The Roslin Institute

Genetics and Genomics

Recent Publications

  • A comparative analysis of host responses to avian influenza infection in ducks and chickens highlights a role for the interferon-induced transmembrane proteins in viral resistance Jacqueline Smith, Nikki Smith, Le Yu, Ian R Paton, Maria Weronika Gutowska, Heather L Forrest, Angela F Danner, J Patrick Seiler, Paul Digard, Robert G Webster, David W Burt — 2015 — BMC Genomics Vol: 16
    Abstract

    BACKGROUND: Chickens are susceptible to infection with a limited number of Influenza A viruses and are a potential source of a human influenza pandemic. In particular, H5 and H7 haemagglutinin subtypes can evolve from low to highly pathogenic strains in gallinaceous poultry. Ducks on the other hand are a natural reservoir for these viruses and are able to withstand most avian influenza strains.

    RESULTS: Transcriptomic sequencing of lung and ileum tissue samples from birds infected with high (H5N1) and low (H5N2) pathogenic influenza viruses has allowed us to compare the early host response to these infections in both these species. Chickens (but not ducks) lack the intracellular receptor for viral ssRNA, RIG-I and the gene for an important RIG-I binding protein, RNF135. These differences in gene content partly explain the differences in host responses to low pathogenic and highly pathogenic avian influenza virus in chicken and ducks. We reveal very different patterns of expression of members of the interferon-induced transmembrane protein (IFITM) gene family in ducks and chickens. In ducks, IFITM1, 2 and 3 are strongly up regulated in response to highly pathogenic avian influenza, where little response is seen in chickens. Clustering of gene expression profiles suggests IFITM1 and 2 have an anti-viral response and IFITM3 may restrict avian influenza virus through cell membrane fusion. We also show, through molecular phylogenetic analyses, that avian IFITM1 and IFITM3 genes have been subject to both episodic and pervasive positive selection at specific codons. In particular, avian IFITM1 showed evidence of positive selection in the duck lineage at sites known to restrict influenza virus infection.

    CONCLUSIONS: Taken together these results support a model where the IFITM123 protein family and RIG-I all play a crucial role in the tolerance of ducks to highly pathogenic and low pathogenic strains of avian influenza viruses when compared to the chicken.

    DOI
    10.1186/s12864-015-1778-8
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    http://www.research.ed.ac.uk/portal/files/21169923/s12864_015_1778_8.pdf
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  • Third Report on Chicken Genes and Chromosomes 2015 Jacqueline Smith, David W. Burt, Alan L. Archibald, Dirk-jan De Koning, Ian C. Dunn, Lel Eory, Valerie Garceau, Almas A. Gheyas, Alan Hart, David A. Hume, Pete Kaiser, Stephen Kemp, Richard Kuo, Heather A. Mccormack and 90 others — Aug 2015 — Cytogenetic and Genome Research Vol: 145 Pages: 78-179
  • Characterization of the avian trojan gene family reveals contrasting evolutionary constraints Petar Petrov, Riikka Syrjänen, Jacqueline Smith, Maria Weronika Gutowska, Tatsuya Uchida, Olli Vainio, David W Burt — 24 Mar 2015 — PLoS One Vol: 10 Pages: e0121672
    Abstract

    "Trojan" is a leukocyte-specific, cell surface protein originally identified in the chicken. Its molecular function has been hypothesized to be related to anti-apoptosis and the proliferation of immune cells. The Trojan gene has been localized onto the Z sex chromosome. The adjacent two genes also show significant homology to Trojan, suggesting the existence of a novel gene/protein family. Here, we characterize this Trojan family, identify homologues in other species and predict evolutionary constraints on these genes. The two Trojan-related proteins in chicken were predicted as a receptor-type tyrosine phosphatase and a transmembrane protein, bearing a cytoplasmic immuno-receptor tyrosine-based activation motif. We identified the Trojan gene family in ten other bird species and found related genes in three reptiles and a fish species. The phylogenetic analysis of the homologues revealed a gradual diversification among the family members. Evolutionary analyzes of the avian genes predicted that the extracellular regions of the proteins have been subjected to positive selection. Such selection was possibly a response to evolving interacting partners or to pathogen challenges. We also observed an almost complete lack of intracellular positively selected sites, suggesting a conserved signaling mechanism of the molecules. Therefore, the contrasting patterns of selection likely correlate with the interaction and signaling potential of the molecules.

    DOI
    10.1371/journal.pone.0121672
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    http://www.research.ed.ac.uk/portal/files/19508995/Characterization_of_the_avian_trojan_gene_family_reveals_contrasting_evolutionary_constraints.pdf
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    http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0121672
  • The development and maintenance of the mononuclear phagocyte system of the chick is controlled by signals from the macrophage colony-stimulating factor (CSF1) receptor Valerie Garceau, Adam Balic, Carla Garcia-Morales, Kristin A Sauter, Mike J McGrew, Jacqueline Smith, Lonneke Vervelde, Adrian Sherman, Troy E Fuller, Theodore Oliphant, John A Shelley, Raksha Tiwari, Thomas L Wilson, Cosmin Chintoan-Uta, Dave W Burt, Mark P Stevens, Helen M Sang, David A Hume — 19 Feb 2015 — BMC Biology Vol: 13 Pages: 121
    Abstract

    BACKGROUND: Macrophages have many functions in development and homeostasis as well as innate immunity. Recent studies in mammals suggest that cells arising in the yolk sac give rise to self-renewing macrophage populations that persist in adult tissues. Macrophage proliferation and differentiation is controlled by macrophage colony-stimulating factor (CSF1) and interleukin 34 (IL34), both agonists of the CSF1 receptor (CSF1R). In the current manuscript we describe the origin, function and regulation of macrophages, and the role of CSF1R signalling during embryonic development, using the chick as a model.

    RESULTS: Based upon RNAseq comparison to bone marrow-derived macrophages (BMDM) grown in CSF1, we show that embryonic macrophages contribute around 2% of the total embryo RNA in day 7 chick embryos, and have similar gene expression profiles to BMDM. To explore the origins of embryonic and adult macrophages, we injected HH16 chick embryos with either yolk-sac derived blood cells, or bone marrow cells from EGFP(+) donors. In both cases, the transferred cells gave rise to large numbers of EGFP(+) tissue macrophages in the embryo. In the case of the yolk sac, these cells were not retained in hatched birds. Conversely, bone marrow EGFP(+) cells gave rise to tissue macrophages in all organs of adult birds, and regenerated CSF1-responsive marrow macrophage progenitors. Surprisingly, they did not contribute to any other hematopoietic lineage. To explore the role of CSF1 further, we injected embryonic or hatchling CSF1R-reporter transgenic birds with a novel chicken CSF1-Fc conjugate. In both cases, the treatment produced a large increase in macrophage numbers in all tissues examined. There were no apparent adverse effects of chCSF1-Fc on embryonic or post-hatch development, but there was an unexpected increase in bone density in the treated hatchlings.

