The Roslin Institute

Genetics and Genomics

Recent Publications

  • Analysis of the human monocyte-derived macrophage transcriptome and response to lipopolysaccharide provides new insights into genetic aetiology of inflammatory bowel disease John Baillie, Erik Arner, Carsten Daub, Michiel De Hoon, Masayoshi Itoh, Hideya Kawaji, Timo Lassmann, Piero Carninci, Alistair R.R. Forrest, Yoshihide Hayashizaki, The FANTOM Consortium, Geoff Faulkner, Christine A. Wells, Michael Rehli, Paul Pavli, Kim Summers, David Hume — 06 Mar 2017 — PLoS Genetics Vol: 13
    Abstract
    The FANTOM5 consortium utilised cap analysis of gene expression (CAGE) to provide an unprecedented insight into transcriptional regulation in human cells and tissues. In the current study, we have used CAGE-based transcriptional profiling on an extended dense time course of the response of human monocyte-derived macrophages grown in macrophage colony-stimulating factor (CSF1) to bacterial lipopolysaccharide (LPS). We propose that this system provides a model for the differentiation and adaptation of monocytes entering the intestinal lamina propria. The response to LPS is shown to be a cascade of successive waves of transient gene expression extending over at least 48 hours, with hundreds of positive and negative regulatory loops. Promoter analysis using motif activity response analysis (MARA) identified some of the transcription factors likely to be responsible for the temporal profile of transcriptional activation. Each LPS-inducible locus was associated with multiple inducible enhancers, and in each case, transient eRNA transcription at multiple sites detected by CAGE preceded the appearance of promoter-associated transcripts. LPS-inducible long non-coding RNAs were commonly associated with clusters of inducible enhancers. We used these data to re-examine the hundreds of loci associated with susceptibility to inflammatory bowel disease (IBD) in genome-wide association studies. Loci associated with IBD were strongly and specifically (relative to rheumatoid arthritis and unrelated traits) enriched for promoters that were regulated in monocyte differentiation or activation. Amongst previously-identified IBD susceptibility loci, the vast majority contained at least one promoter that was regulated in CSF1-dependent monocyte-macrophage transitions and/or in response to LPS. On this basis, we concluded that IBD loci are strongly-enriched for monocyte-specific genes, and identified at least 134 additional candidate genes associated with IBD susceptibility from reanalysis of published GWA studies. We propose that dysregulation of monocyte adaptation to the environment of the gastrointestinal mucosa is the key process leading to inflammatory bowel disease.
    DOI
    10.1371/journal.pgen.1006641
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    http://www.research.ed.ac.uk/portal/files/33353227/journal.pgen.1006641.pdf
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  • Analysis of gene expression in the nervous system identifies key genes and novel candidates for health and disease Sarah M Carpanini, Thomas M Wishart, Thomas H Gillingwater, Jean C Manson, Kim M Summers — Apr 2017 — Neurogenetics Vol: 18 Pages: 81-95
    Abstract
    The incidence of neurodegenerative diseases in the developed world has risen over the last century, concomitant with an increase in average human lifespan. A major challenge is therefore to identify genes that control neuronal health and viability with a view to enhancing neuronal health during ageing and reducing the burden of neurodegeneration. Analysis of gene expression data has recently been used to infer gene functions for a range of tissues from co-expression networks. We have now applied this approach to transcriptomic datasets from the mammalian nervous system available in the public domain. We have defined the genes critical for influencing neuronal health and disease in different neurological cell types and brain regions. The functional contribution of genes in each co-expression cluster was validated using human disease and knockout mouse phenotypes, pathways and GO term annotation. Additionally a number of poorly annotated genes were implicated by this approach in nervous system function. Exploiting gene expression data available in the public domain allowed us to validate key nervous system genes and importantly identify additional genes with minimal functional annotation but the same expression pattern. These genes are thus novel candidates for a role in neurological health and disease, and could now be further investigated to confirm their function and regulation during ageing and neurodegeneration.
    DOI
    10.1007/s10048-017-0509-5
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    http://www.research.ed.ac.uk/portal/files/31168671/art_3A10.1007_2Fs10048_017_0509_5.pdf
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  • Expression of FBN1 during adipogenesis: relevance to the lipodystrophy phenotype in Marfan syndrome and related conditions Margaret R Davis, Erik Arner, Cairnan R E Duffy, Paul De Sousa, Ingrid Dahlman, Peter Arner, Kim Summers — Sep 2016 — Molecular Genetics and Metabolism Vol: 119 Pages: 174-185
    Abstract
    Fibrillin-1 is a large glycoprotein encoded by the FBN1 gene in humans. It provides strength and elasticity to connective tissues and is involved in regulating the bioavailability of the growth factor TGFβ. Mutations in FBN1 may be associated with depleted or abnormal adipose tissue, seen in some patients with Marfan syndrome and lipodystrophies. As this lack of adipose tissue does not result in high morbidity or mortality, it is generally underappreciated but is a cause of psychosocial problems. We examined the role of fibrillin-1 in adipogenesis. In inbred mouse strains we found significant variation in the level of expression in the Fbn1 gene that correlated with variation in several measures of body fat, suggesting that mouse fibrillin-1 is associated with the level of fat tissue. Furthermore, we found that FBN1 mRNA was up-regulated in the adipose tissue of obese women compared to non-obese, and associated with an increase in adipocyte size. We used human mesenchymal stem cells differentiated in culture to adipocytes to show that fibrillin-1 declines after the initiation of differentiation. Gene expression results from a similar experiment (available through the FANTOM5 project) revealed that the decline in fibrillin-1 protein was paralleled by a decline in FBN1 mRNA. Examination of the FBN1 gene showed that the region commonly affected in FBN1- associated lipodystrophy is highly conserved both across the three human fibrillin genes and across genes encoding fibrillin-1 in vertebrates. These results suggest that fibrillin-1 is involved as the undifferentiated mesenchymal stem cells transition to adipogenesis but then declines as the developing adipocytes take on their final phenotype. Since the C-terminal peptide of fibrillin-1 is a glucogenic hormone, individuals with low fibrillin-1 (for example with FBN1 mutations associated with lipodystrophy) may fail to differentiate and/or to accumulate adipocyte lipids, although this needs to be shown experimentally.
    DOI
    10.1016/j.ymgme.2016.06.009
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    http://www.research.ed.ac.uk/portal/files/26420480/1_s2.0_S1096719216301184_main.pdf
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  • Microglial brain region−dependent diversity and selective regional sensitivities to aging Kathleen Renault, Tom Michoel, Michail Karavolos, Sara Clohisey, John Baillie, Mark Stevens, Thomas Freeman, Kim Summers, Barry McColl — Mar 2016 — Nature Neuroscience Vol: 19 Pages: 504-516
    Abstract


    Microglia have critical roles in neural development, homeostasis and neuroinflammation and are increasingly implicated in age-related neurological dysfunction. Neurodegeneration often occurs in disease-specific, spatially restricted patterns, the origins of which are unknown. We performed to our knowledge the first genome-wide analysis of microglia from discrete brain regions across the adult lifespan of the mouse, and found that microglia have distinct region-dependent transcriptional identities and age in a regionally variable manner. In the young adult brain, differences in bioenergetic and immunoregulatory pathways were the major sources of heterogeneity and suggested that cerebellar and hippocampal microglia exist in a more immune-vigilant state. Immune function correlated with regional transcriptional patterns. Augmentation of the distinct cerebellar immunophenotype and a contrasting loss in distinction of the hippocampal phenotype among forebrain regions were key features during aging. Microglial diversity may enable regionally localized homeostatic functions but could also underlie region-specific sensitivities to microglial dysregulation and involvement in age-related neurodegeneration.
    DOI
    10.1038/nn.4222
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    http://www.research.ed.ac.uk/portal/files/22887330/63286_2_merged_1449491165.pdf
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  • Gene regulation. Transcribed enhancers lead waves of coordinated transcription in transitioning mammalian cells Tom C Freeman, Richard Axton, J Kenneth Baillie, Malcolm E Fisher, Lesley Forrester, Thomas Ha, Andru Tomoiu, Kim M Summers, David A Hume and 101 others — 27 Feb 2015 — Science Vol: 347 Pages: 1010-4
    Abstract

    Although it is generally accepted that cellular differentiation requires changes to transcriptional networks, dynamic regulation of promoters and enhancers at specific sets of genes has not been previously studied en masse. Exploiting the fact that active promoters and enhancers are transcribed, we simultaneously measured their activity in 19 human and 14 mouse time courses covering a wide range of cell types and biological stimuli. Enhancer RNAs, then messenger RNAs encoding transcription factors, dominated the earliest responses. Binding sites for key lineage transcription factors were simultaneously overrepresented in enhancers and promoters active in each cellular system. Our data support a highly generalizable model in which enhancer transcription is the earliest event in successive waves of transcriptional change during cellular differentiation or activation.

