2020 |
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Wu, Z.; Harne, R.; Chintoan-Uta, C.; Hu, T. -J.; Wallace, R.; MacCallum, A.; Stevens, M. P.; Kaiser, P.; Balic, A.; Hume, D. A. Regulation and function of macrophage colony-stimulating factor (CSF1) in the chicken immune system (Journal Article) In: Developmental and Comparative Immunology, vol. 105, 2020, ISSN: 0145305X, (Publisher: Elsevier Ltd). @article{wu_regulation_2020,Macrophage colony-stimulating factor (CSF1) is an essential growth factor to control the proliferation, differentiation and survival of cells of the macrophage lineage in vertebrates. We have previously produced a recombinant chicken CSF1-Fc fusion protein and administrated it to birds which produced a substantial expansion of tissue macrophage populations. To further study the biology of CSF1 in the chicken, here we generated anti-chicken CSF1 antibodies (ROS-AV181 and 183) using CSF1-Fc as an immunogen. The specific binding of each monoclonal antibody was confirmed by ELISA, Western blotting and immunohistochemistry on tissue sections. Using the anti-CSF1 antibodies, we show that chicken bone marrow derived macrophages (BMDM) express CSF1 on their surface, and that the level appears to be regulated further by exogenous CSF1. By capture ELISA circulating CSF1 levels increased transiently in both layer and broiler embryos around the day of hatch. The levels of CSF1 in broilers was higher than in layers during the first week after hatch. Antibody ROS-AV183 was able to block CSF1 biological activity in vitro and treatment of hatchlings using this neutralising antibody in vivo impacted on some tissue macrophage populations, but not blood monocytes. After anti-CSF1 treatment, CSF1R-transgene reporter expressing cells were reduced in the bursa of Fabricius and cecal tonsil and TIM4+ Kupffer cells in the liver were almost completely ablated. Anti-CSF1 treatment also produced a reduction in overall bone density, trabecular volume and TRAP+ osteoclasts. Our novel neutralising antibody provides a new tool to study the roles of CSF1 in birds. © 2019 | |
Summers, K. M.; Bush, S. J.; Wu, C.; Su, A. I.; Muriuki, C.; Clark, E. L.; Finlayson, H. A.; Eory, L.; Waddell, L. A.; Talbot, R.; Archibald, A. L.; Hume, D. A. Functional Annotation of the Transcriptome of the Pig, Sus scrofa, Based Upon Network Analysis of an RNAseq Transcriptional Atlas (Journal Article) In: Frontiers in Genetics, vol. 10, 2020, ISSN: 16648021, (Publisher: Frontiers Media S.A.). @article{summers_functional_2020,The domestic pig (Sus scrofa) is both an economically important livestock species and a model for biomedical research. Two highly contiguous pig reference genomes have recently been released. To support functional annotation of the pig genomes and comparative analysis with large human transcriptomic data sets, we aimed to create a pig gene expression atlas. To achieve this objective, we extended a previous approach developed for the chicken. We downloaded RNAseq data sets from public repositories, down-sampled to a common depth, and quantified expression against a reference transcriptome using the mRNA quantitation tool, Kallisto. We then used the network analysis tool Graphia to identify clusters of transcripts that were coexpressed across the merged data set. Consistent with the principle of guilt-by-association, we identified coexpression clusters that were highly tissue or cell-type restricted and contained transcription factors that have previously been implicated in lineage determination. Other clusters were enriched for transcripts associated with biological processes, such as the cell cycle and oxidative phosphorylation. The same approach was used to identify coexpression clusters within RNAseq data from multiple individual liver and brain samples, highlighting cell type, process, and region-specific gene expression. Evidence of conserved expression can add confidence to assignment of orthology between pig and human genes. Many transcripts currently identified as novel genes with ENSSSCG or LOC IDs were found to be coexpressed with annotated neighbouring transcripts in the same orientation, indicating they may be products of the same transcriptional unit. The meta-analytic approach to utilising public RNAseq data is extendable to include new data sets and new species and provides a framework to support the Functional Annotation of Animals Genomes (FAANG) initiative. © Copyright © 2020 Summers, Bush, Wu, Su, Muriuki, Clark, Finlayson, Eory, Waddell, Talbot, Archibald and Hume. | |
Hume, D. A.; Caruso, M.; Ferrari-Cestari, M.; Summers, K. M.; Pridans, C.; Irvine, K. M. Phenotypic impacts of CSF1R deficiencies in humans and model organisms (Journal Article) In: Journal of Leukocyte Biology, vol. 107, no. 2, pp. 205–219, 2020, ISSN: 07415400, (Publisher: John Wiley and Sons Inc.). @article{hume_phenotypic_2020,Mϕ proliferation, differentiation, and survival are controlled by signals from the Mϕ CSF receptor (CSF1R). Mono-allelic gain-of-function mutations in CSF1R in humans are associated with an autosomal-dominant leukodystrophy and bi-allelic loss-of-function mutations with recessive skeletal dysplasia, brain disorders, and developmental anomalies. Most of the phenotypes observed in these human disease states are also observed in mice and rats with loss-of-function mutations in Csf1r or in Csf1 encoding one of its two ligands. Studies in rodent models also highlight the importance of genetic background and likely epistatic interactions between Csf1r and other loci. The impacts of Csf1r mutations on the brain are usually attributed solely to direct impacts on microglial number and function. However, analysis of hypomorphic Csf1r mutants in mice and several other lines of evidence suggest that primary hydrocephalus and loss of the physiological functions of Mϕs in the periphery contribute to the development of brain pathology. In this review, we outline the evidence that CSF1R is expressed exclusively in mononuclear phagocytes and explore the mechanisms linking CSF1R mutations to pleiotropic impacts on postnatal growth and development. © 2019 The Authors. Journal of Leukocyte Biology published by Wiley Periodicals, Inc. on behalf of Society for Leukocyte Biology | |
Hume, D. A.; Gutowska-Ding, M. W.; Garcia-Morales, C.; Kebede, A.; Bamidele, O.; Trujillo, A. V.; Gheyas, A. A.; Smith, J. Functional evolution of the colony-stimulating factor 1 receptor (CSF1R) and its ligands in birds (Journal Article) In: Journal of Leukocyte Biology, vol. 107, no. 2, pp. 237–250, 2020, ISSN: 07415400, (Publisher: John Wiley and Sons Inc.). @article{hume_functional_2020,Macrophage colony-stimulating factor (CSF1 or M-CSF) and interleukin 34 (IL34) are secreted cytokines that control macrophage survival and differentiation. Both act through the CSF1 receptor (CSF1R), a type III transmembrane receptor tyrosine kinase. The functions of CSF1R and both ligands are conserved in birds. We have analyzed protein-coding sequence divergence among avian species. The intracellular tyrosine kinase domain of CSF1R was highly conserved in bird species as in mammals but the extracellular domain of avian CSF1R was more divergent in birds with multiple positively selected amino acids. Based upon crystal structures of the mammalian CSF1/IL34 receptor-ligand interfaces and structure-based alignments, we identified amino acids involved in avian receptor-ligand interactions. The contact amino acids in both CSF1 and CSF1R diverged among avian species. Ligand-binding domain swaps between chicken and zebra finch CSF1 confirmed the function of variants that confer species specificity on the interaction of CSF1 with CSF1R. Based upon genomic sequence analysis, we identified prevalent amino acid changes in the extracellular domain of CSF1R even within the chicken species that distinguished commercial broilers and layers and tropically adapted breeds. The rapid evolution in the extracellular domain of avian CSF1R suggests that at least in birds this ligand-receptor interaction is subjected to pathogen selection. We discuss this finding in the context of expression of CSF1R in antigen-sampling and antigen-presenting cells. © 2019 The Authors. Journal of Leukocyte Biology published by Wiley Periodicals, Inc. on behalf of Society for Leukocyte Biology | |