    CONCLUSIONS: The data indicate that the yolk sac is not the major source of macrophages in adult birds, and that there is a macrophage-restricted, self-renewing progenitor cell in bone marrow. CSF1R is demonstrated to be limiting for macrophage development during development in ovo and post hatch. The chicken provides a novel and tractable model to study the development of the mononuclear phagocyte system and CSF1R signalling.

    DOI
    10.1186/s12915-015-0121-9
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    http://www.research.ed.ac.uk/portal/files/20038920/The_development_and_maintenance_of_the_mononuclear_phagocyte_system_of_the_chick_is_controlled_by_signals_from_the_macrophage_colony_stimulating_factor_CSF1_receptor.pdf
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    http://www.biomedcentral.com/1741-7007/13/12
  • Comparative genomics reveals insights into avian genome evolution and adaptation David W Burt, Jacqueline Smith and 105 others — 12 Dec 2014 — Science Vol: 346 Pages: 1311-20
    Abstract

    Birds are the most species-rich class of tetrapod vertebrates and have wide relevance across many research fields. We explored bird macroevolution using full genomes from 48 avian species representing all major extant clades. The avian genome is principally characterized by its constrained size, which predominantly arose because of lineage-specific erosion of repetitive elements, large segmental deletions, and gene loss. Avian genomes furthermore show a remarkably high degree of evolutionary stasis at the levels of nucleotide sequence, gene synteny, and chromosomal structure. Despite this pattern of conservation, we detected many non-neutral evolutionary changes in protein-coding genes and noncoding regions. These analyses reveal that pan-avian genomic diversity covaries with adaptations to different lifestyles and convergent evolution of traits.

    DOI
    10.1126/science.1251385
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    http://www.sciencemag.org/content/346/6215/1311
  • Analysis of the early immune response to infection by Infectious Bursal Disease Virus (IBDV) in chickens differing in their resistance to the disease Jacqueline Smith, Jean-Remy Sadeyen, Colin Butter, Pete Kaiser, David W Burt — Mar 2015 — Journal of Virology Vol: 89 Pages: 2469-2482
    Abstract

    Chicken whole genome gene expression arrays were used to analyse the host response to infection by Infectious Bursal Disease Virus (IBDV). Spleen and bursal tissue were examined from control and infected birds at 2, 3 and 4 days post-infection from two lines that differ in their resistance to IBDV infection. The host response was evaluated over this period and differences between susceptible and resistant chicken lines were examined. Anti-viral genes, including IFNA, IFNG, MX1, IFITM1, IFITM3 and IFITM5 were up-regulated in response to infection. Evaluation of this gene expression data has allowed us to predicted several genes as candidates for involvement in resistance to IBDV.

    IMPORTANCE: Infectious bursal disease (IBD) is of economic importance to the poultry industry and thus is also important for food security. Vaccines are available but field strains of the virus are of increasing virulence. There is thus an urgent need to explore new control solutions, one of which would be to breed birds with greater resistance to IBD. A goal which is perhaps uniquely achievable with poultry, of all farm animal species, as the genetics of 85% of the 60 billion chickens produced worldwide each year is under the control of essentially two breeding companies. This is the most comprehensive study to try to identify global transcriptomic differences in the target organ of the virus between chicken lines that differ in resistance, and to predict candidate resistance genes.