    DOI
    10.1126/science.1259418
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  • The challenges of pedigree dog health: approaches to combating inherited disease Lindsay Farrell, Jeffrey Schoenebeck, Pam Wiener, Dylan Clements, Kim Summers — 11 Feb 2015 — Canine Genetics and Epidemiology Vol: 2
    Abstract
    The issue of inherited disorders and poor health in pedigree dogs has been widely discussed in recent years. With the advent of genome-wide sequencing technologies and the increasing development of new diagnostic DNA disease tests, the full extent and prevalence of inherited disorders in pedigree dogs is now being realized. In this review we discuss the challenges facing pedigree dog breeds: the common pitfalls and problems associated with combating single gene mediated disorders, phenotypic selection on complex disorders, and ways of managing genetic diversity. Breeding strategies incorporating screening schemes have been shown to be successful in significantly reducing the prevalence of an inherited disorder and improving the overall health in certain breeds. However, with 215 breeds officially recognized by the Kennel Club in the United Kingdom and 396 inherited disorders currently identified, many breeds have reached the point at which successfully breeding away from susceptible individuals at a population-wide scale will require new genomic selection strategies in combination with currently available breeding schemes. Whilst DNA-based tests identifying disease causing mutation(s) remain the most informative and effective approach for single gene disorder disease management, they must be used along with current screening schemes, genomic selection, and pedigree information in breeding programs in the effort to maintain genetic diversity while also significantly reducing the number of inherited disorders in pedigree dogs.
    DOI
    10.1186/s40575-015-0014-9
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    http://www.research.ed.ac.uk/portal/files/19275155/The_challenges_of_pedigree_dog_health_approaches_to_combating_inherited_disease.pdf
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    http://www.cgejournal.org/content/2/1/3
  • A promoter-level mammalian expression atlas J. Kenneth Baillie, Colin A. Semple, Robert S. Young, Malcolm E. Fisher, Thomas J. Ha, Anagha Joshi, Alison Meynert, James G. D. Prendergast, Kim M. Summers, Tom C. Freeman, Martin S. Taylor, David A. Hume and 251 others — 27 Mar 2014 — Nature Vol: 507 Pages: 462-+
    Abstract

    Regulated transcription controls the diversity, developmental pathways and spatial organization of the hundreds of cell types that make up a mammal. Using single-molecule cDNA sequencing, we mapped transcription start sites (TSSs) and their usage in human and mouse primary cells, cell lines and tissues to produce a comprehensive overview of mammalian gene expression across the human body. We find that few genes are truly 'housekeeping', whereas many mammalian promoters are composite entities composed of several closely separated TSSs, with independent cell-type-specific expression profiles. TSSs specific to different cell types evolve at different rates, whereas promoters of broadly expressed genes are the most conserved. Promoter-based expression analysis revealskey transcription factors defining cell states and links them to binding-site motifs. The functions of identified novel transcripts can be predicted by coexpression and sample ontology enrichment analyses. The functional annotation of the mammalian genome 5 (FANTOM5) project provides comprehensive expression profiles and functional annotation of mammalian cell-type-specific transcriptomes with wide applications in biomedical research.

    DOI
    10.1038/nature13182
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  • Recent developments in the diagnosis of Marfan syndrome and related disorders Kim M Summers, Jennifer A West, Annette Hattam, Denis Stark, James J McGill, Malcolm J West — 05 Nov 2012 — The Medical journal of Australia Vol: 197 Pages: 494-7
    Abstract
    Marfan syndrome is a multisystem disorder of connective tissue that is inherited in an autosomal dominant fashion, and results from mutation of the FBN1 gene on human chromosome 15. There are a number of conditions of the connective tissue with a similar phenotype that can be confused with Marfan syndrome. Modifications of the diagnostic criteria have recently been published, facilitating the differentiation of Marfan syndrome from these conditions. It is still difficult to use modern genetic testing for diagnosis because Marfan syndrome can be caused by many different mutations in FBN1, a large gene with 65 coding segments, while mutations in other genes can cause overlapping phenotypes. Several clinical trials of drug therapy, including the antihypertensive drug losartan, are in progress.
    DOI
    10.5694/mja12.10560
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    https://www.mja.com.au/journal/2012/197/9/recent-developments-diagnosis-marfan-syndrome-and-related-disorders
  • Population structure and genetic heterogeneity in popular dog breeds in the UK Richard J Mellanby, Rob Ogden, Dylan N Clements, Anne T French, Adam Gow, Roger Powell, Brendan Corcoran, Johan P Schoeman, Kim M Summers — Apr 2013 — Veterinary Journal Vol: 196 Pages: 92-97
    Abstract
    There is increasing concern that reproductive isolation related to breed specifications in dogs, while maintaining genetic differences among breeds, is likely to promote breed-specific genetic disorders. This study examined genetic diversity among 13 popular dog breed groups in the UK. Most breeds showed high levels of homozygosity when compared with crossbred animals. The Boxer and West Highland white terrier showed the lowest heterozygosity, while the Jack Russell terrier group (not a registered breed in the UK) had a level of heterozygosity comparable to crossbred dogs. Analysis of genetic distance between breeds showed significantly different inbreeding coefficients for pairwise comparisons among registered breeds, with the most divergent breeds being the Boxer and West Highland white terrier. The Rottweiler and Golden retriever showed the highest levels of inbreeding. The least distinct group contained crossbred dogs. The results show that the registered breeds are subject to a 'breed barrier' which promotes reduction in genetic diversity.
    DOI
    10.1016/j.tvjl.2012.08.009
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    http://www.research.ed.ac.uk/portal/files/21730857/population_sructure.pdf
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    http://www.sciencedirect.com/science/article/pii/S1090023312003504
  • Dogslife: A web-based longitudinal study of Labrador Retriever health in the UK Dylan N. Clements, Ian G. Handel, Erica Rose, Damon Querry, Carys Pugh, William E. R. Ollier, Kenton L. Morgan, Lorna J. Kennedy, Jeffery Sampson, Kim M. Summers, Mark Bronsvoort — 18 Jan 2013 — BMC Veterinary Research Vol: 9 Pages: 1-15
    Abstract

    Background: Dogslife is the first large-scale internet-based longitudinal study of canine health. The study has been designed to examine how environmental and genetic factors influence the health and development of a birth cohort of UK-based pedigree Labrador Retrievers.

    Results: In the first 12 months of the study 1,407 Kennel Club (KC) registered eligible dogs were recruited, at a mean age of 119 days of age (SD 69 days, range 3 days - 504 days). Recruitment rates varied depending upon the study team's ability to contact owners. Where owners authorised the provision of contact details 8.4% of dogs were recruited compared to 1.3% where no direct contact was possible. The proportion of dogs recruited was higher for owners who transferred the registration of their puppy from the breeder to themselves with the KC, and for owners who were sent an e-mail or postcard requesting participation in the project. Compliance with monthly updates was highly variable. For the 280 dogs that were aged 400 days or more on the 30th June 2011, we estimated between 39% and 45% of owners were still actively involved in the project. Initial evaluation suggests that the cohort is representative of the general population of the KC registered Labrador Retrievers eligible to enrol with the project. Clinical signs of illnesses were reported in 44.3% of Labrador Retrievers registered with Dogslife (median age of first illness 138 days), although only 44.1% of these resulted in a veterinary presentation (median age 316 days).

    Conclusions: The web-based platform has enabled the recruitment of a representative population of KC registered Labrador Retrievers, providing the first large-scale longitudinal population-based study of dog health. The use of multiple different methods (e-mail, post and telephone) of contact with dog owners was essential to maximise recruitment and retention of the cohort.

