to 70% of patients after surgery. Glial and immune mediators have been implicated in the pathogenesis of chronic postsurgical pain. Our objective was to study cerebrospinal fluid (CSF) and serum concentrations of IL-1β, IL-6, IL-8, IL-10, IFNγ and TNFα over a 72-hour period in patients undergoing a thoracotomy and oesophagectomy. Despite adequate pain control, thoracotomy was still associated with significant central and peripheral inflammation. This must be taken into consideration in planning future strategies to prevent CPSP.
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http://dx.doi.org/10.1016/j.jneuroim.2015.06.010DOI Listing
August 2015

Open-frame system for single-molecule microscopy.

Rev Sci Instrum 2015 Mar;86(3):033701

Department of Physics, McGill University, Montreal, Quebec H3A 2T8, Canada.

We present the design and construction of a versatile, open frame inverted microscope system for wide-field fluorescence and single molecule imaging. The microscope chassis and modular design allow for customization, expansion, and experimental flexibility. We present two components which are included with the microscope which extend its basic capabilities and together create a powerful microscopy system: A Convex Lens-induced Confinement device provides the system with single-molecule imaging capabilities, and a two-color imaging system provides the option of imaging multiple molecular species simultaneously. The flexibility of the open-framed chassis combined with accessible single-molecule, multi-species imaging technology supports a wide range of new measurements in the health, nanotechnology, and materials science research sectors.
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http://dx.doi.org/10.1063/1.4913271DOI Listing
March 2015

poRe: an R package for the visualization and analysis of nanopore sequencing data.

Bioinformatics 2015 Jan 29;31(1):114-5. Epub 2014 Aug 29.

Edinburgh Genomics, The Roslin Institute and R(D)SVS, University of Edinburgh, Easter Bush, Edinburgh EH25 9RG and Edinburgh Genomics, Institute of Evolutionary Biology, Ashworth Laboratories, University of Edinburgh, Edinburgh EH9 3JT, UK.

Motivation: The Oxford Nanopore MinION device represents a unique sequencing technology. As a mobile sequencing device powered by the USB port of a laptop, the MinION has huge potential applications. To enable these applications, the bioinformatics community will need to design and build a suite of tools specifically for MinION data.

Results: Here we present poRe, a package for R that enables users to manipulate, organize, summarize and visualize MinION nanopore sequencing data. As a package for R, poRe has been tested on Windows, Linux and MacOSX. Crucially, the Windows version allows users to analyse MinION data on the Windows laptop attached to the device.

Availability And Implementation: poRe is released as a package for R at http://sourceforge.net/projects/rpore/. A tutorial and further information are available at https://sourceforge.net/p/rpore/wiki/Home/.
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http://dx.doi.org/10.1093/bioinformatics/btu590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4271141PMC
January 2015

SDF-1 chemokine signalling modulates the apoptotic responses to iron deprivation of clathrin-depleted DT40 cells.

PLoS One 2014 27;9(8):e106278. Epub 2014 Aug 27.

Department of Biochemistry, Hopkins Building, University of Cambridge, Cambridge, United Kingdom.

We have previously deleted both endogenous copies of the clathrin heavy-chain gene in the chicken pre B-cell-line DT40 and replaced them with clathrin under the control of a tetracycline-regulatable promoter (Tet-Off). The originally derived cell-line DKO-S underwent apoptosis when clathrin expression was repressed. We have also described a cell-line DKO-R derived from DKO-S cells that was less sensitive to clathrin-depletion. Here we show that the restriction of transferrin uptake, resulting in iron deprivation, is responsible for the lethal consequence of clathrin-depletion. We further show that the DKO-R cells have up-regulated an anti-apoptotic survival pathway based on the chemokine SDF-1 and its receptor CXCR4. Our work clarifies several puzzling features of clathrin-depleted DT40 cells and reveals an example of how SDF-1/CXCR4 signalling can abrogate pro-apoptotic pathways and increase cell survival. We propose that the phenomenon described here has implications for the therapeutic approach to a variety of cancers.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0106278PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4146602PMC
November 2015

Draft Genome Sequence of Escherichia coli MS499, Isolated from the Infected Uterus of a Postpartum Cow with Metritis.

Genome Announc 2014 Jul 3;2(4). Epub 2014 Jul 3.

Specific Escherichia coli strains associated with bovine postpartum uterine infection have recently been described. Many recognized virulence factors are absent in these strains; therefore, to define a prototypic strain, we report here the genome sequence of E. coli isolate MS499 from a cow with the postpartum disease metritis.
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http://dx.doi.org/10.1128/genomeA.00217-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081991PMC
July 2014

Design and development of exome capture sequencing for the domestic pig (Sus scrofa).