Abbott, C. R.; Hume, D. The geometry of generalized loxodromic elements (Journal Article) In: Annales de l'Institut Fourier, vol. 70, no. 4, pp. 1689–1713, 2020, ISSN: 03730956, (Publisher: Association des Annales de l'Institut Fourier). @article{abbott_geometry_2020,We explore geometric conditions which ensure that a given element of a finitely generated group is, or fails to be, generalized loxodromic; as part of this we prove a generalization of Sisto’s result that every generalized loxodromic element is Morse. We provide a sufficient geometric condition for an element of a small cancellation group to be generalized loxodromic in terms of the defining relations and provide a number of constructions which prove that this condition is sharp. © 2020 Association des Annales de l'Institut Fourier. All rights reserved. | |
Warr, A.; Affara, N.; Aken, B.; Beiki, H.; Bickhart, D. M.; Billis, K.; Chow, W.; Eory, L.; Finlayson, H. A.; Flicek, P.; Girón, C. G.; Griffin, D. K.; Hall, R.; Hannum, G.; Hourlier, T.; Howe, K.; Hume, D. A.; Izuogu, O.; Kim, K.; Koren, S.; Liu, H.; Manchanda, N.; Martin, F. J.; Nonneman, D. J.; O'Connor, R. E.; Phillippy, A. M.; Rohrer, G. A.; Rosen, B. D.; Rund, L. A.; Sargent, C. A.; Schook, L. B.; Schroeder, S. G.; Schwartz, A. S.; Skinner, B. M.; Talbot, R.; Tseng, E.; Tuggle, C. K.; Watson, M.; Smith, T. P. L.; Archibald, A. L. An improved pig reference genome sequence to enable pig genetics and genomics research (Journal Article) In: GigaScience, vol. 9, no. 6, 2020, ISSN: 2047217X, (Publisher: Oxford University Press). @article{warr_improved_2020,Background: The domestic pig (Sus scrofa) is important both as a food source and as a biomedical model given its similarity in size, anatomy, physiology, metabolism, pathology, and pharmacology to humans. The draft reference genome (Sscrofa10.2) of a purebred Duroc female pig established using older clone-based sequencing methods was incomplete, and unresolved redundancies, short-range order and orientation errors, and associated misassembled genes limited its utility. Results: We present 2 annotated highly contiguous chromosome-level genome assemblies created with more recent long-read technologies and a whole-genome shotgun strategy, 1 for the same Duroc female (Sscrofa11.1) and 1 for an outbred, composite-breed male (USMARCv1.0). Both assemblies are of substantially higher (textgreater90-fold) continuity and accuracy than Sscrofa10.2. Conclusions: These highly contiguous assemblies plus annotation of a further 11 short-read assemblies provide an unprecedented view of the genetic make-up of this important agricultural and biomedical model species. We propose that the improved Duroc assembly (Sscrofa11.1) become the reference genome for genomic research in pigs. © The Author(s) 2020. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. | |
2019 |
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Rojo, R.; Raper, A.; Ozdemir, D. D.; Lefevre, L.; Grabert, K.; Wollscheid-Lengeling, E.; Bradford, B.; Caruso, M.; Gazova, I.; Sánchez, A.; Lisowski, Z. M.; Alves, J.; Molina-Gonzalez, I.; Davtyan, H.; Lodge, R. J.; Glover, J. D.; Wallace, R.; Munro, D. A. D.; David, E.; Amit, I.; Miron, V. E.; Priller, J.; Jenkins, S. J.; Hardingham, G. E.; Blurton-Jones, M.; Mabbott, N. A.; Summers, K. M.; Hohenstein, P.; Hume, D. A.; Pridans, C. Deletion of a Csf1r enhancer selectively impacts CSF1R expression and development of tissue macrophage populations (Journal Article) In: Nature Communications, vol. 10, no. 1, 2019, ISSN: 20411723, (Publisher: Nature Publishing Group). @article{rojo_deletion_2019,The proliferation, differentiation and survival of mononuclear phagocytes depend on signals from the receptor for macrophage colony-stimulating factor, CSF1R. The mammalian Csf1r locus contains a highly conserved super-enhancer, the fms-intronic regulatory element (FIRE). Here we show that genomic deletion of FIRE in mice selectively impacts CSF1R expression and tissue macrophage development in specific tissues. Deletion of FIRE ablates macrophage development from murine embryonic stem cells. Csf1rΔFIRE/ΔFIRE mice lack macrophages in the embryo, brain microglia and resident macrophages in the skin, kidney, heart and peritoneum. The homeostasis of other macrophage populations and monocytes is unaffected, but monocytes and their progenitors in bone marrow lack surface CSF1R. Finally, Csf1rΔFIRE/ΔFIRE mice are healthy and fertile without the growth, neurological or developmental abnormalities reported in Csf1r−/− rodents. Csf1rΔFIRE/ΔFIRE mice thus provide a model to explore the homeostatic, physiological and immunological functions of tissue-specific macrophage populations in adult animals. © 2019, The Author(s). | |
Low, W. Y.; Tearle, R.; Bickhart, D. M.; Rosen, B. D.; Kingan, S. B.; Swale, T.; Thibaud-Nissen, F.; Murphy, T. D.; Young, R.; Lefevre, L.; Hume, D. A.; Collins, A.; Ajmone-Marsan, P.; Smith, T. P. L.; Williams, J. L. Chromosome-level assembly of the water buffalo genome surpasses human and goat genomes in sequence contiguity (Journal Article) In: Nature Communications, vol. 10, no. 1, 2019, ISSN: 20411723, (Publisher: Nature Publishing Group). @article{low_chromosome-level_2019,Rapid innovation in sequencing technologies and improvement in assembly algorithms have enabled the creation of highly contiguous mammalian genomes. Here we report a chromosome-level assembly of the water buffalo (Bubalus bubalis) genome using single-molecule sequencing and chromatin conformation capture data. PacBio Sequel reads, with a mean length of 11.5 kb, helped to resolve repetitive elements and generate sequence contiguity. All five B. bubalis sub-metacentric chromosomes were correctly scaffolded with centromeres spanned. Although the index animal was partly inbred, 58% of the genome was haplotype-phased by FALCON-Unzip. This new reference genome improves the contig N50 of the previous short-read based buffalo assembly more than a thousand-fold and contains only 383 gaps. It surpasses the human and goat references in sequence contiguity and facilitates the annotation of hard to assemble gene clusters such as the major histocompatibility complex (MHC). © 2019, The Author(s). | |
Freem, L.; Summers, K. M.; Gheyas, A. A.; Psifidi, A.; Boulton, K.; MacCallum, A.; Harne, R.; O’Dell, J.; Bush, S. J.; Hume, D. A. Analysis of the Progeny of Sibling Matings Reveals Regulatory Variation Impacting the Transcriptome of Immune Cells in Commercial Chickens (Journal Article) In: Frontiers in Genetics, vol. 10, 2019, ISSN: 16648021, (Publisher: Frontiers Media S.A.). @article{freem_analysis_2019,There is increasing recognition that the underlying genetic variation contributing to complex traits influences transcriptional regulation and can be detected at a population level as expression quantitative trait loci. At the level of an individual, allelic variation in transcriptional regulation of individual genes can be detected by measuring allele-specific expression in RNAseq data. We reasoned that extreme variants in gene expression could be identified by analysis of inbred progeny with shared grandparents. Commercial chickens have been intensively selected for production traits. Selection is associated with large blocks of linkage disequilibrium with considerable potential for co-selection of closely linked “hitch-hiker alleles” affecting traits unrelated to the feature being selected, such as immune function, with potential impact on the productivity and welfare of the animals. To test this hypothesis that there is extreme allelic variation in immune-associated genes we sequenced a founder population of commercial broiler and layer birds. These birds clearly segregated genetically based upon breed type. Each genome contained numerous candidate null mutations, protein-coding variants predicted to be deleterious and extensive non-coding polymorphism. We mated selected broiler-layer pairs then generated cohorts of F2 birds by sibling mating of the F1 generation. Despite the predicted prevalence of deleterious coding variation in the genomic sequence of the founders, clear detrimental impacts of inbreeding on survival and post-hatch development were detected in only one F2 sibship of 15. There was no effect on circulating leukocyte populations in hatchlings. In selected F2 sibships we performed RNAseq analysis of the spleen and isolated bone marrow-derived macrophages (with and without lipopolysaccharide stimulation). The results confirm the predicted emergence of very large differences in expression of individual genes and sets of genes. Network analysis of the results identified clusters of co-expressed genes that vary between individuals and suggested the existence of trans-acting variation in the expression in macrophages of the interferon response factor family that distinguishes the parental broiler and layer birds and influences the global response to lipopolysaccharide. This study shows that the impact of inbreeding on immune cell gene expression can be substantial at the transcriptional level, and potentially opens a route to accelerate selection using specific alleles known to be associated with desirable expression levels. © Copyright © 2019 Freem, Summers, Gheyas, Psifidi, Boulton, MacCallum, Harne, O’Dell, Bush and Hume. | |