    DOI
    10.1128/JVI.02828-14
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    http://www.research.ed.ac.uk/portal/files/18649018/J._Virol._2015_Smith_2469_82.pdf
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    http://jvi.asm.org/content/early/2014/12/04/JVI.02828-14
  • The duck genome and transcriptome provide insight into an avian influenza virus reservoir species Yinhua Huang, Dave Burt, Jacqueline Smith, Pete Kaiser and 46 others — 2013 — Nature Genetics Vol: 45 Pages: 776-U797
    Abstract
    The duck (Anas platyrhynchos) is one of the principal natural hosts of influenza A viruses. We present the duck genome sequence and perform deep transcriptome analyses to investigate immune-related genes. Our data indicate that the duck possesses a contractive immune gene repertoire, as in chicken and zebra finch, and this repertoire has been shaped through lineage-specific duplications. We identify genes that are responsive to influenza A viruses using the lung transcriptomes of control ducks and ones that were infected with either a highly pathogenic (A/duck/Hubei/49/05) or a weakly pathogenic (A/goose/Hubei/65/05) H5N1 1 virus. Further, we show how the duck’s defense mechanisms against influenza infection have been optimized through the diversification of its b-defensin and butyrophilin-like repertoires. These analyses, in combination with the genomic and transcriptomic data, provide a resource for characterizing the interaction between host and influenza viruses.
    DOI
    10.1038/ng.2657
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    http://www.research.ed.ac.uk/portal/files/8760798/The_duck_genome_and_transcriptome_provide_insight_into_an_avian_influenza_virus_reservoir_species.pdf
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    http://www.nature.com/ng/journal/vaop/ncurrent/full/ng.2657.html
  • Integration of the genetic and physical maps of the chicken macrochromosomes Jacqueline Smith, I R Paton, C K Bruley, D W Burt, D Windsor, D Burke, F A Ponce de Leon — 2000 — Animal Genetics Vol: 31 Pages: 20-27
    Abstract
    A large amount of genetic mapping information has been obtained in the chicken from the East Lansing, Compton and Wageningen reference populations. Physical mapping information has however, been more limited. We have mapped 14 new clones, both genetically and physically, and all 14 have been assigned to macrochromosomes. The orientation of linkage groups E01C01C11W01 (Chr 1), E06C02W02 (Chr 2), E02C03W03 (Chr 3), E05C04W04 (Chr 4), E07E34C05W05 (Chr 5), E11C10W06 (Chr 6), E45C07W07 (Chr 7) and E43C12W11 (Chr 8) has been established. Here we present integrated maps of the eight macrochromosomes and the Z chromosome of the chicken and correlate genetic with physical distances for chromosomes 1-3 and the Z sex chromosome.
    DOI
    10.1046/j.1365-2052.2000.00549.x
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  • Towards the selection of chickens resistant to Salmonella and Campylobacter infections P. Kaiser, M.M. Howell, M. Fife, J.R. Sadeyen, N. Salmon, L. Rothwell, J. Young, T.Y. Poh, M. Stevens, Jacqueline Smith, D. Burt, C. Swaggerty, M. Kogut — 2009 — Bulletin et Memoires de l'Academie Royale de Medecine de Belgique Vol: 164 Pages: 17-25; discussion 25-6
    Abstract
    Resistance to infection with enteric pathogens such as Salmonella and Campylobacter can be at many levels and include both non-immune and immune mechanisms. Immune resistance mechanisms can be specific, at the level of the adaptive immune response, or non-specific, at the level of the innate immune response. Whilst we can extrapolate to some degree in birds from what is known about immune responses to these pathogens in mammals, chickens are not "feathered mice", but have a different repertoire of genes, molecules, cells and organs involved in their immune response compared to mammals. Fundamental work on the chicken's immune response to enteric pathogens is therefore still required. Our studies focus particularly on the innate immune response, as responses of heterophils (the avian neutrophil equivalent) from commercial birds, and macrophages from inbred lines of chickens, correlate with resistance or susceptibility to Salmonella infection with a variety of Salmonella serovars and infection models. We work on two basic resistance mechanisms - resistance to colonization with Salmonella or Campylobacter, and resistance to systemic salmonellosis (or fowl typhoid). To map genes involved in resistance to colonization with Salmonella and Campylobacter, we are using a combination of expression quantitative trait loci (eQTLs) from microarray studies, allied with whole genome SNP arrays (WGA), a candidate gene approach and analysis of copy number variation across the genome. For resistance to systemic salmonellosis, we have refined the location ofa novel resistance locus on Chromosome 5, designated SAL1, using high density SNP panels, combined with advanced back-crossing of resistant and susceptible lines. Using a 6th generation backcross mapping population we have confirmed and refined the SAL1 locus to 8-00 kb of Chromosome 5. This region spans 14 genes, including two very striking functional candidates; CD27-binding protein (Siva) and the RAC-alpha serine/threonine protein kinase homologue, AKT1.
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  • Integrated immunogenics in the chicken: deciphering the immune response to identify disease resistance genes P. Kaiser, J. Howell, M. Fife, J.R. Sadeyan, N. Salmon, L. Rothwell, J. Young, P. Van Diemen, M. Stevens, T.Y. Poh, M. Jones, P. Barrow, C. Swaggerty, M. Kogut, Jacqueline Smith, D. Burt — 2008
    Abstract
    Resistance to infection takes place at many levels, and involves both non-specific and specific immune mechanisms. The chicken has a different repertoire of immune genes, molecules, cells and organs compared to mammals. To understand the role of any disease resistance gene(s), it is therefore important to understand these different repertoires, and the bird's response to a particular pathogen. Our studies focus on the innate immune response, as responses of macrophages from inbred lines of chickens, and heterophils from commercial birds, correlate with resistance or susceptibility to Salmonella infection with a variety of Salmonella serovars and infection models. To map disease resistance genes, we are using a combination of expression quantitative trait loci (eQTLs) from microarray studies, allied with whole genome SNP arrays (WGA) and a candidate gene approach. There are over 500 human genes with the Gene Ontology term "innate immunity. "We have identified over 400 of these genes in the chicken genome, and are actively identifying informative SNPs in them. The segregation of 6,000 WGA SNPs across all of our inbred lines was also assessed, which should yield approximately 900 informative SNPs for a cross between any two lines. The initial focus of these studies is on mapping resistance genes in our inbred lines, but the studies will be extended to commercial flocks.
    DOI
    10.1159/000317144
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    http://www.research.ed.ac.uk/portal/files/11856999/Integrated_immunogenomics_in_the_chicken_deciphering_the_immune_response_to_identify_disease_resistance_genes.pdf
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    http://content.karger.com/ProdukteDB/produkte.asp?doi=10.1159/000317144
  • Systems analysis of immune responses in Marek's disease virus-infected chickens identifies a gene involved in susceptibility and highlights a possible novel pathogenicity mechanism J. Smith, J.-R. Sadeyen, I.R. Paton, P.M. Hocking, N. Salmon, M. Fife, V. Nair, D.W. Burt, P. Kaiser — Nov 2011 — Journal of Virology Vol: 85 Pages: 11146-11158
    Abstract
    Marek's disease virus (MDV) is a highly contagious oncogenic alphaherpesvirus that causes disease that is both a cancer model and a continuing threat to the world's poultry industry. This comprehensive gene expression study analyzes the host response to infection in both resistant and susceptible lines of chickens and inherent expression differences between the two lines following the infection of the host. A novel pathogenicity mechanism, involving the downregulation of genes containing HIC1 transcription factor binding sites as early as 4 days postinfection, was suggested from this analysis. HIC1 drives antitumor mechanisms, suggesting that MDV infection switches off genes involved in antitumor regulation several days before the expression of the MDV oncogene meq. The comparison of the gene expression data to previous QTL data identified several genes as candidates for involvement in resistance to MD. One of these genes, IRG1, was confirmed by single nucleotide polymorphism analysis to be involved in susceptibility. Its precise mechanism remains to be elucidated, although the analysis of gene expression data suggests it has a role in apoptosis. Understanding which genes are involved in susceptibility/resistance to MD and defining the pathological mechanisms of the disease gives us a much greater ability to try to reduce the incidence of this virus, which is costly to the poultry industry in terms of both animal welfare and economics.