    DOI
    10.1186/1746-6148-9-13
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    http://www.research.ed.ac.uk/portal/files/8355715/Dogslife_A_web_based_longitudinal_study_of_Labrador_Retriever_health_in_the_UK.pdf
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    http://www.biomedcentral.com/1746-6148/9/13
  • Experimental and bioinformatic characterisation of the promoter region of the Marfan syndrome gene, FBN1 Kim M Summers, Nilesh J Bokil, John M Baisden, Malcolm J West, Matthew J Sweet, Liza J Raggatt, David A Hume — Oct 2009 — Genomics Vol: 94 Pages: 233-240
    Abstract
    Mutations in the FBN1 gene, encoding the extracellular matrix protein fibrillin-1, result in the dominant connective tissue disease Marfan syndrome. Marfan syndrome has a variable phenotype, even within families carrying the same FBN1 mutation. Differences in gene expression resulting from sequence differences in the promoter region of the FBN1 gene are likely to be involved in causing this phenotypic variability. In this report, we present an analysis of FBN1 transcription start site (TSS) use in mouse and human tissues. We found that transcription of FBN1 initiated primarily from a single CpG-rich promoter which was highly conserved in mammals. It contained potential binding sites for a number of factors implicated in mesenchyme differentiation and gene expression. The human osteosarcoma line MG63 had high levels of FBN1 mRNA and secreted fibrillin-1 protein to form extracellular matrix fibres. The human embryonic kidney line HEK293 and two breast cancer lines MCF7 and MDA-MB-231 had levels of FBN1 mRNA 1000 fold lower and produced negligible amounts of fibrillin-1 protein. Therefore MG63 appears to be the optimal cell line for examining tissue-specific, biologically relevant promoter activity for FBN1. In reporter assays, the conserved promoter region was more active in MG63 cells than in non-FBN1-expressing lines but additional elements outside the proximal promoter are probably required for optimal tissue-specific expression. Understanding the regulation of the FBN1 gene may lead to alternative therapeutic strategies for Marfan syndrome.
    DOI
    10.1016/j.ygeno.2009.06.005
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    http://www.research.ed.ac.uk/portal/files/9138502/Experimental_and_bioinformatic_characterisation_of_the_promoter_region_of_the_Marfan_syndrome_gene_FBN1.pdf
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    http://www.sciencedirect.com/science/article/pii/S0888754309001530
  • Functional clustering and lineage markers: Insights into cellular differentiation and gene function from large-scale microarray studies of purified primary cell populations David A Hume, Kim M Summers, Sobia Raza, Kenneth Baillie, Thomas C Freeman — Jun 2010 — Genomics Vol: 95 Pages: 328-338
    Abstract
    Very large microarray datasets showing gene expression across multiple tissues and cell populations provide a window on the transcriptional networks that underpin the differences in functional activity between biological systems. Clusters of co-expressed genes provide lineage markers, candidate regulators of cell function and, by applying the principle of guilt by association, candidate functions for genes of currently unknown function. We have analysed a dataset comprising pure cell populations from hemopoietic and non-hemopoietic cell types (http://biogps.gnf.org). Using a novel network visualisation and clustering approach, we demonstrate that it is possible to identify very tight expression signatures associated specifically with embryonic stem cells, mesenchymal cells and hematopoietic lineages. Selected examples validate the prediction that gene function can be inferred by co-expression. One expression cluster was enriched in phagocytes, which, alongside endosome-lysosome constituents, contains genes that may make up a 'pathway' for phagocyte differentiation. Promoters of these genes are enriched for binding sites for the ETS/PU.1 and MITF families. Another cluster was associated with the production of a specific extracellular matrix, with high levels of gene expression shared by cells of mesenchymal origin (fibroblasts, adipocytes, osteoblasts and myoblasts). We discuss the limitations placed upon such data by the presence of alternative promoters with distinct tissue specificity within many protein-coding genes.
    DOI
    10.1016/j.ygeno.2010.03.002
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    http://www.sciencedirect.com/science/article/pii/S0888754310000509
  • Co-expression of FBN1 with mesenchyme-specific genes in mouse cell lines: implications for phenotypic variability in Marfan syndrome Kim M Summers, Sobia Raza, Erik van Nimwegen, Thomas C Freeman, David A Hume — Nov 2010 — European Journal of Human Genetics Vol: 18 Pages: 1209-1215
    Abstract
    Mutations in the human FBN1 gene cause Marfan syndrome, a complex disease affecting connective tissues but with a highly variable phenotype. To identify genes that might participate in epistatic interactions with FBN1, and could therefore explain the observed phenotypic variability, we have looked for genes that are co-expressed with Fbn1 in the mouse. Microarray expression data derived from a range of primary mouse cells and cell lines were analysed using the network analysis tool BioLayout Express(3D). A cluster of 205 genes, including Fbn1, were selectively expressed by mouse cell lines of different mesenchymal lineages and by mouse primary mesenchymal cells (preadipocytes, myoblasts, fibroblasts, osteoblasts). Promoter analysis of this gene set identified several candidate transcriptional regulators. Genes within this co-expressed cluster are candidate genetic modifiers for Marfan syndrome and for other connective tissue diseases.
    DOI
    10.1038/ejhg.2010.91
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    http://www.research.ed.ac.uk/portal/files/8145981/Summers_K_M_et_al_2010.pdf
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    http://www.nature.com/ejhg/journal/v18/n11/index.html
  • Molecular genetics of long QT syndrome Nilesh J Bokil, John M Baisden, Dorothy J Radford, Kim M Summers — Sep 2010 — Molecular Genetics and Metabolism Vol: 101 Pages: 1-8
    Abstract
    Long QT syndrome (LQTS) is a cardiac disorder associated with sudden death especially in young, seemingly healthy individuals. It is characterised by abnormalities of the heart beat detected as lengthening of the QT interval during cardiac repolarisation. The incidence of LQTS is given as 1 in 2000 but this may be an underestimation as many cases go undiagnosed, due to the rarity of the condition and the wide spectrum of symptoms. Presently 12 genes associated with LQTS have been identified with differing signs and symptoms, depending on the locus involved. The majority of cases have mutations in the KCNQ1 (LQT1), KCNH2 (LQT2) and SCN5A (LQT3) genes. Genetic testing is increasingly used when a clearly affected proband has been identified, to determine the nature of the mutation in that family. Unfortunately tests on probands may be uninformative, especially if the defect does not lie in the set of genes which are routinely tested. Novel mutations in these known LQTS genes and additional candidate genes are still being discovered. The functional implications of these novel mutations need to be assessed before they can be accepted as being responsible for LQTS. Known epigenetic modification affecting KCNQ1 gene expression may also be involved in phenotypic variability of LQTS. Genetic diagnosis of LQTS is thus challenging. However, where a disease associated mutation is identified, molecular diagnosis can be important in guiding therapy, in family testing and in determining the cause of sudden cardiac death. New developments in technology and understanding offer increasing hope to families with this condition.
    DOI
    10.1016/j.ymgme.2010.05.011
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  • Expression of mesenchyme-specific gene signatures by follicular dendritic cells: insights from the meta-analysis of microarray data from multiple mouse cell populations N.A. Mabbott, J. Kenneth Baillie, A. Kobayashi, D.S. Donaldson, H. Ohmori, S.O. Yoon, A.S. Freedman, T.C. Freeman, K.M. Summers — 2011 — Immunology Vol: 133 Pages: 482-498
    Abstract
    Follicular dendritic cells (FDC) are an important subset of stromal cells within the germinal centres of lymphoid tissues. They are specialized to trap and retain antigen-containing immune complexes on their surfaces to promote B-cell maturation and immunoglobulin isotype class-switching. However, little is known of the cell types from which FDC originate. To address fundamental questions associated with the relationships between FDC and other cell populations, we took advantage of the growing body of publicly available data for transcriptome analysis. We obtained a large number of gene expression data files from a range of different primary mouse cells and cell lines and subjected these data to network-based cluster analysis using BiolayoutExpress(3D) . Genes with related function clustered together in distinct regions of the graph and enabled the identification of transcriptional networks that underpin the functional activity of distinct cell populations. Several gene clusters were identified that were selectively expressed by cells of mesenchymal lineage and contained classic mesenchymal cell markers and extracellular matrix genes including various collagens, Acta2, Bgn, Fbn1 and Twist1. Our analysis showed that FDC also express highly many of these mesenchyme-associated genes. Promoter analysis of the genes comprising the mesenchymal clusters identified several regulatory motifs that are binding sites for candidate transcription factors previously known to be candidate regulators of mesenchyme-specific genes. Together, these data suggest FDC are a specialized mesenchymal cell population within the germinal centres of lymphoid tissues.
    DOI
    10.1111/j.1365-2567.2011.03461.x
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    http://dx.doi.org/10.1111/j.1365-2567.2011.03461.x
  • Integration of quantitated expression estimates from polyA-selected and rRNA-depleted RNA-seq libraries Stephen J Bush, Mary E B McCulloch, Kim M Summers, David A Hume, Emily L Clark — 13 Jun 2017 — BMC Bioinformatics Vol: 18 Pages: 301
    Abstract

    BACKGROUND: The availability of fast alignment-free algorithms has greatly reduced the computational burden of RNA-seq processing, especially for relatively poorly assembled genomes. Using these approaches, previous RNA-seq datasets could potentially be processed and integrated with newly sequenced libraries. Confounding factors in such integration include sequencing depth and methods of RNA extraction and selection. Different selection methods (typically, either polyA-selection or rRNA-depletion) omit different RNAs, resulting in different fractions of the transcriptome being sequenced. In particular, rRNA-depleted libraries sample a broader fraction of the transcriptome than polyA-selected libraries. This study aimed to develop a systematic means of accounting for library type that allows data from these two methods to be compared.

    RESULTS: The method was developed by comparing two RNA-seq datasets from ovine macrophages, identical except for RNA selection method. Gene-level expression estimates were obtained using a two-part process centred on the high-speed transcript quantification tool Kallisto. Firstly, a set of reference transcripts was defined that constitute a standardised RNA space, with expression from both datasets quantified against it. Secondly, a simple ratio-based correction was applied to the rRNA-depleted estimates. The outcome is an almost perfect correlation between gene expression estimates, independent of library type and across the full range of levels of expression.

    CONCLUSION: A combination of reference transcriptome filtering and a ratio-based correction can create equivalent expression profiles from both polyA-selected and rRNA-depleted libraries. This approach will allow meta-analysis and integration of existing RNA-seq data into transcriptional atlas projects.

    DOI
    10.1186/s12859-017-1714-9
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    http://www.research.ed.ac.uk/portal/files/37848870/Integration_of_quantitated_expression_estimates_from_polyA_selected_and_rRNA_depleted_RNA_seq_libraries.pdf
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  • Incidence rates and risk factor analyses for owner reported vomiting and diarrhoea in Labrador Retrievers – findings from the Dogslife Cohort Carys Pugh, Kim Summers, Erica Rose, Ian Handel, Mark Bronsvoort, Damon Querry, Dylan Clements — 01 May 2017 — Preventive Veterinary Medicine
    Abstract
    Dogslife collects data directly from owners of Labrador Retrievers across the UK including information regarding signs of illness irrespective of whether the signs precipitated a veterinary visit. In December 2015, the cohort comprised 6,084 dogs aged up to six years and their owners had made 2,687 and 2,601 reports of diarrhoea and vomiting respectively. The co-occurrence of vomiting and diarrhoea with other signs was described and the frequencies and durations of the two signs were examined with reference to veterinary visitation. Age-specific illness rates were described and Cox Proportional Hazards models were used to estimate risk factors.

    Just 37% of diarrhoea reports were associated with a veterinary visit and the proportion was even lower for vomiting at 28%; indicating that studies of veterinary practice data miss the majority of signs of gastrointestinal upset. In terms of frequency and duration, diarrhoea typically needed to last two days before the dog would be taken to the vet but if the dog vomited at least every six hours, the owner would be more likely to take the dog to the vet after one day.