Muriuki, C.; Bush, S. J.; Salavati, M.; McCulloch, M. E. B.; Lisowski, Z. M.; Agaba, M.; Djikeng, A.; Hume, D. A.; Clark, E. L. A Mini-Atlas of Gene Expression for the Domestic Goat (Capra hircus) (Journal Article) In: Frontiers in Genetics, vol. 10, 2019, ISSN: 16648021, (Publisher: Frontiers Media S.A.). @article{muriuki_mini-atlas_2019,Goats (Capra hircus) are an economically important livestock species providing meat and milk across the globe. They are of particular importance in tropical agri-systems contributing to sustainable agriculture, alleviation of poverty, social cohesion, and utilisation of marginal grazing. There are excellent genetic and genomic resources available for goats, including a highly contiguous reference genome (ARS1). However, gene expression information is limited in comparison to other ruminants. To support functional annotation of the genome and comparative transcriptomics, we created a mini-atlas of gene expression for the domestic goat. RNA-Seq analysis of 17 transcriptionally rich tissues and 3 cell-types detected the majority (90%) of predicted protein-coding transcripts and assigned informative gene names to more than 1000 previously unannotated protein-coding genes in the current reference genome for goat (ARS1). Using network-based cluster analysis, we grouped genes according to their expression patterns and assigned those groups of coexpressed genes to specific cell populations or pathways. We describe clusters of genes expressed in the gastro-intestinal tract and provide the expression profiles across tissues of a subset of genes associated with functional traits. Comparative analysis of the goat atlas with the larger sheep gene expression atlas dataset revealed transcriptional similarities between macrophage associated signatures in the sheep and goats sampled in this study. The goat transcriptomic resource complements the large gene expression dataset we have generated for sheep and contributes to the available genomic resources for interpretation of the relationship between genotype and phenotype in small ruminants. © Copyright © 2019 Muriuki, Bush, Salavati, McCulloch, Lisowski, Agaba, Djikeng, Hume and Clark. | |
Banos, G.; Clark, E. L.; Bush, S. J.; Dutta, P.; Bramis, D. Georgios; Arsenos, G.; Hume, D. A.; Psifidi, A. Genetic and genomic analyses underpin the feasibility of concomitant genetic improvement of milk yield and mastitis resistance in dairy sheep (Journal Article) In: PLoS ONE, vol. 14, no. 11, 2019, ISSN: 19326203, (Publisher: Public Library of Science). @article{banos_genetic_2019,Milk yield is the most important dairy sheep trait and constitutes the key genetic improvement goal via selective breeding. Mastitis is one of the most prevalent diseases, significantly impacting on animal welfare, milk yield and quality, while incurring substantial costs. Our objectives were to determine the feasibility of a concomitant genetic improvement programme for enhanced milk production and resistance to mastitis. Individual records for milk yield, and four mastitis-related traits (milk somatic cell count, California Mastitis Test score, total viable bacterial count in milk and clinical mastitis presence) were collected monthly throughout lactation for 609 ewes of the Chios breed. All ewes were genotyped with a mastitis specific custom-made 960 single nucleotide polymorphism (SNP) array. We performed targeted genomic association studies, (co)variance component estimation and pathway enrichment analysis, and characterised gene expression levels and the extent of allelic expression imbalance. Presence of heritable variation for milk yield was confirmed. There was no significant genetic correlation between milk yield and mastitis traits. Environmental factors appeared to favour both milk production and udder health. There were no overlapping of SNPs associated with mastitis resistance and milk yield in Chios sheep. Furthermore, four distinct Quantitative Trait Loci (QTLs) affecting milk yield were detected on chromosomes 2, 12, 16 and 19, in locations other than those previously identified to affect mastitis resistance. Five genes (DNAJA1, GHR, LYPLA1, NUP35 and OXCT1) located within the QTL regions were highly expressed in both the mammary gland and milk transcriptome, suggesting involvement in milk synthesis and production. Furthermore, the expression of two of these genes (NUP35 and OXCT1) was enriched in immune tissues implying a potentially pleiotropic effect or likely role in milk production during udder infection, which needs to be further elucidated in future studies. In conclusion, the absence of genetic antagonism between milk yield and mastitis resistance suggests that simultaneous genetic improvement of both traits be achievable. © 2019 Banos et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. | |
Stewart, T. A.; Hughes, K.; Hume, D. A.; Davis, F. M. Developmental Stage-Specific Distribution of Macrophages in Mouse Mammary Gland (Journal Article) In: Frontiers in Cell and Developmental Biology, vol. 7, 2019, ISSN: 2296634X, (Publisher: Frontiers Media S.A.). @article{stewart_developmental_2019,Mammary gland development begins in the embryo and continues throughout the reproductive life of female mammals. Tissue macrophages (Mϕs), dependent on signals from the Mϕ colony stimulating factor 1 receptor (CSF1R), have been shown to regulate the generation, regression and regeneration of this organ, which is central for mammalian offspring survival. However, the distribution of Mϕs in the pre- and post-natal mammary gland, as it undergoes distinct phases of development and regression, is unknown or has been inferred from immunostaining of thin tissue sections. Here, we used optical tissue clearing and 3-dimensional imaging of mammary tissue obtained from Csf1r-EGFP mice. Whilst tissue Mϕs were observed at all developmental phases, their abundance, morphology, localization and association with luminal and basal epithelial cells exhibited stage-specific differences. Furthermore, sexual dimorphism was observed at E14.5, when the male mammary bud is severed from the overlying epidermis. These findings provide new insights into the localization and possible functions of heterogeneous tissue Mϕ populations in mammogenesis. © Copyright © 2019 Stewart, Hughes, Hume and Davis. | |
Salavati, M.; Bush, S. J.; Palma-Vera, S.; McCulloch, M. E. B.; Hume, D. A.; Clark, E. L. Elimination of Reference Mapping Bias Reveals Robust Immune Related Allele-Specific Expression in Crossbred Sheep (Journal Article) In: Frontiers in Genetics, vol. 10, 2019, ISSN: 16648021, (Publisher: Frontiers Media S.A.). @article{salavati_elimination_2019,Pervasive allelic variation at both gene and single nucleotide level (SNV) between individuals is commonly associated with complex traits in humans and animals. Allele-specific expression (ASE) analysis, using RNA-Seq, can provide a detailed annotation of allelic imbalance and infer the existence of cis-acting transcriptional regulation. However, variant detection in RNA-Seq data is compromised by biased mapping of reads to the reference DNA sequence. In this manuscript, we describe an unbiased standardized computational pipeline for allele-specific expression analysis using RNA-Seq data, which we have adapted and developed using tools available under open license. The analysis pipeline we present is designed to minimize reference bias while providing accurate profiling of allele-specific expression across tissues and cell types. Using this methodology, we were able to profile pervasive allelic imbalance across tissues and cell types, at both the gene and SNV level, in Texel×Scottish Blackface sheep, using the sheep gene expression atlas data set. ASE profiles were pervasive in each sheep and across all tissue types investigated. However, ASE profiles shared across tissues were limited, and instead, they tended to be highly tissue-specific. These tissue-specific ASE profiles may underlie the expression of economically important traits and could be utilized as weighted SNVs, for example, to improve the accuracy of genomic selection in breeding programs for sheep. An additional benefit of the pipeline is that it does not require parental genotypes and can therefore be applied to other RNA-Seq data sets for livestock, including those available on the Functional Annotation of Animal Genomes (FAANG) data portal. This study is the first global characterization of moderate to extreme ASE in tissues and cell types from sheep. We have applied a robust methodology for ASE profiling to provide both a novel analysis of the multi-dimensional sheep gene expression atlas data set and a foundation for identifying the regulatory and expressed elements of the genome that are driving complex traits in livestock. © Copyright © 2019 Salavati, Bush, Palma-Vera, McCulloch, Hume and Clark. | |