    DOI
    10.1128/JVI.05499-11
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    http://www.research.ed.ac.uk/portal/files/8340990/Systems_analysis_of_immune_responses_in_Marek_s_disease_virus_infected_chickens_identifies_a_gene_involved_in_susceptibility_and_highlights_a_possible_novel_pathogenicity_mechanism.pdf
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    http://jvi.asm.org/content/85/21/11146
  • Molecular evolution of the vertebrate TLR1 gene family - a complex history of gene duplication, gene conversion, positive selection and co-evolution Y.H. Huang, N.D. Temperley, L.M. Ren, Jacqueline Smith, N. Li, D.W. Burt — 2011 — BMC Evolutionary Biology Vol: 11 Pages: 1-17
    Abstract
    Background: The Toll-like receptors represent a large superfamily of type I transmembrane glycoproteins, some common to a wide range of species and others are more restricted in their distribution. Most members of the Toll-like receptor superfamily have few paralogues; the exception is the TLR1 gene family with four closely related genes in mammals TLR1, TLR2, TLR6 and TLR10, and four in birds TLR1A, TLR1B, TLR2A and TLR2B. These genes were previously thought to have arisen by a series of independent gene duplications. To understand the evolutionary pattern of the TLR1 gene family in vertebrates further, we cloned the sequences of TLR1A, TLR1B, TLR2A and TLR2B in duck and turkey, constructed phylogenetic trees, predicted codons under positive selection and identified co-evolutionary amino acid pairs within the TLR1 gene family using sequences from 4 birds, 28 mammals, an amphibian and a fish. Results: This detailed phylogenetic analysis not only clarifies the gene gains and losses within the TLR1 gene family of birds and mammals, but also defines orthologues between these vertebrates. In mammals, we predict amino acid sites under positive selection in TLR1, TLR2 and TLR6 but not TLR10. We detect co-evolution between amino acid residues in TLR2 and the other members of this gene family predicted to maintain their ability to form functional heterodimers. In birds, we predict positive selection in the TLR2A and TLR2B genes at functionally significant amino acid residues. We demonstrate that the TLR1 gene family has mostly been subject to purifying selection but has also responded to directional selection at a few sites, possibly in response to pathogen challenge. Conclusions: Our phylogenetic and structural analyses of the vertebrate TLR1 family have clarified their evolutionary origins and predict amino acid residues likely to be important in the host's defense against invading pathogens.
    DOI
    10.1186/1471-2148-11-149
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    http://www.research.ed.ac.uk/portal/files/7881892/Molecular_evolution_of_the_vertebrate_TLR1_gene_family_a_complex_history_of_gene_duplication_gene_conversion_positive_selection_and_co_evolution.pdf
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    http://www.biomedcentral.com/1471-2148/11/149
  • Pivotal Advance: Avian colony-stimulating factor 1 (CSF-1), interleukin-34 (IL-34), and CSF-1 receptor genes and gene products Valerie Garceau, Jacqueline Smith, Ian R Paton, Megan Davey, Mario A Fares, David P Sester, David W Burt, David A Hume — May 2010 — Journal of Leukocyte Biology Vol: 87 Pages: 753-764
    Abstract
    Macrophages are involved in many aspects of development, host defense, pathology, and homeostasis. Their normal differentiation, proliferation, and survival are controlled by CSF-1 via the activation of the CSF1R. A recently discovered cytokine, IL-34, was shown to bind the same receptor in humans. Chicken is a widely used model organism in developmental biology, but the factors that control avian myelopoiesis have not been identified previously. The CSF-1, IL-34, and CSF1R genes in chicken and zebra finch were identified from respective genomic/cDNA sequence resources. Comparative analysis of the avian CSF1R loci revealed likely orthologs of mammalian macrophage-specific promoters and enhancers, and the CSF1R gene is expressed in the developing chick embryo in a pattern consistent with macrophage-specific expression. Chicken CSF-1 and IL-34 were expressed in HEK293 cells and shown to elicit macrophage growth from chicken BM cells in culture. Comparative sequence and co-evolution analysis across all vertebrates suggests that the two ligands interact with distinct regions of the CSF1R. These studies demonstrate that there are two separate ligands for a functional CSF1R across all vertebrates.
    DOI
    10.1189/jlb.0909624
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    http://www.jleukbio.org/content/87/5/753.abstract
  • Multi-Platform Next-Generation Sequencing of the Domestic Turkey (Meleagris gallopavo): Genome Assembly and Analysis D. W. Burt, P. Kaiser, Sungwon Kim, Jacqueline Smith and 67 others — Sep 2010 — PLoS Biology Vol: 8
    Abstract
    A synergistic combination of two next-generation sequencing platforms with a detailed comparative BAC physical contig map provided a cost-effective assembly of the genome sequence of the domestic turkey (Meleagris gallopavo). Heterozygosity of the sequenced source genome allowed discovery of more than 600,000 high quality single nucleotide variants. Despite this heterozygosity, the current genome assembly (~1.1 Gb) includes 917 Mb of sequence assigned to specific turkey chromosomes. Annotation identified nearly 16,000 genes, with 15,093 recognized as protein coding and 611 as non-coding RNA genes. Comparative analysis of the turkey, chicken, and zebra finch genomes, and comparing avian to mammalian species, supports the characteristic stability of avian genomes and identifies genes unique to the avian lineage. Clear differences are seen in number and variety of genes of the avian immune system where expansions and novel genes are less frequent than examples of gene loss. The turkey genome sequence provides resources to further understand the evolution of vertebrate genomes and genetic variation underlying economically important quantitative traits in poultry. This integrated approach may be a model for providing both gene and chromosome level assemblies of other species with agricultural, ecological, and evolutionary interest.
    DOI
    10.1371/journal.pbio.1000475
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    http://www.research.ed.ac.uk/portal/files/7904443/Multi_platform_next_generation_sequencing_of_the_domestic_turkey_Meleagris_gallopavo_genome_assembly_and_analysis.pdf
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    http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1000475
  • The genomic architecture of resistance to Campylobacter jejuni intestinal colonisation in chickens Androniki Psifidi, Mark Fife, Joanna Howell, Oswald Matika, Pauline Vandiemen, Richard Kuo, Jacqueline Smith, Paul Hocking, Nigel Salmon, Michael A. Jones, David Hume, Georgios Banos, Mark Stevens, Peter Kaiser — 18 Apr 2016 — BMC Genomics Vol: 17
    Abstract
    BACKGROUND: Campylobacter is the leading cause of foodborne diarrhoeal illness in humans and is mostly acquired from consumption or handling of contaminated poultry meat. In the absence of effective licensed vaccines and inhibitors, selection for chickens with increased resistance to Campylobacter could potentially reduce its subsequent entry into the food chain. Campylobacter intestinal colonisation levels are influenced by the host genetics of the chicken. In the present study, two chicken populations were used to investigate the genetic architecture of avian resistance to colonisation: (i) a back-cross of two White Leghorn derived inbred lines [(61 x N) x N] known to differ in resistance to Campylobacter colonisation and (ii) a 9(th) generation advanced intercross (61 x N) line.