    The illness rates of both signs peaked when the dogs were aged between three and six months. There was also a seasonal pattern to the incidents with the lowest hazards for both in May. Diarrhoea incidents peaked in August-September each year but, while vomiting appeared to be higher in September, it peaked in February. Having another dog in the household was associated with a lower hazard for both vomiting and diarrhoea but having a cat was only associated with a reduced hazard of vomiting.

    In addition to the distinct seasonal patterns of reporting, there were clear differences in the geographic risks for the two signs. The hazard of diarrhoea was positively associated with human population density within Great Britain (according to home post code) whereas no significant geographical association was found with vomiting.

    This study is particularly relevant for dog owners because it highlights the wealth of gastrointestinal illnesses in dogs that are dealt with by owners but never seen by veterinarians. The risk factor analyses make use of owner-reported demographic information, highlighting the differences between vomiting and diarrhoea. The analyses give rise to the possibility that the presence of other pets in households may affect rates of illness and indicate new avenues for investigations of these distinct, and oft-suffered conditions.
    DOI
    10.1016/j.prevetmed.2017.02.014
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    http://www.research.ed.ac.uk/portal/files/32547418/1_s2.0_S0167587716304354_main.pdf
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  • Comparative transcriptome analysis of equine alveolar macrophages A E Karagianni, R Kapetanovic, K M Summers, B C McGorum, D A Hume, R S Pirie — May 2017 — Equine Veterinary Journal Vol: 49 Pages: 375-382
    Abstract

    REASONS FOR PERFORMING STUDY: Alveolar macrophages (AMs) are the first line of defense against pathogens in the lungs of all mammalian species and therefore may constitute an appropriate therapeutic target cell in the treatment and prevention of opportunistic airway infections. Therefore, acquiring a better understanding of equine macrophage biology is of paramount importance in addressing this issue in relation to the horse.

    STUDY DESIGN: Gene expression study of the equine AM.

    OBJECTIVES: To compare the transcriptome of equine AMs to that of equine peritoneal macrophages (PMs) and investigate the effect of lipopolysaccharide (LPS) on the equine AM.

    METHODS: Cells were isolated and cryopreserved from both bronchoalveolar and peritoneal lavage fluid from systemically healthy horses after euthanasia. RNA was extracted and comparative microarray analyses were performed between AMs and PMs, and between LPS treated and untreated AMs. Comparisons were also made with published data derived from human AM studies, with particular focus on their LPS induced inflammatory status.

    RESULTS: The comparison between AMs and PMs revealed the differential basal expression of 451 genes. Gene expression analysis revealed an alternative (M2) macrophage polarisation profile in AMs and a hybrid macrophage activation profile in PMs, a phenomenon potentially attributable to a degree of induced endotoxin tolerance. The change in gene expression profile of equine AMs following LPS stimulation revealed a significant change in the expression of 240 genes, including well known upregulated inflammatory genes. This LPS induced gene expression profile of equine AMs more closely resembled that of human macrophages than murine macrophages.

    CONCLUSIONS: This study improves our understanding of equine macrophage biology. Our data suggest that the horse may represent a suitable animal model for the study of human macrophage-associated lung inflammation and data derived from human macrophage studies may have significant relevance to the horse. This article is protected by copyright. All rights reserved.

    DOI
    10.1111/evj.12584
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    http://www.research.ed.ac.uk/portal/files/26603645/Karagianni_et_al_2016_Equine_Veterinary_Journal.pdf
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  • Myxomatous Degeneration of the Canine Mitral Valve: From Gross Changes to Molecular Events Greg Markby, Kim Summers, Victoria MacRae, Jorge Del-Pozo, Brendan Corcoran — 10 Apr 2017 — Journal of Comparative Pathology
    Abstract
    Myxomatous mitral valve disease (MMVD) is the single most common acquired heart
    disease of the dog, but is also of emerging importance in human medicine, with some features of the disease shared between both species. There has been increased understanding of this disease in recent years, with most research aiming to elucidate the cellular and molecular events of disease pathogenesis. For gross and histological changes, much of our understanding is based on historical studies and there has been no comprehensive re-appraisal of the pathology of MMVD. This paper reviews the gross, histological, ultrastructural, cellular and molecular changes in canine MMVD.
    DOI
    10.1016/j.jcpa.2017.01.009
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  • Analysis of gene expression in the nervous system identifies key genes and novel candidates for health and disease Sarah M Carpanini, Thomas M Wishart, Thomas H Gillingwater, Jean C Manson, Kim M Summers — Apr 2017 — Neurogenetics Vol: 18 Pages: 81-95
    Abstract
    The incidence of neurodegenerative diseases in the developed world has risen over the last century, concomitant with an increase in average human lifespan. A major challenge is therefore to identify genes that control neuronal health and viability with a view to enhancing neuronal health during ageing and reducing the burden of neurodegeneration. Analysis of gene expression data has recently been used to infer gene functions for a range of tissues from co-expression networks. We have now applied this approach to transcriptomic datasets from the mammalian nervous system available in the public domain. We have defined the genes critical for influencing neuronal health and disease in different neurological cell types and brain regions. The functional contribution of genes in each co-expression cluster was validated using human disease and knockout mouse phenotypes, pathways and GO term annotation. Additionally a number of poorly annotated genes were implicated by this approach in nervous system function. Exploiting gene expression data available in the public domain allowed us to validate key nervous system genes and importantly identify additional genes with minimal functional annotation but the same expression pattern. These genes are thus novel candidates for a role in neurological health and disease, and could now be further investigated to confirm their function and regulation during ageing and neurodegeneration.
    DOI
    10.1007/s10048-017-0509-5
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    http://www.research.ed.ac.uk/portal/files/31168671/art_3A10.1007_2Fs10048_017_0509_5.pdf
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  • Analysis of the human monocyte-derived macrophage transcriptome and response to lipopolysaccharide provides new insights into genetic aetiology of inflammatory bowel disease John Baillie, Erik Arner, Carsten Daub, Michiel De Hoon, Masayoshi Itoh, Hideya Kawaji, Timo Lassmann, Piero Carninci, Alistair R.R. Forrest, Yoshihide Hayashizaki, The FANTOM Consortium, Geoff Faulkner, Christine A. Wells, Michael Rehli, Paul Pavli, Kim Summers, David Hume — 06 Mar 2017 — PLoS Genetics Vol: 13
    Abstract
    The FANTOM5 consortium utilised cap analysis of gene expression (CAGE) to provide an unprecedented insight into transcriptional regulation in human cells and tissues. In the current study, we have used CAGE-based transcriptional profiling on an extended dense time course of the response of human monocyte-derived macrophages grown in macrophage colony-stimulating factor (CSF1) to bacterial lipopolysaccharide (LPS). We propose that this system provides a model for the differentiation and adaptation of monocytes entering the intestinal lamina propria. The response to LPS is shown to be a cascade of successive waves of transient gene expression extending over at least 48 hours, with hundreds of positive and negative regulatory loops. Promoter analysis using motif activity response analysis (MARA) identified some of the transcription factors likely to be responsible for the temporal profile of transcriptional activation. Each LPS-inducible locus was associated with multiple inducible enhancers, and in each case, transient eRNA transcription at multiple sites detected by CAGE preceded the appearance of promoter-associated transcripts. LPS-inducible long non-coding RNAs were commonly associated with clusters of inducible enhancers. We used these data to re-examine the hundreds of loci associated with susceptibility to inflammatory bowel disease (IBD) in genome-wide association studies. Loci associated with IBD were strongly and specifically (relative to rheumatoid arthritis and unrelated traits) enriched for promoters that were regulated in monocyte differentiation or activation. Amongst previously-identified IBD susceptibility loci, the vast majority contained at least one promoter that was regulated in CSF1-dependent monocyte-macrophage transitions and/or in response to LPS. On this basis, we concluded that IBD loci are strongly-enriched for monocyte-specific genes, and identified at least 134 additional candidate genes associated with IBD susceptibility from reanalysis of published GWA studies. We propose that dysregulation of monocyte adaptation to the environment of the gastrointestinal mucosa is the key process leading to inflammatory bowel disease.
    DOI
    10.1371/journal.pgen.1006641
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    http://www.research.ed.ac.uk/portal/files/33353227/journal.pgen.1006641.pdf
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  • Vascular calcification and the cardiovascular transcriptome H. Tsang, L. Cui, C. Farquharson, B. M. Corcoran, K. M. Summers, V. E. MacRae — Oct 2016 — International Journal of Experimental Pathology Vol: 97 Pages: A2-A3
  • Macrophage colony-stimulating factor (CSF1) controls monocyte production and maturation and the steady-state size of the liver in pigs Kristin A Sauter, Lindsey A Waddell, Zofia M Lisowski, Rachel Young, Lucas Lefevre, Gemma M Davis, Sara M Clohisey, Mary B. McCulloch, Elizabeth Magowan, Neil A Mabbott, Kim M Summers, David A Hume — 09 Sep 2016 — American Journal of Physiology - Gastrointestinal and Liver Physiology Vol: 311 Pages: G533-G547
    Abstract

    Macrophage colony-stimulating factor (CSF1) is an essential growth and differentiation factor for cells of the macrophage lineage. To explore the practical applications of CSF1 therapy, we developed a bioactive protein with a longer half-life in circulation by fusing pig CSF1 with Fc region of pig IgG1a. Three consecutive daily doses of CSF1-Fc in 8 week old pigs expanded macrophage populations in blood and organs, accelerated maturation of macrophage populations in peripheral blood monocytes, and expanded progenitor pools in bone marrow. The hepatosplenomegaly present after CSF1-Fc administration was partially due to a substantial increase in macrophage numbers in both organs as well as an increase in proliferating cells in the liver. Despite the large influx of macrophages a panel of biochemical tests to measure liver damage demonstrated normal function in CSF1-Fc treated pigs. Additionally microarray data confirmed that the increase in total liver weight must be primarily due to the extensive proliferation and subsequent increase in hepatocyte numbers. In the current study we have extended our previous finding that CSF1-Fc increased the size of the liver in mice to the domestic pig, an animal that is considerably more human-like in size and vascular biology. CSF1-dependent monocyte recruitment is both necessary and sufficient to drive hepatic proliferation and CSF1-Fc treatment can push it beyond the homeostatic limits even in a large animal. Treatment confirms the existence of a homeostatic feedback loop linking macrophages of the liver with bone marrow and blood monocytes which together regulate the physiological hepatostat as a "macrostat".