Chundru, V. K.; Marioni, R. E.; Prendergast, J. G. D.; Vallerga, C. L.; Lin, T.; Beveridge, A. J.; Gratten, J.; Hume, D. A.; Deary, I. J.; Wray, N. R.; Visscher, P. M.; McRae, A. F. Examining the impact of imputation errors on fine-mapping using DNA methylation QTL as a model trait (Journal Article) In: Genetics, vol. 212, no. 3, pp. 577–586, 2019, ISSN: 00166731, (Publisher: Genetics Society of America). @article{chundru_examining_2019,Genetic variants disrupting DNA methylation at CpG dinucleotides (CpG-SNP) provide a set of known causal variants to serve as models to test fine-mapping methodology. We use 1716 CpG-SNPs to test three fine-mapping approaches (Bayesian imputation-based association mapping, Bayesian sparse linear mixed model, and the J-test), assessing the impact of imputation errors and the choice of reference panel by using both whole-genome sequence (WGS), and genotype array data on the same individuals (n = 1166). The choice of imputation reference panel had a strong effect on imputation accuracy, with the 1000 Genomes Project Phase 3 (1000G) reference panel (n = 2504 from 26 populations) giving a mean nonreference discordance rate between imputed and sequenced genotypes of 3.2% compared to 1.6% when using the Haplotype Reference Consortium (HRC) reference panel (n = 32,470 Europeans). These imputation errors had an impact on whether the CpG-SNP was included in the 95% credible set, with a difference of 23% and 7% between the WGS and the 1000G and HRC imputed datasets, respectively. All of the fine-mapping methods failed to reach the expected 95% coverage of the CpG-SNP. This is attributed to secondary cis genetic effects that are unable to be statistically separated from the CpG-SNP, and through a masking mechanism where the effect of the methylation disrupting allele at the CpG-SNP is hidden by the effect of a nearby SNP that has strong linkage disequilibrium with the CpG-SNP. The reduced accuracy in fine-mapping a known causal variant in a low-level biological trait with imputed genetic data has implications for the study of higher-order complex traits and disease. © 2019 Chundru et al. | |
Pridans, C.; Raper, A.; Davis, G. M.; Alves, J.; Sauter, K. A.; Lefevre, L.; Regan, T.; Meek, S.; Sutherland, L.; Thomson, A. J.; Clohisey, S.; Bush, S. J.; Rojo, R.; Lisowski, Z. M.; Wallace, R.; Grabert, K.; Upton, K. R.; Tsai, Y. T.; Brown, D.; Smith, L. B.; Summers, K. M.; Mabbott, N. A.; Piccardo, P.; Cheeseman, M. T.; Burdon, T.; Hume, D. A. In: Journal of Immunology, vol. 202, no. 11, pp. 3334–3335, 2019, ISSN: 00221767, (Publisher: American Association of Immunologists). @article{pridans_erratum_2019,In the analysis of gene expression in the brain, the sample labels for the pituitary gland and olfactory bulb were reversed. As a consequence, the clusters in Fig. 10B were mislabeled. A corrected version of Fig. 10 is shown below, along with the corrected figure legend. These corrections have been made to the online version of the article, which now differs from the print version as originally published. A corrected version of Supplemental Table I has also been published online. The current online supplemental material therefore differs from what was originally published online. The relevant text in the Results section under the heading “Network analysis of gene expression in the brain of Csf1r-deficient rats” now reads as follows: Fig. 10B shows the network graph for the combined analysis of the four brain regions; gene lists are provided in Supplemental Table I. The largest cluster was cluster 1 (4283 genes), containing pituitary gland-associated genes. Other region-specific clusters were cluster 3 (olfactory bulb; 878 genes), cluster 5 (hippocampus; 513 genes), and cluster 7 (striatum; 384 genes). The second largest cluster (cluster 2; 1253 genes) contained genes that were more highly expressed in both hippocampus and striatum. Two other main clusters also shared highly expressed genes between tissues: cluster 4 (olfactory bulb, striatum, and hippocampus; 757 genes) and cluster 6 (pituitary gland and olfactory bulb; 471 genes). None of these clusters showed any evidence of genotype association. (Figure Presented). Copyright © 2019 The Authors | |
Karagianni, A. E.; Summers, K. M.; Couroucé, A.; Depecker, M.; McGorum, B. C.; Hume, D. A.; Pirie, R. S. The Effect of Race Training on the Basal Gene Expression of Alveolar Macrophages Derived From Standardbred Racehorses (Journal Article) In: Journal of Equine Veterinary Science, vol. 75, pp. 48–54, 2019, ISSN: 07370806, (Publisher: W.B. Saunders). @article{karagianni_effect_2019,Mild-to-moderate equine asthma is prevalent in young racehorses, particularly early in their training period. Although the precise etiopathogenesis remains undetermined, it is possible that the susceptibility of this population might partly reflect an exercise-associated immune derangement at the level of the airway. We performed a genome-wide basal gene expression scan on alveolar macrophages (AMs) isolated from Standardbred racehorses before and after commencement of competition race training with a view to identifying any exercise-associated gene expression modulation consistent with functional alterations, which might reflect training-associated immunological derangement. Microarray technology was used to analyze the basal gene expression profiles of bronchoalveolar fluid–derived AMs, harvested from six systemically healthy Standardbred racehorses before (T0) and after (T1) entry into training. In addition, AM lipopolysaccharide (LPS)-induced TNF-α and IL-10 release at T0 and T1 was assessed. Although the data revealed significant interhorse heterogeneity in relation to the magnitude of individual gene expression at each timepoint, within each horse, several inflammatory-related genes [e.g., chemokine ligands, interferons, and nuclear factor kappa-light-chain-enhancer of activated B cells (NFKB)] declined in expression from T0 to T1. Entry into training did not significantly alter AM LPS-induced TNF-α or IL-10 release. The data support a direct effect of training on AM basal gene expression, particularly with respect to immune-related genes. The pattern of training-associated differential gene expression may indicate relative downregulation of inflammatory-related genes, consistent with an immunosuppressive effect of training and an increased susceptibility to opportunistic pathogens. © 2019 Elsevier Inc. | |
Gow, D. J.; Jackson, H.; Forsythe, P.; Gow, A. G.; Mellanby, R. J.; Hume, D. A.; Nuttall, T. Measurement of serum macrophage migration inhibitory factor (MIF) and correlation with severity and pruritus scores in client owned dogs with atopic dermatitis (Journal Article) In: Veterinary Dermatology, vol. 30, no. 2, pp. 115–e32, 2019, ISSN: 09594493, (Publisher: Blackwell Publishing Ltd). @article{gow_measurement_2019,Background: Atopic dermatitis (AD) is a common inflammatory skin disease of dogs. Macrophage migration inhibitory factor (MIF) initiates pro-inflammatory cytokine release in human AD and serum concentrations are correlated with disease severity. Hypothesis: Canine serum MIF concentrations are increased in dogs with AD and correlate with clinical lesion and pruritus scores. Animals: Client owned dogs (n = 49) diagnosed with AD and 17 healthy, unaffected control dogs were used for the study. Methods and materials: A commercially available MIF ELISA was optimized for the dog and serum from clinical cases used. Information regarding treatment, Canine Atopic Dermatitis Extent and Severity Index, (CADESI-4) and pruritus Visual Analog Scale (pVAS) were recorded for each dog at the time of serum collection. Results: Dogs with AD which had not received steroid therapy and those treated with oclacitinib had significantly elevated serum MIF concentrations compared to controls. Concentrations of MIF were not significantly different in AD dogs receiving steroids compared to controls. There was no significant correlation between MIF concentrations and clinical scores (CADESI-4 or pVAS). Conclusions and clinical importance: Serum MIF concentrations are increased in dogs with AD and MIF might be a target for therapy. © 2019 ESVD and ACVD | |