BMC Genomics 2014 Jul 3;15:550. Epub 2014 Jul 3.

The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Edinburgh EH25 9RG, UK.

Background: The domestic pig (Sus scrofa) is both an important livestock species and a model for biomedical research. Exome sequencing has accelerated identification of protein-coding variants underlying phenotypic traits in human and mouse. We aimed to develop and validate a similar resource for the pig.

Results: We developed probe sets to capture pig exonic sequences based upon the current Ensembl pig gene annotation supplemented with mapped expressed sequence tags (ESTs) and demonstrated proof-of-principle capture and sequencing of the pig exome in 96 pigs, encompassing 24 capture experiments. For most of the samples at least 10x sequence coverage was achieved for more than 90% of the target bases. Bioinformatic analysis of the data revealed over 236,000 high confidence predicted SNPs and over 28,000 predicted indels.

Conclusions: We have achieved coverage statistics similar to those seen with commercially available human and mouse exome kits. Exome capture in pigs provides a tool to identify coding region variation associated with production traits, including loss of function mutations which may explain embryonic and neonatal losses, and to improve genomic assemblies in the vicinity of protein coding genes in the pig.
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http://dx.doi.org/10.1186/1471-2164-15-550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4099480PMC
July 2014

The sheep genome illuminates biology of the rumen and lipid metabolism.

Science 2014 Jun;344(6188):1168-1173

CSIRO Animal Food and Health Sciences, St Lucia, QLD 4067, Australia.

Sheep (Ovis aries) are a major source of meat, milk, and fiber in the form of wool and represent a distinct class of animals that have a specialized digestive organ, the rumen, that carries out the initial digestion of plant material. We have developed and analyzed a high-quality reference sheep genome and transcriptomes from 40 different tissues. We identified highly expressed genes encoding keratin cross-linking proteins associated with rumen evolution. We also identified genes involved in lipid metabolism that had been amplified and/or had altered tissue expression patterns. This may be in response to changes in the barrier lipids of the skin, an interaction between lipid metabolism and wool synthesis, and an increased role of volatile fatty acids in ruminants compared with nonruminant animals.
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http://dx.doi.org/10.1126/science.1252806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157056PMC
June 2014

Draft Genome Sequence of Trueperella pyogenes, Isolated from the Infected Uterus of a Postpartum Cow with Metritis.

Genome Announc 2014 Apr 24;2(2). Epub 2014 Apr 24.

Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.

Trueperella pyogenes is a common commensal bacterium and an opportunistic pathogen associated with chronic purulent disease, particularly in ruminants. We report here the genome sequence of a T. pyogenes isolate from a severe case of bovine metritis. This is the first full record of a T. pyogenes genome.
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http://dx.doi.org/10.1128/genomeA.00194-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3999489PMC
April 2014

Genomic variation in macrophage-cultured European porcine reproductive and respiratory syndrome virus Olot/91 revealed using ultra-deep next generation sequencing.

Virol J 2014 Mar 4;11:42. Epub 2014 Mar 4.

The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Edinburgh EH25 9RG, UK.

Background: Porcine Reproductive and Respiratory Syndrome (PRRS) is a disease of major economic impact worldwide. The etiologic agent of this disease is the PRRS virus (PRRSV). Increasing evidence suggest that microevolution within a coexisting quasispecies population can give rise to high sequence heterogeneity in PRRSV.

Findings: We developed a pipeline based on the ultra-deep next generation sequencing approach to first construct the complete genome of a European PRRSV, strain Olot/9, cultured on macrophages and then capture the rare variants representative of the mixed quasispecies population. Olot/91 differs from the reference Lelystad strain by about 5% and a total of 88 variants, with frequencies as low as 1%, were detected in the mixed population. These variants included 16 non-synonymous variants concentrated in the genes encoding structural and nonstructural proteins; including Glycoprotein 2a and 5.

Conclusion: Using an ultra-deep sequencing methodology, the complete genome of Olot/91 was constructed without any prior knowledge of the sequence. Rare variants that constitute minor fractions of the heterogeneous PRRSV population could successfully be detected to allow further exploration of microevolutionary events.
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http://dx.doi.org/10.1186/1743-422X-11-42DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3945042PMC
March 2014

Development and validation of a high density SNP genotyping array for Atlantic salmon (Salmo salar).

BMC Genomics 2014 Feb 6;15:90. Epub 2014 Feb 6.

The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian EH25 9RG, UK.