    RESULTS: The level of colonisation with Campylobacter jejuni following experimental infection was found to be a quantitative trait. A back-cross experiment using 1,243 fully informative single nucleotide polymorphism (SNP) markers revealed quantitative trait loci (QTL) on chromosomes 7, 11 and 14. In the advanced intercross line study, the location of the QTL on chromosome 14 was confirmed and refined and two new QTLs were identified located on chromosomes 4 and 16. Pathway and re-sequencing data analysis of the genes located in the QTL candidate regions identified potential pathways, networks and candidate resistance genes. Finally, gene expression analyses were performed for some of the candidate resistance genes to support the results.

    CONCLUSION: Campylobacter resistance in chickens is a complex trait, possibly involving the Major Histocompatibility Complex, innate and adaptive immune responses, cadherins and other factors. Two of the QTLs for Campylobacter resistance are co-located with Salmonella resistance loci, indicating that it may be possible to breed simultaneously for enhanced resistance to both zoonoses.
    DOI
    10.1186/s12864-016-2612-7
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    http://www.research.ed.ac.uk/portal/files/25056339/art_3A10.1186_2Fs12864_016_2612_7.pdf
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  • Animal genomics and infectious disease resistance in poultry J Smith, A Gheyas, D W Burt — 01 Apr 2016 — Revue scientifique et technique-Office international des epizooties Vol: 35 Pages: 105-19
    Abstract

    Avian pathogens are responsible for major costs to society, both in terms of huge economic losses to the poultry industry and their implications for human health. The health and welfare of millions of birds is under continued threat from many infectious diseases, some of which are increasing in virulence and thus becoming harder to control, such as Marek's disease virus and avian influenza viruses. The current era in animal genomics has seen huge developments in both technologies and resources, which means that researchers have never been in a better position to investigate the genetics of disease resistance and determine the underlying genes/mutations which make birds susceptible or resistant to infection. Avian genomics has reached a point where the biological mechanisms of infectious diseases can be investigated and understood in poultry and other avian species. Knowledge of genes conferring disease resistance can be used in selective breeding programmes or to develop vaccines which help to control the effects of these pathogens, which have such a major impact on birds and humans alike.

    DOI
    10.20506/rst.35.1.2421
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    http://www.research.ed.ac.uk/portal/files/25439806/SmithGheyasBurt_back_from_author.doc
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  • The early immune response to infection of chickens with Infectious Bronchitis Virus (IBV) in susceptible and resistant birds Jacqueline Smith, Jean-Remy Sadeyen, David Cavanagh, Pete Kaiser, David W Burt — 09 Oct 2015 — BMC Veterinary Research Vol: 11
    Abstract

    BACKGROUND: Infectious Bronchitis is a highly contagious respiratory disease which causes tracheal lesions and also affects the reproductive tract and is responsible for large economic losses to the poultry industry every year. This is due to both mortality (either directly provoked by IBV itself or due to subsequent bacterial infection) and lost egg production. The virus is difficult to control by vaccination, so new methods to curb the impact of the disease need to be sought. Here, we seek to identify genes conferring resistance to this coronavirus, which could help in selective breeding programs to rear chickens which do not succumb to the effects of this disease.

    METHODS: Whole genome gene expression microarrays were used to analyse the gene expression differences, which occur upon infection of birds with Infectious Bronchitis Virus (IBV). Tracheal tissue was examined from control and infected birds at 2, 3 and 4 days post-infection in birds known to be either susceptible or resistant to the virus. The host innate immune response was evaluated over these 3 days and differences between the susceptible and resistant lines examined.

    RESULTS: Genes and biological pathways involved in the early host response to IBV infection were determined andgene expression differences between susceptible and resistant birds were identified. Potential candidate genes for resistance to IBV are highlighted.

    CONCLUSIONS: The early host response to IBV is analysed and potential candidate genes for disease resistance are identified. These putative resistance genes can be used as targets for future genetic and functional studies to prove a causative link with resistance to IBV.

    DOI
    10.1186/s12917-015-0575-6
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    http://www.research.ed.ac.uk/portal/files/21807210/s12917_015_0575_6.pdf
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  • Third Report on Chicken Genes and Chromosomes 2015 Jacqueline Smith, David W. Burt, Alan L. Archibald, Dirk-jan De Koning, Ian C. Dunn, Lel Eory, Valerie Garceau, Almas A. Gheyas, Alan Hart, David A. Hume, Pete Kaiser, Stephen Kemp, Richard Kuo, Heather A. Mccormack and 90 others — Aug 2015 — Cytogenetic and Genome Research Vol: 145 Pages: 78-179
  • Characterization of the avian trojan gene family reveals contrasting evolutionary constraints Petar Petrov, Riikka Syrjänen, Jacqueline Smith, Maria Weronika Gutowska, Tatsuya Uchida, Olli Vainio, David W Burt — 24 Mar 2015 — PLoS One Vol: 10 Pages: e0121672
    Abstract

    "Trojan" is a leukocyte-specific, cell surface protein originally identified in the chicken. Its molecular function has been hypothesized to be related to anti-apoptosis and the proliferation of immune cells. The Trojan gene has been localized onto the Z sex chromosome. The adjacent two genes also show significant homology to Trojan, suggesting the existence of a novel gene/protein family. Here, we characterize this Trojan family, identify homologues in other species and predict evolutionary constraints on these genes. The two Trojan-related proteins in chicken were predicted as a receptor-type tyrosine phosphatase and a transmembrane protein, bearing a cytoplasmic immuno-receptor tyrosine-based activation motif. We identified the Trojan gene family in ten other bird species and found related genes in three reptiles and a fish species. The phylogenetic analysis of the homologues revealed a gradual diversification among the family members. Evolutionary analyzes of the avian genes predicted that the extracellular regions of the proteins have been subjected to positive selection. Such selection was possibly a response to evolving interacting partners or to pathogen challenges. We also observed an almost complete lack of intracellular positively selected sites, suggesting a conserved signaling mechanism of the molecules. Therefore, the contrasting patterns of selection likely correlate with the interaction and signaling potential of the molecules.

    DOI
    10.1371/journal.pone.0121672
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    http://www.research.ed.ac.uk/portal/files/19508995/Characterization_of_the_avian_trojan_gene_family_reveals_contrasting_evolutionary_constraints.pdf
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    http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0121672
  • Analysis of the early immune response to infection by Infectious Bursal Disease Virus (IBDV) in chickens differing in their resistance to the disease Jacqueline Smith, Jean-Remy Sadeyen, Colin Butter, Pete Kaiser, David W Burt — Mar 2015 — Journal of Virology Vol: 89 Pages: 2469-2482
    Abstract

    Chicken whole genome gene expression arrays were used to analyse the host response to infection by Infectious Bursal Disease Virus (IBDV). Spleen and bursal tissue were examined from control and infected birds at 2, 3 and 4 days post-infection from two lines that differ in their resistance to IBDV infection. The host response was evaluated over this period and differences between susceptible and resistant chicken lines were examined. Anti-viral genes, including IFNA, IFNG, MX1, IFITM1, IFITM3 and IFITM5 were up-regulated in response to infection. Evaluation of this gene expression data has allowed us to predicted several genes as candidates for involvement in resistance to IBDV.