Prendergast, J. G. D.; Pugh, C.; Harris, S. E.; Hume, D. A.; Deary, I. J.; Beveridge, A.; Zhang, G. Linked Mutations at Adjacent Nucleotides Have Shaped Human Population Differentiation and Protein Evolution (Journal Article) In: Genome Biology and Evolution, vol. 11, no. 3, pp. 759–775, 2019, ISSN: 17596653, (Publisher: Oxford University Press). @article{prendergast_linked_2019,Despite the fundamental importance of single nucleotide polymorphisms (SNPs) to human evolution, there are still large gaps in our understanding of the forces that shape theirdistribution across the genome. SNPshavebeenshowntonotbe distributedevenly,with directly adjacent SNPs found unusually frequently.Why this is the case is unclear.We illustratehowneighboring SNPs that cannot be explained by a singlemutation event (thatwe termhere sequential dinucleotidemutations [SDMs]) are driven by distinct processes to SNPs and multinucleotide polymorphisms (MNPs). By studying variation across populations, including a novel cohort of 1,358 Scottish genomes,we show that, SDMs are over twice as common asMNPs and like SNPs display distinctmutational spectra across populations. These biases are not only different to those observed among SNPs and MNPs but are also more divergent between human population groups.We show that the changes that make up SDMs are not independent and identify a distinct mutational profile, CA! CG! TG, that is observed an order of magnitude more often than expected from background SNP rates and the numbers of other SDMs involving the gain and deamination of CpG sites. Intriguingly particular pathways through the amino acid code appear to have been favored relative to that expected fromintergenic SDMrates and the occurrences of coding SNPs, and in particular those that lead to the creation of single codon amino acids. We finally present evidence that epistatic selection has potentially disfavored sequential nonsynonymous changes in the human genome. © The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. | |
Dunning, J.; Blankley, S.; Hoang, L. T.; Cox, M.; Graham, C. M.; James, P. L.; Bloom, C. I.; Chaussabel, D.; Banchereau, J.; Brett, S. J.; Habibi, M. S.; Johnston, S. L.; Hansel, T. T.; Levin, M.; Thwaites, R. S.; Warner, J. O.; Cookson, W. O.; Gazzard, B. G.; Hay, A.; McCauley, J.; Aylin, P.; Ashby, D.; Barclay, W. S.; Elderfield, R. A.; Nadel, S.; Herberg, J. A.; Drumright, L. N.; Garcia-Alvarez, L.; Holmes, A. H.; Kon, O. M.; Aston, S. J.; Gordon, S. B.; Hussell, T.; Thompson, C.; Zambon, M. C.; Baillie, K. J.; Hume, D. A.; Simmonds, P.; Hayward, A.; Smyth, R. L.; McNamara, P. S.; Semple, M. G.; Nguyen-Van-Tam, J. S.; Ho, L. -P.; McMichael, A. J.; Kellam, P.; Adamson, W. E.; Carman, W. F.; Griffiths, M. J.; Moffatt, M. F.; O’Garra, A.; Openshaw, P. J. M.; Investigators, MOSAIC In: Nature Immunology, vol. 20, no. 3, pp. 373, 2019, ISSN: 15292908, (Publisher: Nature Publishing Group). @article{dunning_correction_2019,In the version of this article initially published, a source of funding was not included in the Acknowledgements section. That section should include the following: P.J.M.O. was supported by EU FP7 PREPARE project 602525. The error has been corrected in the HTML and PDF version of the article. © 2019, Springer Nature America, Inc. | |
Cordes, M.; Hume, D. Relatively hyperbolic groups with fixed peripherals (Journal Article) In: Israel Journal of Mathematics, vol. 230, no. 1, pp. 443–470, 2019, ISSN: 00212172, (Publisher: Springer New York LLC). @article{cordes_relatively_2019,We build quasi-isometry invariants of relatively hyperbolic groups which detect the hyperbolic parts of the group; these are variations of the stable dimension constructions previously introduced by the authors. We prove that, given any finite collection of finitely generated groups H each of which either has finite stable dimension or is non-relatively hyperbolic, there exist infinitely many quasi-isometry types of one-ended groups which are hyperbolic relative to H. The groups are constructed using classical small cancellation theory over free products. © 2019, The Hebrew University of Jerusalem. | |
Batoon, L.; Millard, S. M.; Wullschleger, M. E.; Preda, C.; Wu, A. C. -K.; Kaur, S.; Tseng, H. -W.; Hume, D. A.; Levesque, J. -P.; Raggatt, L. J.; Pettit, A. R. CD169+ macrophages are critical for osteoblast maintenance and promote intramembranous and endochondral ossification during bone repair (Journal Article) In: Biomaterials, vol. 196, pp. 51–66, 2019, ISSN: 01429612, (Publisher: Elsevier Ltd). @article{batoon_cd169_2019,Osteal macrophages (osteomacs) contribute to bone homeostasis and regeneration. To further distinguish their functions from osteoclasts, which share many markers and growth factor requirements, we developed a rapid, enzyme-free osteomac enrichment protocol that permitted characterization of minimally manipulated osteomacs by flow cytometry. Osteomacs differ from osteoclasts in expression of Siglec1 (CD169). This distinction was confirmed using the CD169-diphtheria toxin (DT) receptor (DTR) knock-in model. DT treatment of naïve CD169-DTR mice resulted in selective and striking loss of osteomacs, whilst osteoclasts and trabecular bone area were unaffected. Consistent with a previously-reported trophic interaction, osteomac loss was accompanied by a concomitant and proportionately striking reduction in osteoblasts. The impact of CD169+ macrophage depletion was assessed in two models of bone injury that heal via either intramembranous (tibial injury) or endochondral (internally-plated femoral fracture model) ossification. In both models, CD169+ macrophage, including osteomac depletion compromised bone repair. Importantly, DT treatment in CD169-DTR mice did not affect osteoclast frequency in either model. In the femoral fracture model, the magnitude of callus formation correlated with the number of F4/80+ macrophages that persisted within the callus. Overall these observations provide compelling support that CD169+ osteomacs, independent of osteoclasts, provide vital pro-anabolic support to osteoblasts during both bone homeostasis and repair. © 2017 Elsevier Ltd | |
Giotti, B.; Chen, S. -H.; Barnett, M. W.; Regan, T.; Ly, T.; Wiemann, S.; Hume, D. A.; Freeman, T. C. Assembly of a parts list of the human mitotic cell cycle machinery (Journal Article) In: Journal of Molecular Cell Biology, vol. 11, no. 8, pp. 703–718, 2019, ISSN: 16742788, (Publisher: Oxford University Press). @article{giotti_assembly_2019,The set of proteins required for mitotic division remains poorly characterized. Here, an extensive series of correlation analyses of human and mouse transcriptomics data were performed to identify genes strongly and reproducibly associated with cells undergoing S/G2-M phases of the cell cycle. In so doing, 701 cell cycle-associated genes were defined and while it was shown that many are only expressed during these phases, the expression of others is also driven by alternative promoters. Of this list, 496 genes have known cell cycle functions, whereas 205 were assigned as putative cell cycle genes, 53 of which are functionally uncharacterized. Among these, 27 were screened for subcellular localization revealing many to be nuclear localized and at least three to be novel centrosomal proteins. Furthermore, 10 others inhibited cell proliferation upon siRNA knockdown. This study presents the first comprehensive list of human cell cycle proteins, identifying many new candidate proteins. © 2019 The Author(s). | |