    DOI
    10.1152/ajpgi.00116.2016
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    http://www.research.ed.ac.uk/portal/files/27781291/G533.full.pdf
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  • Expression of FBN1 during adipogenesis: relevance to the lipodystrophy phenotype in Marfan syndrome and related conditions Margaret R Davis, Erik Arner, Cairnan R E Duffy, Paul De Sousa, Ingrid Dahlman, Peter Arner, Kim Summers — Sep 2016 — Molecular Genetics and Metabolism Vol: 119 Pages: 174-185
    Abstract
    Fibrillin-1 is a large glycoprotein encoded by the FBN1 gene in humans. It provides strength and elasticity to connective tissues and is involved in regulating the bioavailability of the growth factor TGFβ. Mutations in FBN1 may be associated with depleted or abnormal adipose tissue, seen in some patients with Marfan syndrome and lipodystrophies. As this lack of adipose tissue does not result in high morbidity or mortality, it is generally underappreciated but is a cause of psychosocial problems. We examined the role of fibrillin-1 in adipogenesis. In inbred mouse strains we found significant variation in the level of expression in the Fbn1 gene that correlated with variation in several measures of body fat, suggesting that mouse fibrillin-1 is associated with the level of fat tissue. Furthermore, we found that FBN1 mRNA was up-regulated in the adipose tissue of obese women compared to non-obese, and associated with an increase in adipocyte size. We used human mesenchymal stem cells differentiated in culture to adipocytes to show that fibrillin-1 declines after the initiation of differentiation. Gene expression results from a similar experiment (available through the FANTOM5 project) revealed that the decline in fibrillin-1 protein was paralleled by a decline in FBN1 mRNA. Examination of the FBN1 gene showed that the region commonly affected in FBN1- associated lipodystrophy is highly conserved both across the three human fibrillin genes and across genes encoding fibrillin-1 in vertebrates. These results suggest that fibrillin-1 is involved as the undifferentiated mesenchymal stem cells transition to adipogenesis but then declines as the developing adipocytes take on their final phenotype. Since the C-terminal peptide of fibrillin-1 is a glucogenic hormone, individuals with low fibrillin-1 (for example with FBN1 mutations associated with lipodystrophy) may fail to differentiate and/or to accumulate adipocyte lipids, although this needs to be shown experimentally.
    DOI
    10.1016/j.ymgme.2016.06.009
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    http://www.research.ed.ac.uk/portal/files/26420480/1_s2.0_S1096719216301184_main.pdf
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  • Datasets of genes coexpressed with FBN1 in mouse adipose tissue and during human adipogenesis Margaret R Davis, Erik Arner, Cairnan R E Duffy, Paul De Sousa, Ingrid Dahlman, Peter Arner, Kim Summers — 05 Jul 2016 — Data in brief Vol: 8 Pages: 851-857
    Abstract
    This article contains data related to the research article entitled “Expression of FBN1 during adipogenesis: relevance to the lipodystrophy phenotype in Marfan syndrome and related conditions” [1]. The article concerns the expression of FBN1, the gene encoding the extracellular matrix protein fibrillin-1, during adipogenesis in vitro and in relation to adipose tissue in vivo. The encoded protein has recently been shown to produce a short glucogenic peptide hormone, “Asprosin, a Fasting-Induced Glucogenic Protein Hormone” [2], and this gene is therefore a key gene for regulating blood glucose levels. FBN1 and coexpressed genes were examined in mouse strains and human cells undergoing adipogenesis. The data show the genes that were coexpressed with FBN1, including genes coding for other connective tissue proteins and the proteases that modify them and for the transcription factors that control their expression. Data analysed were derived from datasets available in the public domain and the analysis highlights the utility of such datasets for ongoing analysis and hence reduction in the use of experimental animals.
    DOI
    10.1016/j.dib.2016.06.055
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    http://www.research.ed.ac.uk/portal/files/26630676/96_Davis_et_al_2016b.pdf
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  • Cumulative incidence and risk factors for Limber Tail in the Dogslife Labrador Retriever cohort Carys Pugh, Mark Bronsvoort, Ian Handel, Damon Querry, Erica Rose, Kim Summers, Dylan Clements — 27 Jun 2016 — Veterinary Record Vol: 179 Pages: 275-U290
    Abstract
    Limber tail is a condition that typically affects larger working breeds causing tail-limpness and pain, resolving without veterinary intervention. It is poorly understood and the disease burden has not been well characterised. Data collected from owners of the Dogslife cohort of Labrador Retrievers have been used to describe incidents and a case-control study was undertaken to elucidate risk factors with 38 cases and 86 controls. The cumulative incidence of unexplained tail-limpness was 9.7%. Swimming is not a necessary precursor for limber tail but it is a risk factor (OR = 4.7) and working dogs were more susceptible than non-working dogs (OR = 5.1). Higher latitudes were shown to be a risk factor for developing the condition and the case dogs were more related to each other than might be expected by chance. This suggests that dogs may have an underlying genetic predisposition to developing the condition. This study is the first, large-scale investigation of limber tail and the findings reveal an unexpectedly high illness burden. Anecdotally accepted risk factors have been confirmed and the extent of their impact has been quantified. Identifying latitude and a potential underlying genetic predisposition suggests avenues for future work on this painful and distressing condition.
    DOI
    10.1136/vr.103729
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    http://www.research.ed.ac.uk/portal/files/26420335/Veterinary_Record_2016_Pugh_vr.103729.pdf
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  • Transcriptional regulation and macrophage differentiation David Hume, Kim Summers, Michael Rehli — 03 Jun 2016 — Microbiology Spectrum Vol: 4
    Abstract
    Monocytes and macrophages are professional phagocytes that occupy specific niches in every tissue of the body. Their survival, proliferation, and differentiation are controlled by signals from the macrophage colony-stimulating factor receptor (CSF-1R) and its two ligands, CSF-1 and interleukin-34. In this review, we address the developmental and transcriptional relationships between hematopoietic progenitor cells, blood monocytes, and tissue macrophages as well as the distinctions from dendritic cells. A huge repertoire of receptors allows monocytes, tissue-resident macrophages,
    or pathology-associated macrophages to adapt to specific microenvironments. These processes create a broad spectrum of macrophages with different functions and individual effector capacities. The production of large transcriptomic data sets in mouse, human, and other species provides new insights into the mechanisms that underlie macrophage functional plasticity.
    DOI
    10.1128/microbiolspec.MCHD-0024-2015
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    http://www.research.ed.ac.uk/portal/files/26630693/93_Hume_et_al_2016.pdf
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  • A deletion in the canine POMC gene is associated with weight and appetite in obesity prone Labrador retriever dogs Eleanor Raffan, Rowena J Dennis, Conor J O'Donovan, Julia M Becker, Robert A Scott, Stephen P Smith, David J Withers, Claire J Wood, Elena Conci, Dylan N Clements, Kim Summers, Alexander J German, Cathryn S Mellersh, Maja L Arendt, Valentine P Iyemere, E Withers, Josefin Soder, Sara Wernersson, Goran Andersson, Kerstin Lindblad-Toh, Giles S H Yeo, Stephen O'Rahilly — 03 May 2016 — Cell Metabolism Vol: 23 Pages: 893-900
    Abstract
    Sequencing of candidate genes for obesity in Labrador retriever dogs identified a 14 bp deletion in pro-opiomelanocortin (POMC) with an allele frequency of 12%. The deletion disrupts the b-MSH and b-endorphin coding sequences and is associated with body weight (per allele effect of 0.33 SD), adiposity, and greater food motivation. Among other dog breeds, the deletion was only found in the closely related flat-coat retriever (FCR), where it is similarly associated with body weight and food motivation. The mutation is significantly more common in Labrador retrievers selected to become assistance dogs than pets. In conclusion, the deletion in POMC is a significant modifier of weight and appetite in Labrador retrievers and FCRs and may influence other behavioral traits.
    DOI
    10.1016/j.cmet.2016.04.012
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    http://www.research.ed.ac.uk/portal/files/25180380/1_s2.0_S1550413116301632_main.pdf
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  • Microglial brain region−dependent diversity and selective regional sensitivities to aging Kathleen Renault, Tom Michoel, Michail Karavolos, Sara Clohisey, John Baillie, Mark Stevens, Thomas Freeman, Kim Summers, Barry McColl — Mar 2016 — Nature Neuroscience Vol: 19 Pages: 504-516
    Abstract