    IMPORTANCE: Infectious bursal disease (IBD) is of economic importance to the poultry industry and thus is also important for food security. Vaccines are available but field strains of the virus are of increasing virulence. There is thus an urgent need to explore new control solutions, one of which would be to breed birds with greater resistance to IBD. A goal which is perhaps uniquely achievable with poultry, of all farm animal species, as the genetics of 85% of the 60 billion chickens produced worldwide each year is under the control of essentially two breeding companies. This is the most comprehensive study to try to identify global transcriptomic differences in the target organ of the virus between chicken lines that differ in resistance, and to predict candidate resistance genes.

    DOI
    10.1128/JVI.02828-14
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    http://www.research.ed.ac.uk/portal/files/18649018/J._Virol._2015_Smith_2469_82.pdf
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    http://jvi.asm.org/content/early/2014/12/04/JVI.02828-14
  • The development and maintenance of the mononuclear phagocyte system of the chick is controlled by signals from the macrophage colony-stimulating factor (CSF1) receptor Valerie Garceau, Adam Balic, Carla Garcia-Morales, Kristin A Sauter, Mike J McGrew, Jacqueline Smith, Lonneke Vervelde, Adrian Sherman, Troy E Fuller, Theodore Oliphant, John A Shelley, Raksha Tiwari, Thomas L Wilson, Cosmin Chintoan-Uta, Dave W Burt, Mark P Stevens, Helen M Sang, David A Hume — 19 Feb 2015 — BMC Biology Vol: 13 Pages: 121
    Abstract

    BACKGROUND: Macrophages have many functions in development and homeostasis as well as innate immunity. Recent studies in mammals suggest that cells arising in the yolk sac give rise to self-renewing macrophage populations that persist in adult tissues. Macrophage proliferation and differentiation is controlled by macrophage colony-stimulating factor (CSF1) and interleukin 34 (IL34), both agonists of the CSF1 receptor (CSF1R). In the current manuscript we describe the origin, function and regulation of macrophages, and the role of CSF1R signalling during embryonic development, using the chick as a model.

    RESULTS: Based upon RNAseq comparison to bone marrow-derived macrophages (BMDM) grown in CSF1, we show that embryonic macrophages contribute around 2% of the total embryo RNA in day 7 chick embryos, and have similar gene expression profiles to BMDM. To explore the origins of embryonic and adult macrophages, we injected HH16 chick embryos with either yolk-sac derived blood cells, or bone marrow cells from EGFP(+) donors. In both cases, the transferred cells gave rise to large numbers of EGFP(+) tissue macrophages in the embryo. In the case of the yolk sac, these cells were not retained in hatched birds. Conversely, bone marrow EGFP(+) cells gave rise to tissue macrophages in all organs of adult birds, and regenerated CSF1-responsive marrow macrophage progenitors. Surprisingly, they did not contribute to any other hematopoietic lineage. To explore the role of CSF1 further, we injected embryonic or hatchling CSF1R-reporter transgenic birds with a novel chicken CSF1-Fc conjugate. In both cases, the treatment produced a large increase in macrophage numbers in all tissues examined. There were no apparent adverse effects of chCSF1-Fc on embryonic or post-hatch development, but there was an unexpected increase in bone density in the treated hatchlings.

    CONCLUSIONS: The data indicate that the yolk sac is not the major source of macrophages in adult birds, and that there is a macrophage-restricted, self-renewing progenitor cell in bone marrow. CSF1R is demonstrated to be limiting for macrophage development during development in ovo and post hatch. The chicken provides a novel and tractable model to study the development of the mononuclear phagocyte system and CSF1R signalling.

    DOI
    10.1186/s12915-015-0121-9
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    http://www.research.ed.ac.uk/portal/files/20038920/The_development_and_maintenance_of_the_mononuclear_phagocyte_system_of_the_chick_is_controlled_by_signals_from_the_macrophage_colony_stimulating_factor_CSF1_receptor.pdf
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    http://www.biomedcentral.com/1741-7007/13/12
  • A comparative analysis of host responses to avian influenza infection in ducks and chickens highlights a role for the interferon-induced transmembrane proteins in viral resistance Jacqueline Smith, Nikki Smith, Le Yu, Ian R Paton, Maria Weronika Gutowska, Heather L Forrest, Angela F Danner, J Patrick Seiler, Paul Digard, Robert G Webster, David W Burt — 2015 — BMC Genomics Vol: 16
    Abstract

    BACKGROUND: Chickens are susceptible to infection with a limited number of Influenza A viruses and are a potential source of a human influenza pandemic. In particular, H5 and H7 haemagglutinin subtypes can evolve from low to highly pathogenic strains in gallinaceous poultry. Ducks on the other hand are a natural reservoir for these viruses and are able to withstand most avian influenza strains.

    RESULTS: Transcriptomic sequencing of lung and ileum tissue samples from birds infected with high (H5N1) and low (H5N2) pathogenic influenza viruses has allowed us to compare the early host response to these infections in both these species. Chickens (but not ducks) lack the intracellular receptor for viral ssRNA, RIG-I and the gene for an important RIG-I binding protein, RNF135. These differences in gene content partly explain the differences in host responses to low pathogenic and highly pathogenic avian influenza virus in chicken and ducks. We reveal very different patterns of expression of members of the interferon-induced transmembrane protein (IFITM) gene family in ducks and chickens. In ducks, IFITM1, 2 and 3 are strongly up regulated in response to highly pathogenic avian influenza, where little response is seen in chickens. Clustering of gene expression profiles suggests IFITM1 and 2 have an anti-viral response and IFITM3 may restrict avian influenza virus through cell membrane fusion. We also show, through molecular phylogenetic analyses, that avian IFITM1 and IFITM3 genes have been subject to both episodic and pervasive positive selection at specific codons. In particular, avian IFITM1 showed evidence of positive selection in the duck lineage at sites known to restrict influenza virus infection.

    CONCLUSIONS: Taken together these results support a model where the IFITM123 protein family and RIG-I all play a crucial role in the tolerance of ducks to highly pathogenic and low pathogenic strains of avian influenza viruses when compared to the chicken.