Background: Dense single nucleotide polymorphism (SNP) genotyping arrays provide extensive information on polymorphic variation across the genome of species of interest. Such information can be used in studies of the genetic architecture of quantitative traits and to improve the accuracy of selection in breeding programs. In Atlantic salmon (Salmo salar), these goals are currently hampered by the lack of a high-density SNP genotyping platform. Therefore, the aim of the study was to develop and test a dense Atlantic salmon SNP array.

Results: SNP discovery was performed using extensive deep sequencing of Reduced Representation (RR-Seq), Restriction site-Associated DNA (RAD-Seq) and mRNA (RNA-Seq) libraries derived from farmed and wild Atlantic salmon samples (n = 283) resulting in the discovery of > 400 K putative SNPs. An Affymetrix Axiom® myDesign Custom Array was created and tested on samples of animals of wild and farmed origin (n = 96) revealing a total of 132,033 polymorphic SNPs with high call rate, good cluster separation on the array and stable Mendelian inheritance in our sample. At least 38% of these SNPs are from transcribed genomic regions and therefore more likely to include functional variants. Linkage analysis utilising the lack of male recombination in salmonids allowed the mapping of 40,214 SNPs distributed across all 29 pairs of chromosomes, highlighting the extensive genome-wide coverage of the SNPs. An identity-by-state clustering analysis revealed that the array can clearly distinguish between fish of different origins, within and between farmed and wild populations. Finally, Y-chromosome-specific probes included on the array provide an accurate molecular genetic test for sex.

Conclusions: This manuscript describes the first high-density SNP genotyping array for Atlantic salmon. This array will be publicly available and is likely to be used as a platform for high-resolution genetics research into traits of evolutionary and economic importance in salmonids and in aquaculture breeding programs via genomic selection.
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http://dx.doi.org/10.1186/1471-2164-15-90DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3923896PMC
February 2014

The early phase transcriptome of bovine monocyte-derived macrophages infected with Staphylococcus aureus in vitro.

BMC Genomics 2013 Dec 17;14:891. Epub 2013 Dec 17.

Department of Basic Sciences and Aquatic Medicine, Norwegian School of Veterinary Science, P,O, Box 8146 Dep, NO-0033 Oslo, Norway.

Background: In the mammary gland, local recruitment and action of macrophages is a key immunological defence mechanism against infection. Macrophages are members of the innate immune system, serve as the first line of the defence against invading pathogens and are critical effectors and regulators of inflammation. We have examined the early phase response of bovine macrophages to infection with live Staphylococcus aureus. Genome-wide transcript profiling of blood monocyte-derived macrophages from six Norwegian Red heifers infected with live S. aureus for 2 and 6 hours in vitro was performed.

Results: About 420 of the 17 000 genes on the ARK-Genomics bovine cDNA array were differentially regulated at 6 hours post infection. Approximately 70% of the responding genes had a known identity (Entrez Gene ID) and were used in the identification of overrepresented pathways and biological functions in the dataset.Analysis of a subset of differentially regulated genes (List eQG) obtained by comparison with data from genome-wide association mapping in Norwegian Red cattle identified anti-inflammatory cytokines interleukin 4 and interleukin 13 as putative expression quantitative trait loci, suggesting that S. aureus infection triggers alternative activation of macrophages. Moreover, several classical activation pathways were found, mainly cellular immune response and cytokine signaling pathways, i.e. triggering receptor expressed on myeloid cells 1 (TREM1) and nucleotide-binding and oligomerization domain-like receptor (NLR) pathways. Tumor necrosis factor receptor superfamily member 5 (CD40 ligand) was identified as an upstream regulator which points toward CD40 likely acting as a co-stimulatory receptor during Toll-like receptor 2(TLR2)-mediated inflammatory response of bovine macrophages to S. aureus infection. Furthermore, peptidoglycan was identified as an upstream regulator in the List eQG, which indicates that this bacterial cell-wall component might be pivotal in macrophage intracellular bacterial recognition during early inflammation.

Conclusions: Here we have shown that in vitro infection of bovine macrophages with live S. aureus induced both alternative and classical activation pathways. Alternative activation of macrophages may be a mechanism contributing to intracellular persistence of S. aureus in the course of inflammation such as during mastitis in dairy cattle.
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http://dx.doi.org/10.1186/1471-2164-14-891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3878444PMC
December 2013

Controlled hypertension induces cerebrovascular and gene alterations in Cyp1a1-Ren2 transgenic rats.

J Am Soc Hypertens 2013 Nov-Dec;7(6):411-9. Epub 2013 Oct 8.