    Microglia have critical roles in neural development, homeostasis and neuroinflammation and are increasingly implicated in age-related neurological dysfunction. Neurodegeneration often occurs in disease-specific, spatially restricted patterns, the origins of which are unknown. We performed to our knowledge the first genome-wide analysis of microglia from discrete brain regions across the adult lifespan of the mouse, and found that microglia have distinct region-dependent transcriptional identities and age in a regionally variable manner. In the young adult brain, differences in bioenergetic and immunoregulatory pathways were the major sources of heterogeneity and suggested that cerebellar and hippocampal microglia exist in a more immune-vigilant state. Immune function correlated with regional transcriptional patterns. Augmentation of the distinct cerebellar immunophenotype and a contrasting loss in distinction of the hippocampal phenotype among forebrain regions were key features during aging. Microglial diversity may enable regionally localized homeostatic functions but could also underlie region-specific sensitivities to microglial dysregulation and involvement in age-related neurodegeneration.
    DOI
    10.1038/nn.4222
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    http://www.research.ed.ac.uk/portal/files/22887330/63286_2_merged_1449491165.pdf
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  • Large animal models of cardiovascular disease Hiu-Gwen Tsang, Nabil Rashdan, Christopher Whitelaw, Brendan Corcoran, Kim Summers, Victoria MacRae — 24 Feb 2016 — Cell Biochemistry and Function Vol: 34 Pages: 113–132
    Abstract
    The human cardiovascular system is a complex arrangement of specialised structures with distinct functions. The molecular landscape, including the genome, transcriptome, and proteome, is pivotal to the biological complexity of both normal and abnormal mammalian processes. Despite our advancing knowledge and understanding of cardiovascular disease (CVD) through the principal use of rodent models, this continues to be an increasing issue in today’s world. For instance, as the aging population increases, so does the incidence of heart valve dysfunction. This may be due to changes in molecular composition and structure of the extracellular matrix, or from the pathological process of vascular calcification in which bone-formation related factors cause ectopic mineralisation. However, significant differences between mice and men exist in terms of cardiovascular anatomy, physiology and pathology. In contrast, large animal models can show considerably greater similarity to humans. Furthermore, precise and efficient genome editing techniques enable the generation of tailored models for translational research. These novel systems provide a huge potential for large animal models to investigate the regulatory factors and molecular pathways that contribute to CVD in vivo. In turn, this will help bridge the gap between basic science and clinical applications by facilitating the refinement of therapies for cardiovascular disease.
    DOI
    10.1002/cbf.3173
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    http://www.research.ed.ac.uk/portal/files/25122546/Tsang_et_al_2016_Cell_Biochemistry_and_Function.pdf
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    http://onlinelibrary.wiley.com/doi/10.1002/cbf.3173/abstract
  • Validity of Internet-Based Longitudinal Study Data: The elephant in the virtual room Carys Pugh, Kim Summers, Mark Bronsvoort, Ian Handel, Dylan Clements — 16 Apr 2015 — Journal of medical Internet research Vol: 17
    Abstract
    Background: Internet-based data collection relies on well-designed and validated questionnaires. The theory behind designing and validating questionnaires is well described, but few practical examples of how to approach validation are available in the literature.

    Objective: We aimed to validate data collected in an ongoing Internet-based longitudinal health study through direct visits to participants and recall of their health records. We demonstrate that despite extensive pre-planning, social desirability can still affect data in unexpected ways and that anticipation of poor quality data may be confounded by positive validation.

    Methods: Dogslife is a large-scale, Web-based longitudinal study of canine health, in which owners of Labrador Retrievers were recruited and questioned at regular intervals about the lifestyle and health of their dogs using an Internet-based questionnaire. The Dogslife questionnaire predominantly consists of closed-answer questions. In our work, two separate validation methodologies were used: (1) direct interviews with 43 participants during visits to their households and (2) comparison of owner-entered health reports with 139 historical health records.

    Results: Our results indicate that user-derived measures should not be regarded as a single category; instead, each measurement should be considered separately as each presents its own challenge to participants. We recommend trying to ascertain the extent of recall decay within a study and, if necessary, using this to guide data collection timepoints and analyses. Finally, we recommend that multiple methods of communication facilitate validation studies and aid cohort engagement.

    Conclusions: Our study highlighted how the theory underpinning online questionnaire design and validation translates into practical data issues when applied to Internet-based studies. Validation should be regarded as an extension of questionnaire design, and that validation work should commence as soon as sufficient data are available. We believe that validation is a crucial step and hope our suggested guidelines will help facilitate validation of other Internet-based cohort studies.
    DOI
    10.2196/jmir.3530
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    http://www.research.ed.ac.uk/portal/files/19381879/Validity_of_Internet_Based_Longitudinal_Study_Data.pdf
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    http://www.jmir.org/2015/4/e96/
  • Gene regulation. Transcribed enhancers lead waves of coordinated transcription in transitioning mammalian cells Tom C Freeman, Richard Axton, J Kenneth Baillie, Malcolm E Fisher, Lesley Forrester, Thomas Ha, Andru Tomoiu, Kim M Summers, David A Hume and 101 others — 27 Feb 2015 — Science Vol: 347 Pages: 1010-4
    Abstract

    Although it is generally accepted that cellular differentiation requires changes to transcriptional networks, dynamic regulation of promoters and enhancers at specific sets of genes has not been previously studied en masse. Exploiting the fact that active promoters and enhancers are transcribed, we simultaneously measured their activity in 19 human and 14 mouse time courses covering a wide range of cell types and biological stimuli. Enhancer RNAs, then messenger RNAs encoding transcription factors, dominated the earliest responses. Binding sites for key lineage transcription factors were simultaneously overrepresented in enhancers and promoters active in each cellular system. Our data support a highly generalizable model in which enhancer transcription is the earliest event in successive waves of transcriptional change during cellular differentiation or activation.

    DOI
    10.1126/science.1259418
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  • The challenges of pedigree dog health: approaches to combating inherited disease Lindsay Farrell, Jeffrey Schoenebeck, Pam Wiener, Dylan Clements, Kim Summers — 11 Feb 2015 — Canine Genetics and Epidemiology Vol: 2
    Abstract
    The issue of inherited disorders and poor health in pedigree dogs has been widely discussed in recent years. With the advent of genome-wide sequencing technologies and the increasing development of new diagnostic DNA disease tests, the full extent and prevalence of inherited disorders in pedigree dogs is now being realized. In this review we discuss the challenges facing pedigree dog breeds: the common pitfalls and problems associated with combating single gene mediated disorders, phenotypic selection on complex disorders, and ways of managing genetic diversity. Breeding strategies incorporating screening schemes have been shown to be successful in significantly reducing the prevalence of an inherited disorder and improving the overall health in certain breeds. However, with 215 breeds officially recognized by the Kennel Club in the United Kingdom and 396 inherited disorders currently identified, many breeds have reached the point at which successfully breeding away from susceptible individuals at a population-wide scale will require new genomic selection strategies in combination with currently available breeding schemes. Whilst DNA-based tests identifying disease causing mutation(s) remain the most informative and effective approach for single gene disorder disease management, they must be used along with current screening schemes, genomic selection, and pedigree information in breeding programs in the effort to maintain genetic diversity while also significantly reducing the number of inherited disorders in pedigree dogs.
    DOI
    10.1186/s40575-015-0014-9
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    http://www.research.ed.ac.uk/portal/files/19275155/The_challenges_of_pedigree_dog_health_approaches_to_combating_inherited_disease.pdf
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    http://www.cgejournal.org/content/2/1/3
  • Microglial transcriptome diversity in the healthy adult brain reveals regional heterogeneity in immunoregulatory and metabolic function and selective sensitivity to ageing K. Renault, T. Michoel, M. Karavolos, M. Stevens, T. Freeman, K. Summers, B. McColl — 2015 — Glia Vol: 63 Pages: E192-E192
  • Dogslife: a cohort study of Labrador retrievers in the UK Carys Pugh, Mark Bronsvoort, Ian Handel, Kim Summers, Dylan Clements — 2015 — Preventive Veterinary Medicine Vol: 122 Pages: 426-435
    Abstract
    Studies of animals that visit primary and secondary veterinary centres dominate companion animal epidemiology. Dogslife is a research initiative that collects data directly from owners about the health and lifestyle of Kennel Club (KC) registered Labrador Retrievers (LR) in the UK. The ultimate aim is to seek associations between canine lifestyle and health. A selection of data from Dogslife regarding the height, weight and lifestyle of 4307 LR up to four years of age is reported here.

    The majority of the dogs were household pets, living with at least one other pet, in families or households with more than one adult. The dogs typically ate diets of dried food and daily meal frequency decreased as the dogs aged. Working dogs spent more time exercising than pets, and dogs in Wales and Scotland were exercised more than their counterparts in England. Dogs in households with children spent less time exercising than dogs in other types of households. There was considerable variation in height and weight measurements indicative of a highly heterogeneous population. The average male height at the shoulders was 2-3 cm taller than the UK breed standard. Dog weights continued to increase between one and four years of age. Those with chocolate coloured coats were heavier than their yellow and black counterparts. Greater dog weight was also associated with dogs whose owners reported restricting their dog's exercise due to where they lived.