    DOI
    10.1186/s12864-015-1778-8
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    http://www.research.ed.ac.uk/portal/files/21169923/s12864_015_1778_8.pdf
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  • Comparative genomics reveals insights into avian genome evolution and adaptation David W Burt, Jacqueline Smith and 105 others — 12 Dec 2014 — Science Vol: 346 Pages: 1311-20
    Abstract

    Birds are the most species-rich class of tetrapod vertebrates and have wide relevance across many research fields. We explored bird macroevolution using full genomes from 48 avian species representing all major extant clades. The avian genome is principally characterized by its constrained size, which predominantly arose because of lineage-specific erosion of repetitive elements, large segmental deletions, and gene loss. Avian genomes furthermore show a remarkably high degree of evolutionary stasis at the levels of nucleotide sequence, gene synteny, and chromosomal structure. Despite this pattern of conservation, we detected many non-neutral evolutionary changes in protein-coding genes and noncoding regions. These analyses reveal that pan-avian genomic diversity covaries with adaptations to different lifestyles and convergent evolution of traits.

    DOI
    10.1126/science.1251385
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    http://www.sciencemag.org/content/346/6215/1311
  • Systems analysis of immune responses in Marek's disease virus-infected chickens identifies a gene involved in susceptibility and highlights a possible novel pathogenicity mechanism J. Smith, J.-R. Sadeyen, I.R. Paton, P.M. Hocking, N. Salmon, M. Fife, V. Nair, D.W. Burt, P. Kaiser — Nov 2011 — Journal of Virology Vol: 85 Pages: 11146-11158
    Abstract
    Marek's disease virus (MDV) is a highly contagious oncogenic alphaherpesvirus that causes disease that is both a cancer model and a continuing threat to the world's poultry industry. This comprehensive gene expression study analyzes the host response to infection in both resistant and susceptible lines of chickens and inherent expression differences between the two lines following the infection of the host. A novel pathogenicity mechanism, involving the downregulation of genes containing HIC1 transcription factor binding sites as early as 4 days postinfection, was suggested from this analysis. HIC1 drives antitumor mechanisms, suggesting that MDV infection switches off genes involved in antitumor regulation several days before the expression of the MDV oncogene meq. The comparison of the gene expression data to previous QTL data identified several genes as candidates for involvement in resistance to MD. One of these genes, IRG1, was confirmed by single nucleotide polymorphism analysis to be involved in susceptibility. Its precise mechanism remains to be elucidated, although the analysis of gene expression data suggests it has a role in apoptosis. Understanding which genes are involved in susceptibility/resistance to MD and defining the pathological mechanisms of the disease gives us a much greater ability to try to reduce the incidence of this virus, which is costly to the poultry industry in terms of both animal welfare and economics.
    DOI
    10.1128/JVI.05499-11
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    http://www.research.ed.ac.uk/portal/files/8340990/Systems_analysis_of_immune_responses_in_Marek_s_disease_virus_infected_chickens_identifies_a_gene_involved_in_susceptibility_and_highlights_a_possible_novel_pathogenicity_mechanism.pdf
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    http://jvi.asm.org/content/85/21/11146
  • Molecular evolution of the vertebrate TLR1 gene family - a complex history of gene duplication, gene conversion, positive selection and co-evolution Y.H. Huang, N.D. Temperley, L.M. Ren, Jacqueline Smith, N. Li, D.W. Burt — 2011 — BMC Evolutionary Biology Vol: 11 Pages: 1-17
    Abstract
    Background: The Toll-like receptors represent a large superfamily of type I transmembrane glycoproteins, some common to a wide range of species and others are more restricted in their distribution. Most members of the Toll-like receptor superfamily have few paralogues; the exception is the TLR1 gene family with four closely related genes in mammals TLR1, TLR2, TLR6 and TLR10, and four in birds TLR1A, TLR1B, TLR2A and TLR2B. These genes were previously thought to have arisen by a series of independent gene duplications. To understand the evolutionary pattern of the TLR1 gene family in vertebrates further, we cloned the sequences of TLR1A, TLR1B, TLR2A and TLR2B in duck and turkey, constructed phylogenetic trees, predicted codons under positive selection and identified co-evolutionary amino acid pairs within the TLR1 gene family using sequences from 4 birds, 28 mammals, an amphibian and a fish. Results: This detailed phylogenetic analysis not only clarifies the gene gains and losses within the TLR1 gene family of birds and mammals, but also defines orthologues between these vertebrates. In mammals, we predict amino acid sites under positive selection in TLR1, TLR2 and TLR6 but not TLR10. We detect co-evolution between amino acid residues in TLR2 and the other members of this gene family predicted to maintain their ability to form functional heterodimers. In birds, we predict positive selection in the TLR2A and TLR2B genes at functionally significant amino acid residues. We demonstrate that the TLR1 gene family has mostly been subject to purifying selection but has also responded to directional selection at a few sites, possibly in response to pathogen challenge. Conclusions: Our phylogenetic and structural analyses of the vertebrate TLR1 family have clarified their evolutionary origins and predict amino acid residues likely to be important in the host's defense against invading pathogens.
    DOI
    10.1186/1471-2148-11-149
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    http://www.research.ed.ac.uk/portal/files/7881892/Molecular_evolution_of_the_vertebrate_TLR1_gene_family_a_complex_history_of_gene_duplication_gene_conversion_positive_selection_and_co_evolution.pdf
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    http://www.biomedcentral.com/1471-2148/11/149
  • Multi-Platform Next-Generation Sequencing of the Domestic Turkey (Meleagris gallopavo): Genome Assembly and Analysis D. W. Burt, P. Kaiser, Sungwon Kim, Jacqueline Smith and 67 others — Sep 2010 — PLoS Biology Vol: 8
    Abstract
    A synergistic combination of two next-generation sequencing platforms with a detailed comparative BAC physical contig map provided a cost-effective assembly of the genome sequence of the domestic turkey (Meleagris gallopavo). Heterozygosity of the sequenced source genome allowed discovery of more than 600,000 high quality single nucleotide variants. Despite this heterozygosity, the current genome assembly (~1.1 Gb) includes 917 Mb of sequence assigned to specific turkey chromosomes. Annotation identified nearly 16,000 genes, with 15,093 recognized as protein coding and 611 as non-coding RNA genes. Comparative analysis of the turkey, chicken, and zebra finch genomes, and comparing avian to mammalian species, supports the characteristic stability of avian genomes and identifies genes unique to the avian lineage. Clear differences are seen in number and variety of genes of the avian immune system where expansions and novel genes are less frequent than examples of gene loss. The turkey genome sequence provides resources to further understand the evolution of vertebrate genomes and genetic variation underlying economically important quantitative traits in poultry. This integrated approach may be a model for providing both gene and chromosome level assemblies of other species with agricultural, ecological, and evolutionary interest.