Hu, T.; Wu, Z.; Bush, S. J.; Freem, L.; Vervelde, L.; Summers, K. M.; Hume, D. A.; Balic, A.; Kaiser, P. Characterization of subpopulations of chicken mononuclear phagocytes that express TIM4 and CSF1R (Journal Article) In: Journal of Immunology, vol. 202, no. 4, pp. 1186–1199, 2019, ISSN: 00221767, (Publisher: American Association of Immunologists). @article{hu_characterization_2019,The phosphatidylserine receptor TIM4, encoded by TIMD4, mediates the phagocytic uptake of apoptotic cells. We applied anti-chicken TIM4 mAbs in combination with CSF1R reporter transgenes to dissect the function of TIM4 in the chick (Gallus gallus). During development in ovo, TIM4 was present on the large majority of macrophages, but expression became more heterogeneous posthatch. Blood monocytes expressed KUL01, class II MHC, and CSF1R-mApple uniformly. Around 50% of monocytes were positive for surface TIM4. They also expressed many other monocyte-specific transcripts at a higher level than TIM4 2 monocytes. In liver, highly phagocytic TIM4 hi cells shared many transcripts with mammalian Kupffer cells and were associated with uptake of apoptotic cells. Although they expressed CSF1R mRNA, Kupffer cells did not express the CSF1R-mApple transgene, suggesting that additional CSF1R transcriptional regulatory elements are required by these cells. By contrast, CSF1R-mApple was detected in liver TIM4 lo and TIM4 2 cells, which were not phagocytic and were more abundant than Kupffer cells. These cells expressed CSF1R alongside high levels of FLT3, MHCII, XCR1, and other markers associated with conventional dendritic cells in mice. In bursa, TIM4 was present on the cell surface of two populations. Like Kupffer cells, bursal TIM4 hi phagocytes coexpressed many receptors involved in apoptotic cell recognition. TIM4 lo cells appear to be a subpopulation of bursal B cells. In overview, TIM4 is associated with phagocytes that eliminate apoptotic cells in the chick. In the liver, TIM4 and CSF1R reporters distinguished Kupffer cells from an abundant population of dendritic cell–like cells. The Journal of Immunology, 2019, 202: 1186–1199. Copyright © 2019 by The American Association of Immunologists, Inc. All rights reserved. | |
Bush, S. J.; McCulloch, M. E. B.; Muriuki, C.; Salavati, M.; Davis, G. M.; Farquhar, I. L.; Lisowski, Z. M.; Archibald, A. L.; Hume, D. A.; Clark, E. L. In: G3: Genes, Genomes, Genetics, vol. 9, no. 2, pp. 359–373, 2019, ISSN: 21601836, (Publisher: Genetics Society of America). @article{bush_comprehensive_2019,One of the most significant physiological challenges to neonatal and juvenile ruminants is the development and establishment of the rumen. Using a subset of RNA-Seq data from our high-resolution atlas of gene expression in sheep (Ovis aries) we have provided the first comprehensive characterization of transcription of the entire gastrointestinal (GI) tract during the transition from pre-ruminant to ruminant. The dataset comprises 164 tissue samples from sheep at four different time points (birth, one week, 8 weeks and adult). Using network cluster analysis we illustrate how the complexity of the GI tract is reflected in tissueand developmental stage-specific differences in gene expression. The most significant transcriptional differences between neonatal and adult sheep were observed in the rumen complex. Comparative analysis of gene expression in three GI tract tissues from age-matched sheep and goats revealed species-specific differences in genes involved in immunity and metabolism. This study improves our understanding of the transcriptomic mechanisms involved in the transition from pre-ruminant to ruminant by identifying key genes involved in immunity, microbe recognition and metabolism. The results form a basis for future studies linking gene expression with microbial colonization of the developing GI tract and provide a foundation to improve ruminant efficiency and productivity through identifying potential targets for novel therapeutics and gene editing. © 2019 Chen et al. | |
Hume, D. A.; Irvine, K. M.; Pridans, C. The Mononuclear Phagocyte System: The Relationship between Monocytes and Macrophages (Journal Article) In: Trends in Immunology, vol. 40, no. 2, pp. 98–112, 2019, ISSN: 14714906, (Publisher: Elsevier Ltd). @article{hume_mononuclear_2019,The mononuclear phagocyte system (MPS) is defined as a cell lineage in which committed marrow progenitors give rise to blood monocytes and tissue macrophages. Here, we discuss the concept of self-proscribed macrophage territories and homeostatic regulation of tissue macrophage abundance through growth factor availability. Recent studies have questioned the validity of the MPS model and argued that tissue-resident macrophages are a separate lineage seeded during development and maintained by self-renewal. We address this issue; discuss the limitations of inbred mouse models of monocyte-macrophage homeostasis; and summarize the evidence suggesting that during postnatal life, monocytes can replace resident macrophages in all major organs and adopt their tissue-specific gene expression. We conclude that the MPS remains a valid and accurate framework for understanding macrophage development and homeostasis. © 2018 Elsevier Ltd | |
Halachev, M.; Meynert, A.; Taylor, M. S.; Vitart, V.; Kerr, S. M.; Klaric, L.; Consortium, S. G. P.; Aitman, T. J.; Haley, C. S.; Prendergast, J. G.; Pugh, C.; Hume, D. A.; Harris, S. E.; Liewald, D. C.; Deary, I. J.; Semple, C. A.; Wilson, J. F. Increased ultra-rare variant load in an isolated Scottish population impacts exonic and regulatory regions (Journal Article) In: PLoS Genetics, vol. 15, no. 11, 2019, ISSN: 15537390, (Publisher: Public Library of Science). @article{halachev_increased_2019,Human population isolates provide a snapshot of the impact of historical demographic processes on population genetics. Such data facilitate studies of the functional impact of rare sequence variants on biomedical phenotypes, as strong genetic drift can result in higher frequencies of variants that are otherwise rare. We present the first whole genome sequencing (WGS) study of the VIKING cohort, a representative collection of samples from the isolated Shetland population in northern Scotland, and explore how its genetic characteristics compare to a mainland Scottish population. Our analyses reveal the strong contributions played by the founder effect and genetic drift in shaping genomic variation in the VIKING cohort. About one tenth of all high-quality variants discovered are unique to the VIKING cohort or are seen at frequencies at least ten fold higher than in more cosmopolitan control populations. Multiple lines of evidence also suggest relaxation of purifying selection during the evolutionary history of the Shetland isolate. We demonstrate enrichment of ultra-rare VIKING variants in exonic regions and for the first time we also show that ultra-rare variants are enriched within regulatory regions, particularly promoters, suggesting that gene expression patterns may diverge relatively rapidly in human isolates. © 2019 Halachev et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. | |
Balic, A.; Chintoan-Uta, C.; Vohra, P.; Sutton, K. M.; Cassady-Cain, R. L.; Hu, T.; Donaldson, D. S.; Stevens, M. P.; Mabbott, N. A.; Hume, D. A.; Sang, H. M.; Vervelde, L. Antigen sampling csf1r-expressing epithelial cells are the functional equivalents of mammalian m cells in the avian follicle-associated epithelium (Journal Article) In: Frontiers in Immunology, vol. 10, no. OCT, 2019, ISSN: 16643224, (Publisher: Frontiers Media S.A.). @article{balic_antigen_2019,The follicle-associated epithelium (FAE) is a specialized structure that samples luminal antigens and transports them into mucosa-associated lymphoid tissues (MALT). In mammals, transcytosis of antigens across the gut epithelium is performed by a subset of FAE cells known as M cells. Here we show that colony-stimulating factor 1 receptor (CSF1R) is expressed by a subset of cells in the avian bursa of Fabricius FAE. Expression was initially detected using a CSF1R-reporter transgene that also label subsets of bursal macrophages. Immunohistochemical detection using a specific monoclonal antibody confirmed abundant expression of CSF1R on the basolateral membrane of FAE cells. CSF1R-transgene expressing bursal FAE cells were enriched for expression of markers previously reported as putative M cell markers, including annexin A10 and CD44. They were further distinguished from a population of CSF1R-transgene negative epithelial cells within FAE by high apical F-actin expression and differential staining with the lectins jacalin, PHA-L and SNA. Bursal FAE cells that express the CSF1R-reporter transgene were responsible for the bulk of FAE transcytosis of labeled microparticles in the size range 0.02–0.1 µm. Unlike mammalian M cells, they did not readily take up larger bacterial sized microparticles (0.5 µm). Their role in uptake of bacteria was tested using Salmonella, which can enter via M cells in mammals. Labeled Salmonella enterica serovar Typhimurium entered bursal tissue via the FAE. Entry was partially dependent upon Type III secretion system-1. However, the majority of invading bacteria were localized to CSF1R-negative FAE cells and in resident phagocytes that express the phosphatidylserine receptor TIM4. CSF1R-expressing FAE cells in infected follicles showed evidence of cell death and shedding into the bursal lumen. In mammals, CSF1R expression in the gut is restricted to macrophages which only indirectly control M cell differentiation. The novel expression of CSF1R in birds suggests that these functional equivalents to mammalian M cells may have different ontological origins and their development and function are likely to be regulated by different growth factors. © 2019 Balic, Chintoan-Uta, Vohra, Sutton, Cassady-Cain, Hu, Donaldson, Stevens, Mabbott, Hume, Sang and Vervelde. | |