    These findings highlight the utility of wide public engagement in the collation of phenotypic measures, providing a unique insight into the physical development and lifestyle of a cohort of LRs. In combination with concurrently collected data on the health of the cohort, phenotypic data from the Dogslife Project will contribute to understanding the relationship between dog lifestyle and health.
    DOI
    10.1016/j.prevetmed.2015.06.020
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    http://www.research.ed.ac.uk/portal/files/20067520/Dogslife_a_cohort_study_of_Labrador_retrievers_in_the_UK.pdf
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    http://linkinghub.elsevier.com/retrieve/pii/S0167587715002329
  • Limited genetic divergence between dog breeds from geographically isolated countries K M Summers, Rob Ogden, D N Clements, A T French, A G Gow, R Powell, B Corcoran, R J Mellanby, J P Schoeman — 20 Oct 2014 — Veterinary Record Vol: 175
  • What can cohort studies in the dog tell us? Carys Pugh, Mark Bronsvoort, Ian G Handel, Kim M Summers, Dylan N Clements — 15 May 2014 — Canine Genetics and Epidemiology Vol: 1 Pages: 5
    Abstract
    This paper addresses the use of cohort studies in canine medicine to date and highlights the benefits of wider use of such studies in the future. Uniquely amongst observational studies, cohort studies offer the investigator an opportunity to assess the temporal relationship between hypothesised risk factors and diseases. In human medicine cohort studies were initially used to investigate specific exposures but there has been a movement in recent years to more broadly assess the impact of complex lifestyles on morbidity and mortality. Such studies do not focus on narrow prior hypotheses but rather generate new theories about the impact of environmental and genetic risk factors on disease. Unfortunately cohort studies are expensive both in terms of initial investment and on-going costs. There is inevitably a delay between set up and the reporting of meaningful results. Expense and time constraints are likely why this study design has been used sparingly in the field of canine health studies. Despite their rather limited numbers, canine cohort studies have made a valuable contribution to the understanding of dog health, in areas such as the dynamics of infectious disease. Individual exposures such as neutering and dietary restriction have also been directly investigated. More recently, following the trend in human health, large cohort studies have been set up to assess the wider impact of dog lifestyle on their health. Such studies have the potential to develop and test hypotheses and stimulate new theories regarding the maintenance of life-long health in canine populations.
    DOI
    10.1186/2052-6687-1-5
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    http://www.research.ed.ac.uk/portal/files/15400586/What_can_cohort_studies_in_the_dog_tell_us.pdf
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    http://www.cgejournal.org/content/1/1/5
  • Transcriptional profiling of the human fibrillin/LTBP gene family, key regulators of mesenchymal cell functions Margaret R. Davis, Robin Andersson, Jessica Severin, Michiel De Hoon, Nicolas Bertin, J. Kenneth Baillie, Hideya Kawaji, Albin Sandelin, Alistair R.r. Forrest, Kim M. Summers, Fantom Consortium — 01 May 2014 — Molecular Genetics and Metabolism Vol: 112 Pages: 73-83
    Abstract
    The fibrillins and latent transforming growth factor binding proteins (LTBPs) form a superfamily of extracellular matrix (ECM) proteins characterized by the presence of a unique domain, the 8-cysteine transforming growth factor beta (TGFβ) binding domain. These proteins are involved in the structure of the extracellular matrix and controlling the bioavailability of TGFβ family members. Genes encoding these proteins show differential expression in mesenchymal cell types which synthesize the extracellular matrix. We have investigated the promoter regions of the seven gene family members using the FANTOM5 CAGE database for human. While the protein and nucleotide sequences show considerable sequence similarity, the promoter regions were quite diverse. Most genes had a single predominant transcription start site region but LTBP1 and LTBP4 had two regions initiating different transcripts. Most of the family members were expressed in a range of mesenchymal and other cell types, often associated with use of alternative promoters or transcription start sites within a promoter in different cell types. FBN3 was the lowest expressed gene, and was found only in embryonic and fetal tissues. The different promoters for one gene were more similar to each other in expression than to promoters of the other family members. Notably expression of all 22 LTBP2 promoters was tightly correlated and quite distinct from all other family members. We located candidate enhancer regions likely to be involved in expression of the genes. Each gene was associated with a unique subset of transcription factors across multiple promoters although several motifs including MAZ, SP1, GTF2I and KLF4 showed overrepresentation across the gene family. FBN1 and FBN2, which had similar expression patterns, were regulated by different transcription factors. This study highlights the role of alternative transcription start sites in regulating the tissue specificity of closely related genes and suggests that this important class of extracellular matrix proteins is subject to subtle regulatory variations that explain the differential roles of members of this gene family.
    DOI
    10.1016/j.ymgme.2013.12.006
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    http://www.research.ed.ac.uk/portal/files/15230812/1_s2.0_S1096719213004204_main.pdf
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    http://www.sciencedirect.com/science/article/pii/S1096719213004204
  • A promoter-level mammalian expression atlas J. Kenneth Baillie, Colin A. Semple, Robert S. Young, Malcolm E. Fisher, Thomas J. Ha, Anagha Joshi, Alison Meynert, James G. D. Prendergast, Kim M. Summers, Tom C. Freeman, Martin S. Taylor, David A. Hume and 251 others — 27 Mar 2014 — Nature Vol: 507 Pages: 462-+
    Abstract

    Regulated transcription controls the diversity, developmental pathways and spatial organization of the hundreds of cell types that make up a mammal. Using single-molecule cDNA sequencing, we mapped transcription start sites (TSSs) and their usage in human and mouse primary cells, cell lines and tissues to produce a comprehensive overview of mammalian gene expression across the human body. We find that few genes are truly 'housekeeping', whereas many mammalian promoters are composite entities composed of several closely separated TSSs, with independent cell-type-specific expression profiles. TSSs specific to different cell types evolve at different rates, whereas promoters of broadly expressed genes are the most conserved. Promoter-based expression analysis revealskey transcription factors defining cell states and links them to binding-site motifs. The functions of identified novel transcripts can be predicted by coexpression and sample ontology enrichment analyses. The functional annotation of the mammalian genome 5 (FANTOM5) project provides comprehensive expression profiles and functional annotation of mammalian cell-type-specific transcriptomes with wide applications in biomedical research.

    DOI
    10.1038/nature13182
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  • Transcriptional switching in macrophages associated with the peritoneal foreign body response J.E. Mooney, K.M. Summers, M. Gongora, S.M. Grimmond, J.H. Campbell, D.A. Hume, B.E. Rolfe — 18 Mar 2014 — Immunology and Cell Biology Vol: 92 Pages: 518-526
    Abstract
    We previously demonstrated that myeloid cells are the source of fibrotic tissue induced by foreign material implanted in the peritoneal cavity. This study utilised the MacGreen mouse, in which the Csf1r promoter directs myeloid-specific enhanced green fluorescent protein (EGFP) expression, to determine the temporal gene expression profile of myeloid subpopulations recruited to the peritoneal cavity to encapsulate implanted foreign material (cubes of boiled egg white). Cells with high EGFP expression (EGFP) were purified from exudate and encapsulating tissue at different times during the foreign body response, gene expression profiles determined using cDNA microarrays, and data clustered using the network analysis tool, Biolayout Express. EGFP cells from all time points expressed high levels of Csf1r, Emr1 (encoding F4/80), Cd14 and Itgam (encoding Mac-1) providing internal validation of their myeloid nature. Exudate macrophages (days 4-7) expressed a large cluster of cell cycle genes; these were switched off in capsule cells. Early in capsule formation, Csf1r-EGFP cells expressed genes associated with tissue turnover, but later expressed both pro- and anti-inflammatory genes alongside a subset of mesenchyme-associated genes, a pattern of gene expression that adds weight to the concept of a continuum of macrophage phenotypes rather than distinct M1/M2 subsets. Moreover, rather than transdifferentiating to myofibroblasts, macrophages contributing to later stages of the peritoneal foreign body response warrant their own classification as 'fibroblastoid' macrophages.Immunology and Cell Biology advance online publication, 18 March 2014; doi:10.1038/icb.2014.19.
    DOI
    10.1038/icb.2014.19
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  • Whole exome sequencing is a sensitive cost-effective method of detecting mutations in osteogenesis imperfecta and Marfan syndrome. A M MCinerney-Leo, M S Marshall, B Gardiner, P J Coucke, L Van Laer, B L Loeys, Kim Summers, S Symoens, J A West, M J West, B P Wordsworth, A Zankl, P J Leo, M A Brown, E L Duncan — 04 Dec 2013 — BoneKEy reports Vol: 2
  • Refining Methods for Studying Microglial Diversity in the Healthy and Ageing Brain Kathleen Renault, James Vincenti, Kim Summers, Barry McColl — Jul 2013 — Glia Vol: 61 Pages: S110
  • Population structure and genetic heterogeneity in popular dog breeds in the UK Richard J Mellanby, Rob Ogden, Dylan N Clements, Anne T French, Adam Gow, Roger Powell, Brendan Corcoran, Johan P Schoeman, Kim M Summers — Apr 2013 — Veterinary Journal Vol: 196 Pages: 92-97
    Abstract
    There is increasing concern that reproductive isolation related to breed specifications in dogs, while maintaining genetic differences among breeds, is likely to promote breed-specific genetic disorders. This study examined genetic diversity among 13 popular dog breed groups in the UK. Most breeds showed high levels of homozygosity when compared with crossbred animals. The Boxer and West Highland white terrier showed the lowest heterozygosity, while the Jack Russell terrier group (not a registered breed in the UK) had a level of heterozygosity comparable to crossbred dogs. Analysis of genetic distance between breeds showed significantly different inbreeding coefficients for pairwise comparisons among registered breeds, with the most divergent breeds being the Boxer and West Highland white terrier. The Rottweiler and Golden retriever showed the highest levels of inbreeding. The least distinct group contained crossbred dogs. The results show that the registered breeds are subject to a 'breed barrier' which promotes reduction in genetic diversity.
    DOI
    10.1016/j.tvjl.2012.08.009
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    http://www.research.ed.ac.uk/portal/files/21730857/population_sructure.pdf
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    http://www.sciencedirect.com/science/article/pii/S1090023312003504
  • Dogslife: A web-based longitudinal study of Labrador Retriever health in the UK Dylan N. Clements, Ian G. Handel, Erica Rose, Damon Querry, Carys Pugh, William E. R. Ollier, Kenton L. Morgan, Lorna J. Kennedy, Jeffery Sampson, Kim M. Summers, Mark Bronsvoort — 18 Jan 2013 — BMC Veterinary Research Vol: 9 Pages: 1-15
    Abstract

    Background: Dogslife is the first large-scale internet-based longitudinal study of canine health. The study has been designed to examine how environmental and genetic factors influence the health and development of a birth cohort of UK-based pedigree Labrador Retrievers.