Centre for Neuroregeneration, University of Edinburgh, Edinburgh, UK; Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh, UK. Electronic address:

Hypertension is a major risk factor for small vessel disease and dementia, but the pathogenic mechanisms are not fully known. This study aimed to assess cerebrovascular alterations in response to different durations (4 or 6 months) of controlled hypertension in an inducible transgenic rat model of hypertension (Cyp1a1-Ren2) as compared with normotensive litter mate controls. After 6 months of hypertension as compared with controls, a significant reduction in vascular width was paralleled by an increase in the protein levels of claudin-5, an endothelial tight junction protein. Notably, vascular alterations were associated with increased microglia, and these changes were preceded by increased eNOS expression. Investigation of global gene expression by microarray analysis indicated alterations in predominantly growth factor related genes. Herein, we show that modest, sustained levels of hypertension are sufficient to cause cerebrovascular alterations accompanied by endothelial and inflammatory changes. These changes are paralleled by alterations in growth factor expression suggestive of a mechanistic role.
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http://dx.doi.org/10.1016/j.jash.2013.07.011DOI Listing
September 2014

Development of a high density 600K SNP genotyping array for chicken.

BMC Genomics 2013 Jan 28;14:59. Epub 2013 Jan 28.

Aviagen Ltd, Midlothian, UK.

Background: High density (HD) SNP genotyping arrays are an important tool for genetic analyses of animals and plants. Although the chicken is one of the most important farm animals, no HD array is yet available for high resolution genetic analysis of this species.

Results: We report here the development of a 600 K Affymetrix® Axiom® HD genotyping array designed using SNPs segregating in a wide variety of chicken populations. In order to generate a large catalogue of segregating SNPs, we re-sequenced 243 chickens from 24 chicken lines derived from diverse sources (experimental, commercial broiler and layer lines) by pooling 10-15 samples within each line. About 139 million (M) putative SNPs were detected by mapping sequence reads to the new reference genome (Gallus_gallus_4.0) of which ~78 M appeared to be segregating in different lines. Using criteria such as high SNP-quality score, acceptable design scores predicting high conversion performance in the final array and uniformity of distribution across the genome, we selected ~1.8 M SNPs for validation through genotyping on an independent set of samples (n = 282). About 64% of the SNPs were polymorphic with high call rates (>98%), good cluster separation and stable Mendelian inheritance. Polymorphic SNPs were further analysed for their population characteristics and genomic effects. SNPs with extreme breach of Hardy-Weinberg equilibrium (P < 0.00001) were excluded from the panel. The final array, designed on the basis of these analyses, consists of 580,954 SNPs and includes 21,534 coding variants. SNPs were selected to achieve an essentially uniform distribution based on genetic map distance for both broiler and layer lines. Due to a lower extent of LD in broilers compared to layers, as reported in previous studies, the ratio of broiler and layer SNPs in the array was kept as 3:2. The final panel was shown to genotype a wide range of samples including broilers and layers with over 100 K to 450 K informative SNPs per line. A principal component analysis was used to demonstrate the ability of the array to detect the expected population structure which is an important pre-investigation step for many genome-wide analyses.

Conclusions: This Affymetrix® Axiom® array is the first SNP genotyping array for chicken that has been made commercially available to the public as a product. This array is expected to find widespread usage both in research and commercial application such as in genomic selection, genome-wide association studies, selection signature analyses, fine mapping of QTLs and detection of copy number variants.
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http://dx.doi.org/10.1186/1471-2164-14-59DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3598943PMC
January 2013

Escherichia coli- and Staphylococcus aureus-induced mastitis differentially modulate transcriptional responses in neighbouring uninfected bovine mammary gland quarters.

BMC Genomics 2013 Jan 16;14:36. Epub 2013 Jan 16.

Division of Infection & Immunity, The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, UK.

Background: The most important disease of dairy cattle is mastitis, caused by the infection of the mammary gland by various micro-organisms. Although the transcriptional response of bovine mammary gland cells to in vitro infection has been studied, the interplay and consequences of these responses in the in vivo environment of the mammary gland are less clear. Previously mammary gland quarters were considered to be unaffected by events occurring in neighbouring quarters. More recently infection of individual quarters with mastitis causing pathogens, especially Escherichia coli, has been shown to influence the physiology of neighbouring uninfected quarters. Therefore, the transcriptional responses of uninfected mammary gland quarters adjacent to quarters infected with two major mastitis causing pathogens, E. coli and Staphylococcus aureus, were compared.