Young, R.; Lefevre, L.; Bush, S. J.; Joshi, A.; Singh, S. H.; Jadhav, S. K.; Lisowski, Z. M.; Iamartino, D.; Summers, K. M.; Williams, J. L.; Archibald, A. L.; Gokhale, S.; Kumar, S.; Hume, D. A. A gene expression atlas of the domestic water buffalo (Bubalus bubalis) (Journal Article) In: Frontiers in Genetics, vol. 10, no. JUN, 2019, ISSN: 16648021, (Publisher: Frontiers Media S.A.). @article{young_gene_2019, | |
Arzhantseva, G. N.; Cashen, C. H.; Gruber, D.; Hume, D. Negative curvature in graphical small cancellation groups (Journal Article) In: Groups, Geometry, and Dynamics, vol. 13, no. 2, pp. 579–632, 2019, ISSN: 16617207, (Publisher: European Mathematical Society Publishing House). @article{arzhantseva_negative_2019,We use the interplay between combinatorial and coarse geometric versions of negative curvature to investigate the geometry of infinitely presented graphical Gr0 1=6/ small cancellation groups. In particular, we characterize their ‘contracting geodesics,’ which should be thought of as the geodesics that behave hyperbolically. We show that every degree of contraction can be achieved by a geodesic in a finitely generated group. We construct the first example of a finitely generated group G containing an element g that is strongly contracting with respect to one finite generating set of G and not strongly contracting with respect to another. In the case of classical C 0 1=6/ small cancellation groups we give complete characterizations of geodesics that are Morse and that are strongly contracting. We show that many graphical Gr0 1=6/ small cancellation groups contain strongly contracting elements and, in particular, are growth tight. We construct uncountably many quasi-isometry classes of finitely generated, torsion-free groups in which every maximal cyclic subgroup is hyperbolically embedded. These are the first examples of this kind that are not subgroups of hyperbolic groups. In the course of our analysis we show that if the defining graph of a graphical Gr0 1=6/ small cancellation group has finite components, then the elements of the group have translation lengths that are rational and bounded away from zero. © European Mathematical Society. | |
Irvine, K. M.; Ratnasekera, I.; Powell, E. E.; Hume, D. A. Corrigendum: Causes and consequences of innate immune dysfunction in cirrhosis (Frontiers in Immunology (2019) 10 (293) DOI: 10.3389/fimmu.2019.00293) (Journal Article) In: Frontiers in Immunology, vol. 10, no. APR, 2019, ISSN: 16643224, (Publisher: Frontiers Media S.A.). @article{irvine_corrigendum_2019,In the original article, we neglected to include the funder "Equity Trustees." The funding statement has therefore been revised as follows: "KI, IR, and DH are grateful for research funding support from the Mater Research Foundation and Equity Trustees, Australia." The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated. Copyright © 2019 Irvine, Ratnasekera, Powell and Hume. | |
Irvine, K. M.; Ratnasekera, I.; Powell, E. E.; Hume, D. A. Casuses and consequences of innate immune dysfucntion in cirrhosis (Journal Article) In: Frontiers in Immunology, vol. 10, no. FEB, 2019, ISSN: 16643224, (Publisher: Frontiers Media S.A.). @article{irvine_casuses_2019,Liver cirrhosis is an increasing health burden and public health concern. Regardless of etiology, patients with cirrhosis are at risk of a range of life-threatening complications, including the development of infections, which are associated with high morbidity and mortality and frequent hospital admissions. The term Cirrhosis-Associated Immune Dysfunction (CAID) refers to a dynamic spectrum of immunological perturbations that develop in patients with cirrhosis, which are intimately linked to the underlying liver disease, and negatively correlated with prognosis. At the two extremes of the CAID spectrum are systemic inflammation, which can exacerbate clinical manifestations of cirrhosis such as hemodynamic derangement and kidney injury; and immunodeficiency, which contributes to the high rate of infection in patients with decompensated cirrhosis. Innate immune cells, in particular monocytes/macrophages and neutrophils, are pivotal effector and target cells in CAID. This review focuses on the pathophysiological mechanisms leading to impaired innate immune function in cirrhosis. Knowledge of the phenotypic manifestation and pathophysiological mechanisms of cirrhosis associated immunosuppression may lead to immune targeted therapies to reduce susceptibility to infection in patients with cirrhosis, and better biomarkers for risk stratification, and assessment of efficacy of novel immunotherapies. © 2019 Frew. | |
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Sehgal, Anuj; Donaldson, David S.; Pridans, Clare; Sauter, Kristin A.; Hume, David A.; Mabbott, Neil A. The role of CSF1R-dependent macrophages in control of the intestinal stem-cell niche (Journal Article) In: Nature Communications, vol. 9, no. 1, pp. 1272, 2018, ISSN: 2041-1723. @article{sehgal_role_2018, | |
Hamilton, Carly A.; Young, Rachel; Jayaraman, Siddharth; Sehgal, Anuj; Paxton, Edith; Thomson, Sarah; Katzer, Frank; Hope, Jayne; Innes, Elisabeth; Morrison, Liam J.; Mabbott, Neil A. Development of in vitro enteroids derived from bovine small intestinal crypts (Journal Article) In: Veterinary Research, vol. 49, no. 1, pp. 54, 2018, ISSN: 1297-9716. @article{hamilton_development_2018, | |
Sehgal, Anuj; Donaldson, David S.; Pridans, Clare; Sauter, Kristin A.; Hume, David A.; Mabbott, Neil A. The role of CSF1R-dependent macrophages in control of the intestinal stem-cell niche (Journal Article) In: Nature Communications, vol. 9, no. 1, pp. 1272, 2018, ISSN: 2041-1723. @article{sehgal_role_2018b, | |
Herron, L. R.; Pridans, C.; Turnbull, M. L.; Smith, N.; Lillico, S.; Sherman, A.; Gilhooley, H. J.; Wear, M.; Kurian, D.; Papadakos, G.; Digard, P.; Hume, D. A.; Gill, A. C.; Sang, H. M. A chicken bioreactor for efficient production of functional cytokines (Journal Article) In: BMC Biotechnology, vol. 18, no. 1, 2018, ISSN: 14726750, (Publisher: BioMed Central Ltd.). @article{herron_chicken_2018,Background: The global market for protein drugs has the highest compound annual growth rate of any pharmaceutical class but their availability, especially outside of the US market, is compromised by the high cost of manufacture and validation compared to traditional chemical drugs. Improvements in transgenic technologies allow valuable proteins to be produced by genetically-modified animals; several therapeutic proteins from such animal bioreactors are already on the market after successful clinical trials and regulatory approval. Chickens have lagged behind mammals in bioreactor development, despite a number of potential advantages, due to the historic difficulty in producing transgenic birds, but the production of therapeutic proteins in egg white of transgenic chickens would substantially lower costs across the entire production cycle compared to traditional cell culture-based production systems. This could lead to more affordable treatments and wider markets, including in developing countries and for animal health applications. Results: Here we report the efficient generation of new transgenic chicken lines to optimize protein production in eggs. As proof-of-concept, we describe the expression, purification and functional characterization of three pharmaceutical proteins, the human cytokine interferon α2a and two species-specific Fc fusions of the cytokine CSF1. Conclusion: Our work optimizes and validates a transgenic chicken system for the cost-effective production of pure, high quality, biologically active protein for therapeutics and other applications. © 2018 The Author(s). | |