    Results: In the first 12 months of the study 1,407 Kennel Club (KC) registered eligible dogs were recruited, at a mean age of 119 days of age (SD 69 days, range 3 days - 504 days). Recruitment rates varied depending upon the study team's ability to contact owners. Where owners authorised the provision of contact details 8.4% of dogs were recruited compared to 1.3% where no direct contact was possible. The proportion of dogs recruited was higher for owners who transferred the registration of their puppy from the breeder to themselves with the KC, and for owners who were sent an e-mail or postcard requesting participation in the project. Compliance with monthly updates was highly variable. For the 280 dogs that were aged 400 days or more on the 30th June 2011, we estimated between 39% and 45% of owners were still actively involved in the project. Initial evaluation suggests that the cohort is representative of the general population of the KC registered Labrador Retrievers eligible to enrol with the project. Clinical signs of illnesses were reported in 44.3% of Labrador Retrievers registered with Dogslife (median age of first illness 138 days), although only 44.1% of these resulted in a veterinary presentation (median age 316 days).

    Conclusions: The web-based platform has enabled the recruitment of a representative population of KC registered Labrador Retrievers, providing the first large-scale longitudinal population-based study of dog health. The use of multiple different methods (e-mail, post and telephone) of contact with dog owners was essential to maximise recruitment and retention of the cohort.

    DOI
    10.1186/1746-6148-9-13
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    http://www.research.ed.ac.uk/portal/files/8355715/Dogslife_A_web_based_longitudinal_study_of_Labrador_Retriever_health_in_the_UK.pdf
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    http://www.biomedcentral.com/1746-6148/9/13
  • Structure and function of the mammalian fibrillin gene family: Implications for human connective tissue diseases M. R. Davis, K. M. Summers — Dec 2012 — Molecular Genetics and Metabolism Vol: 107 Pages: 635-647
    Abstract
    Fibrillins and latent transforming growth factor beta binding proteins (LTBPs) are components of the extracellular matrix of connective tissue. While fibrillins are integral to the 10nm microfibrils, and often associated with elastin, all family members are likely to have an additional role in regulating the bioavailability of transforming growth factor beta (TGBbeta). Both fibrillins and LTBPs are large glycoproteins, containing a series of calcium binding epidermal growth factor domains as well as a number of copies of a unique 8 cysteine domain found only in this protein superfamily. There are three mammalian fibrillins and four LTBPs. Fibrillin monomers link head to tail in microfibrils which can then form two and three dimensional structures. In some tissues elastin is recruited to the fibrillin microfibrils to provide elasticity to the tissue. LTBPs are part of the TGBbeta large latent complex which sequesters TGBbeta in the extracellular matrix. Fibrillin-1 appears to bind to LTBPs to assist in this process and is thus involved in regulating the bioavailability of TGBbeta. Mutation of fibrillin genes results in connective tissue phenotypes which reflect both the increased level of active TGBbeta and the structural failure of the extracellular matrix due to the absence or abnormality of fibrillin protein. Fibrillinopathies include Marfan syndrome, familial ectopia lentis, familial thoracic aneurysm (mutations of FBN1) and congenital contractural arachnodactyly (mutation of FBN2). There are no diseases currently associated with mutation of FBN3 in humans, and this gene is no longer active in rodents. Expression patterns of fibrillin genes are consistent with their role in extracellular matrix structure of connective tissue. FBN1 expression is high in most cell types of mesenchymal origin, particularly bone. Human and mouse FBN2 expression is high in fetal cells and has more restricted expression in mesenchymal cell types postnatally. FBN3 is expressed early in development (embryonic and fetal tissues) in humans. The fibrillins are thus important in maintaining the structure and integrity of the extracellular matrix and, in combination with their sequence family members the LTBPs, also contribute to the regulation of the TGFbeta family of major growth factors.
    DOI
    10.1016/j.ymgme.2012.07.023
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    http://www.sciencedirect.com/science/article/pii/S1096719212002983
  • A gene expression atlas of the domestic pig Tom C Freeman, Alasdair Ivens, J Kenneth Baillie, Dario Beraldi, Mark W Barnett, David Dorward, Alison Downing, Lynsey Fairbairn, Ronan Kapetanovic, Sobia Raza, Andru Tomoiu, Ramiro Alberio, Chunlei Wu, Andrew I Su, Kim M Summers, Christopher K Tuggle, Alan L Archibald, David A Hume — 15 Nov 2012 — BMC Biology Vol: 10
    Abstract
    BACKGROUND: This work describes the first genome-wide analysis of the transcriptional landscape of the pig. A new porcine Affymetrix expression array was designed in order to provide comprehensive coverage of the known pig transcriptome. The new array was used to generate a genome-wide expression atlas of pig tissues derived from 62 tissue/cell types. These data were subjected to network correlation analysis and clustering. RESULTS: The analysis presented here provides a detailed functional clustering of the pig transcriptome where transcripts are grouped according to their expression pattern, so one can infer the function of an uncharacterized gene from the company it keeps and the locations in which it is expressed. We describe the overall transcriptional signatures present in the tissue atlas, where possible assigning those signatures to specific cell populations or pathways. In particular, we discuss the expression signatures associated with the gastrointestinal tract, an organ that was sampled at 15 sites along its length and whose biology in the pig is similar to human. We identify sets of genes that define specialized cellular compartments and region-specific digestive functions. Finally, we performed a network analysis of the transcription factors expressed in the gastrointestinal tract and demonstrate how they sub-divide into functional groups that may control cellular gastrointestinal development. CONCLUSIONS: As an important livestock animal with a physiology that is more similar than mouse to man, we provide a major new resource for understanding gene expression with respect to the known physiology of mammalian tissues and cells. The data and analyses are available on the websites http://biogps.org and http://www.macrophages.com/pig-atlas.
    DOI
    10.1186/1741-7007-10-90
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    http://www.research.ed.ac.uk/portal/files/8169051/BMC_2012_Ivens_A.pdf
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    http://biogps.org
    http://www.biomedcentral.com/1741-7007/10/90
  • Recent developments in the diagnosis of Marfan syndrome and related disorders Kim M Summers, Jennifer A West, Annette Hattam, Denis Stark, James J McGill, Malcolm J West — 05 Nov 2012 — The Medical journal of Australia Vol: 197 Pages: 494-7
    Abstract
    Marfan syndrome is a multisystem disorder of connective tissue that is inherited in an autosomal dominant fashion, and results from mutation of the FBN1 gene on human chromosome 15. There are a number of conditions of the connective tissue with a similar phenotype that can be confused with Marfan syndrome. Modifications of the diagnostic criteria have recently been published, facilitating the differentiation of Marfan syndrome from these conditions. It is still difficult to use modern genetic testing for diagnosis because Marfan syndrome can be caused by many different mutations in FBN1, a large gene with 65 coding segments, while mutations in other genes can cause overlapping phenotypes. Several clinical trials of drug therapy, including the antihypertensive drug losartan, are in progress.
    DOI
    10.5694/mja12.10560
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    https://www.mja.com.au/journal/2012/197/9/recent-developments-diagnosis-marfan-syndrome-and-related-disorders
  • Genome-wide analysis of mitral valve disease in Cavalier King Charles Spaniels A.T. French, Rob Ogden, C. Eland, G. Hemani, R. Pong-Wong, B.M. Corcoran, K.M. Summers — 2012 — The Veterinary Journal Vol: 193 Pages: 283-286
    Abstract
    The Cavalier King Charles Spaniel (CKCS) is prone to severe early onset mitral valve disease. In this study, 36 purebred CKCS dogs were evaluated for mitral valve murmur and divided into early and late onset groups. A genome-wide genetic approach was used to assess whether the condition is determined by a small number of genetic factors. There were no regions of highly discrepant homo/heterozygosity in the two groups. Similarly, there was no evidence for loci associated with mitral valve murmur in a genome-wide association study. This analysis suggests that familial occurrence of mitral valve murmur in the CKCS breed is not due to a single major gene effect, indicating that breeding strategies to eliminate the disease cannot be based on genotype information at this time.
    DOI
    10.1016/j.tvjl.2011.09.011
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    http://www.sciencedirect.com/science/article/pii/S1090023311003650