    DOI
    10.1371/journal.pbio.1000475
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    http://www.research.ed.ac.uk/portal/files/7904443/Multi_platform_next_generation_sequencing_of_the_domestic_turkey_Meleagris_gallopavo_genome_assembly_and_analysis.pdf
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    http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1000475
  • Pivotal Advance: Avian colony-stimulating factor 1 (CSF-1), interleukin-34 (IL-34), and CSF-1 receptor genes and gene products Valerie Garceau, Jacqueline Smith, Ian R Paton, Megan Davey, Mario A Fares, David P Sester, David W Burt, David A Hume — May 2010 — Journal of Leukocyte Biology Vol: 87 Pages: 753-764
    Abstract
    Macrophages are involved in many aspects of development, host defense, pathology, and homeostasis. Their normal differentiation, proliferation, and survival are controlled by CSF-1 via the activation of the CSF1R. A recently discovered cytokine, IL-34, was shown to bind the same receptor in humans. Chicken is a widely used model organism in developmental biology, but the factors that control avian myelopoiesis have not been identified previously. The CSF-1, IL-34, and CSF1R genes in chicken and zebra finch were identified from respective genomic/cDNA sequence resources. Comparative analysis of the avian CSF1R loci revealed likely orthologs of mammalian macrophage-specific promoters and enhancers, and the CSF1R gene is expressed in the developing chick embryo in a pattern consistent with macrophage-specific expression. Chicken CSF-1 and IL-34 were expressed in HEK293 cells and shown to elicit macrophage growth from chicken BM cells in culture. Comparative sequence and co-evolution analysis across all vertebrates suggests that the two ligands interact with distinct regions of the CSF1R. These studies demonstrate that there are two separate ligands for a functional CSF1R across all vertebrates.
    DOI
    10.1189/jlb.0909624
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    http://www.jleukbio.org/content/87/5/753.abstract
  • Molecular immunotyping of lungs in naive and vaccinated chickens early after pulmonary avian influenxa A (H9N2) virus infection W. G. J. Degen, J. Smith, B. J. Simmelink, E. J. Glass, D. W. Burt, V. E. J. C. Schijns — 2009 — Veterinary Immunology and Immunopathology Vol: 128 Pages: 325
    Abstract
    In a respiratory infection model we study immune reactions in chickens infected with the low pathogenic avian influenza A H9N2 virus strain. For molecular immune response profiling we employed a recently developed chicken immuno-microarray containing approximately 5000 cDNA elements in duplicate (Smith et al., 2006 J. Smith, D. Speed, P.M. Hocking, R.T. Talbot, W.G. Degen, V.E. Schijns, E.J. Glass and D.W. Burt, Development of a chicken 5 K microarray targeted towards immune function, BMC Genomics 7 (2006), p. 49. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (0)Smith et al., 2006). In a first experiment, broiler-type chickens were either mock-immunized (referred to as non-immune), vaccinated with inactivated viral antigen only (immune), or with viral antigen in distinct Th1 or Th2 polarizing immunopotentiators (immune potentiated). Three weeks after vaccination all animals were given a respiratory infection with H9N2 via the oculo-nasal-intratracheal route. From these animals lungs and spleens were removed, RNA was isolated and subsequently used for microarray analysis. In general, we noted less host gene expression in immune potentiated, i.e. adjuvanted, birds when compared to non-immune, infected chickens. Immune potentiated birds showed reduced innate responses, mainly restricted to heat shock proteins, which, likely, are sufficient to control the pulmonary infection together with induced antibodies and T cells. Evaluation of the microarray data suggested gene pathways unique to or common amongst the differently immune groups (Degen et al., 2006). In subsequent experiments we have analyzed, and still are analyzing, the influence of age and type (broiler versus layer) of the chickens, challenge route (oculo-nasal-intratracheal versus spray), and the use of other immune response polarizing immunopotentiators on the host gene expression profiles by using the microarray and quantitative RT-PCR (Q-RT-PCR), as well as classical immune parameters. In this presentation we will highlight our findings. The data collected in this natural influenza A virus target Species, i.e. chicken, are of interest for the design of future human pandemic and seasonal vaccines containing immune response modifying immunopotentiators.
    DOI
    10.1016/j.vetimm.2008.10.245
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    http://www.sciencedirect.com/science/article/pii/S0165242708006442
  • Towards the selection of chickens resistant to Salmonella and Campylobacter infections P. Kaiser, M.M. Howell, M. Fife, J.R. Sadeyen, N. Salmon, L. Rothwell, J. Young, T.Y. Poh, M. Stevens, Jacqueline Smith, D. Burt, C. Swaggerty, M. Kogut — 2009 — Bulletin et Memoires de l'Academie Royale de Medecine de Belgique Vol: 164 Pages: 17-25; discussion 25-6
    Abstract
    Resistance to infection with enteric pathogens such as Salmonella and Campylobacter can be at many levels and include both non-immune and immune mechanisms. Immune resistance mechanisms can be specific, at the level of the adaptive immune response, or non-specific, at the level of the innate immune response. Whilst we can extrapolate to some degree in birds from what is known about immune responses to these pathogens in mammals, chickens are not "feathered mice", but have a different repertoire of genes, molecules, cells and organs involved in their immune response compared to mammals. Fundamental work on the chicken's immune response to enteric pathogens is therefore still required. Our studies focus particularly on the innate immune response, as responses of heterophils (the avian neutrophil equivalent) from commercial birds, and macrophages from inbred lines of chickens, correlate with resistance or susceptibility to Salmonella infection with a variety of Salmonella serovars and infection models. We work on two basic resistance mechanisms - resistance to colonization with Salmonella or Campylobacter, and resistance to systemic salmonellosis (or fowl typhoid). To map genes involved in resistance to colonization with Salmonella and Campylobacter, we are using a combination of expression quantitative trait loci (eQTLs) from microarray studies, allied with whole genome SNP arrays (WGA), a candidate gene approach and analysis of copy number variation across the genome. For resistance to systemic salmonellosis, we have refined the location ofa novel resistance locus on Chromosome 5, designated SAL1, using high density SNP panels, combined with advanced back-crossing of resistant and susceptible lines. Using a 6th generation backcross mapping population we have confirmed and refined the SAL1 locus to 8-00 kb of Chromosome 5. This region spans 14 genes, including two very striking functional candidates; CD27-binding protein (Siva) and the RAC-alpha serine/threonine protein kinase homologue, AKT1.
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