Results: The bacteriologically sterile, within-animal control quarters exhibited a transcriptional response to the infection of neighbouring quarters. The greatest response was associated with E. coli infection, while a weaker, yet significant, response occurred during S. aureus infection. The transcriptional responses of these uninfected quarters included the enhanced expression of many genes previously associated with mammary gland infections. Comparison of the transcriptional response of uninfected quarters to S. aureus and E. coli infection identified 187 differentially expressed genes, which were particularly associated with cellular responses, e.g. response to stress. The most affected network identified by Ingenuity Pathway analysis has the immunosuppressor transforming growth factor beta 1 (TGFB1) at its hub and largely consists of genes more highly expressed in control quarters from S. aureus infected cows.

Conclusions: Uninfected mammary gland quarters reacted to the infection of neighbouring quarters and the responses were dependent on pathogen type. Therefore, bovine udder quarters exhibit interdependence and should not be considered as separate functional entities. This suggests that mastitis pathogens not only interact directly with host mammary cells, but also influence discrete sites some distance away, which will affect their response to the subsequent spread of the infection. Understanding the underlying mechanisms may provide further clues for ways to control mammary gland infections. These results also have implications for the design of experimental studies investigating immune regulatory mechanisms in the bovine mammary gland.
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http://dx.doi.org/10.1186/1471-2164-14-36DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3598231PMC
January 2013

Reprogramming pig fetal fibroblasts reveals a functional LIF signaling pathway.

Cell Reprogram 2012 Apr 17;14(2):112-22. Epub 2012 Feb 17.

The Roslin Institute and Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Easter Bush, Midlothian, United Kingdom.

Distinct signaling pathways are reported to maintain pluripotency in embryo-derived stem cells. Mouse embryonic stem cells (ESCs) respond to leukemia inhibitory factor (LIF) and bone morphogenetic protein (BMP)-mediated activity, whereas human ESCs depend upon Fibroblast growth factor (FGF) and activin signaling. In the majority of mammals investigated, however, the signals that support stem cell pluripotency are not well defined, as is evident by the persistent difficulties in maintaining authentic stable ESC lines. Induction of pluripotency by transcription factor-mediated reprogramming could provide an alternative way to produce ESC-like cells from nonpermissive species, and facilitate identification of core ESC signaling requirements. To evaluate the effectiveness of this approach in pigs, we transduced porcine foetal fibroblasts with retroviruses expressing Oct4, Sox2, Klf4, and c-Myc, and maintained the resulting cultures in medium containing either LIF or FGF2. Alkaline phosphatase positive colonies with compact, mouse ESC-like morphology were preferentially recovered using serum-free medium supplemented with LIF. These cell lines expressed the endogenous stem cell transcription factors, OCT4, NANOG, and SOX2, and the cell surface marker SSEA-4, consistent with acquisition of an undifferentiated state. However, restricted differentiation potential, and persistent expression of retroviral transgenes indicated that reprogramming was incomplete. Interestingly, LIF activated both the transcription factor STAT3 and its target gene SOCS3, and stimulated cell growth, indicating functional coupling of the signaling pathway in these cells. This demonstration of LIF-dependence in reprogrammed pig cells supports the notion that the connection between LIF/STAT3 signaling and the core regulatory network of pluripotent stem cells is a conserved pathway in mammals.
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http://dx.doi.org/10.1089/cell.2011.0078DOI Listing
April 2012

Somatic retrotransposition alters the genetic landscape of the human brain.

Nature 2011 Oct 30;479(7374):534-7. Epub 2011 Oct 30.

Division of Genetics and Genomics, The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Edinburgh EH25 9RG, UK.

Retrotransposons are mobile genetic elements that use a germline 'copy-and-paste' mechanism to spread throughout metazoan genomes. At least 50 per cent of the human genome is derived from retrotransposons, with three active families (L1, Alu and SVA) associated with insertional mutagenesis and disease. Epigenetic and post-transcriptional suppression block retrotransposition in somatic cells, excluding early embryo development and some malignancies. Recent reports of L1 expression and copy number variation in the human brain suggest that L1 mobilization may also occur during later development. However, the corresponding integration sites have not been mapped. Here we apply a high-throughput method to identify numerous L1, Alu and SVA germline mutations, as well as 7,743 putative somatic L1 insertions, in the hippocampus and caudate nucleus of three individuals. Surprisingly, we also found 13,692 somatic Alu insertions and 1,350 SVA insertions. Our results demonstrate that retrotransposons mobilize to protein-coding genes differentially expressed and active in the brain. Thus, somatic genome mosaicism driven by retrotransposition may reshape the genetic circuitry that underpins normal and abnormal neurobiological processes.
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http://dx.doi.org/10.1038/nature10531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3224101PMC
October 2011