Boulton, K.; Nolan, M. J.; Wu, Z.; Psifidi, A.; Riggio, V.; Harman, K.; Bishop, S. C.; Kaiser, P.; Abrahamsen, M. S.; Hawken, R.; Watson, K. A.; Tomley, F. M.; Blake, D. P.; Hume, D. A. Phenotypic and genetic variation in the response of chickens to Eimeria tenella induced coccidiosis (Journal Article) In: Genetics Selection Evolution, vol. 50, no. 1, 2018, ISSN: 0999193X, (Publisher: BioMed Central Ltd.). @article{boulton_phenotypic_2018,Background: Coccidiosis is a major contributor to losses in poultry production. With emerging constraints on the use of in-feed prophylactic anticoccidial drugs and the relatively high costs of effective vaccines, there are commercial incentives to breed chickens with greater resistance to this important production disease. To identify phenotypic biomarkers that are associated with the production impacts of coccidiosis, and to assess their covariance and heritability, 942 Cobb500 commercial broilers were subjected to a defined challenge with Eimeria tenella (Houghton). Three traits were measured: weight gain (WG) during the period of infection, caecal lesion score (CLS) post mortem, and the level of a serum biomarker of intestinal inflammation, i.e. circulating interleukin 10 (IL-10), measured at the height of the infection. Results: Phenotypic analysis of the challenged chicken cohort revealed a significant positive correlation between CLS and IL-10, with significant negative correlations of both these traits with WG. Eigenanalysis of phenotypic covariances between measured traits revealed three distinct eigenvectors. Trait weightings of the first eigenvector, (EV1 | |
Nirmal, A. J.; Regan, T.; Shih, B. B.; Hume, D. A.; Sims, A. H.; Freeman, T. C. Immune cell gene signatures for profiling the microenvironment of solid tumors (Journal Article) In: Cancer Immunology Research, vol. 6, no. 11, pp. 1388–1400, 2018, ISSN: 23266066, (Publisher: American Association for Cancer Research Inc.). @article{nirmal_immune_2018,The immune composition of the tumor microenvironment regulates processes including angiogenesis, metastasis, and the response to drugs or immunotherapy. To facilitate the characterization of the immune component of tumors from transcriptomics data, a number of immune cell transcriptome signatures have been reported that are made up of lists of marker genes indicative of the presence a given immune cell population. The majority of these gene signatures have been defined through analysis of isolated blood cells. However, blood cells do not reflect the differentiation or activation state of similar cells within tissues, including tumors, and consequently markers derived from blood cells do not necessarily transfer well to tissues. To address this issue, we generated a set of immune gene signatures derived directly from tissue transcriptomics data using a network-based deconvolution approach. We define markers for seven immune cell types, collectively named ImSig, and demonstrate how these markers can be used for the quantitative estimation of the immune cell content of tumor and nontumor tissue samples. The utility of ImSig is demonstrated through the stratification of melanoma patients into subgroups of prognostic significance and the identification of immune cells with the use of single-cell RNA-sequencing data derived from tumors. Use of ImSig is facilitated by an R package (imsig). © 2018 American Association for Cancer Research. | |
Pridans, C.; Raper, A.; Davis, G. M.; Alves, J.; Sauter, K. A.; Lefevre, L.; Regan, T.; Meek, S.; Sutherland, L.; Thomson, A. J.; Clohisey, S.; Bush, S. J.; Rojo, R.; Lisowski, Z. M.; Wallace, R.; Grabert, K.; Upton, K. R.; Tsai, Y. T.; Brown, D.; Smith, L. B.; Summers, K. M.; Mabbott, N. A.; Piccardo, P.; Cheeseman, M. T.; Burdon, T.; Hume, D. A. Pleiotropic Impacts of Macrophage and Microglial Deficiency on Development in Rats with Targeted Mutation of the Csf1r Locus (Journal Article) In: Journal of Immunology, vol. 201, no. 9, pp. 2683–2699, 2018, ISSN: 00221767, (Publisher: American Association of Immunologists). @article{pridans_pleiotropic_2018,We have produced Csf1r-deficient rats by homologous recombination in embryonic stem cells. Consistent with the role of Csf1r in macrophage differentiation, there was a loss of peripheral blood monocytes, microglia in the brain, epidermal Langerhans cells, splenic marginal zone macrophages, bone-associated macrophages and osteoclasts, and peritoneal macrophages. Macrophages of splenic red pulp, liver, lung, and gut were less affected. The pleiotropic impacts of the loss of macrophages on development of multiple organ systems in rats were distinct from those reported in mice. Csf1r-/- rats survived well into adulthood with postnatal growth retardation, distinct skeletal and bone marrow abnormalities, infertility, and loss of visceral adipose tissue. Gene expression analysis in spleen revealed selective loss of transcripts associated with the marginal zone and, in brain regions, the loss of known and candidate novel microglia-associated transcripts. Despite the complete absence of microglia, there was little overt phenotype in brain, aside from reduced myelination and increased expression of dopamine receptor-associated transcripts in striatum. The results highlight the redundant and nonredundant functions of CSF1R signaling and of macrophages in development, organogenesis, and homeostasis. © 2018 by The American Association of Immunologists, Inc. | |
Waddell, L. A.; Lefevre, L.; Bush, S. J.; Raper, A.; Young, R.; Lisowski, Z. M.; McCulloch, M. E. B.; Muriuki, C.; Sauter, K. A.; Clark, E. L.; Irvine, K. M.; Pridans, C.; Hope, J. C.; Hume, D. A. ADGRE1 (EMR1, F4/80) is a rapidly-evolving gene expressed in mammalian monocyte-macrophages (Journal Article) In: Frontiers in Immunology, vol. 9, no. OCT, 2018, ISSN: 16643224, (Publisher: Frontiers Media S.A.). @article{waddell_adgre1_2018,The F4/80 antigen, encoded by the Adgre1 locus, has been widely-used as a monocyte-macrophage marker in mice, but its value as a macrophage marker in other species is unclear, and has even been questioned. ADGRE1 is a seven transmembrane G protein-coupled receptor with an extracellular domain containing repeated Epidermal Growth Factor (EGF)-like calcium binding domains. Using a new monoclonal antibody, we demonstrated that ADGRE1 is a myeloid differentiation marker in pigs, absent from progenitors in bone marrow, highly-expressed in mature granulocytes, monocytes, and tissue macrophages and induced by macrophage colony-stimulating factor (CSF1) treatment in vivo. Based upon these observations, we utilized RNA-Seq to assess the expression of ADGRE1 mRNA in bone marrow or monocyte-derived macrophages (MDM) and alveolar macrophages from 8 mammalian species including pig, human, rat, sheep, goat, cow, water buffalo, and horse. ADGRE1 mRNA was expressed by macrophages in each species, with inter-species variation both in expression level and response to lipopolysaccharide (LPS) stimulation. Analysis of the RNA-Seq data also revealed additional exons in several species compared to current Ensembl annotations. The ruminant species and horses appear to encode a complete duplication of the 7 EGF-like domains. In every species, Sashimi plots revealed evidence of exon skipping of the EGF-like domains, which are highly-variable between species and polymorphic in humans. Consistent with these expression patterns, key elements of the promoter and a putative enhancer are also conserved across all species. The rapid evolution of this molecule and related ADGRE family members suggests immune selection and a role in pathogen recognition. © 2018 Waddell, Lefevre, Bush, Raper, Young, Lisowski, McCulloch, Muriuki, Sauter, Clark, Irvine, Pridans, Hope and Hume. | |
Brown, S. M.; Bush, S. J.; Summers, K. M.; Hume, D. A.; Lawrence, A. B. Environmentally enriched pigs have transcriptional profiles consistent with neuroprotective effects and reduced microglial activity (Journal Article) In: Behavioural Brain Research, vol. 350, pp. 6–15, 2018, ISSN: 01664328, (Publisher: Elsevier B.V.). @article{brown_environmentally_2018,Environmental enrichment (EE) is widely used to study the effects of external factors on brain development, function and health in rodent models, but very little is known of the effects of EE on the brain in a large animal model such as the pig. Twenty-four young pigs (aged 5 weeks at start of study, 1:1 male: female ratio) were housed in environmentally enriched (EE) pens and provided with additional enrichment stimulation (a bag filled with straw) once daily. Litter, weight and sex matched controls n= (24) were housed in barren (B) conditions. Behaviour was recorded on alternate days from study day 10. After 21 days, RNA-sequencing of the frontal cortex of male piglets culled one hour after the enrichment stimulation, but not those at 4 h after stimulation, showed upregulation of genes involved in neuronal activity and synaptic plasticity in the EE compared to the B condition. This result is mirrored in the behavioural response to the stimulation which showed a peak in activity around the 1 h time-point. By contrast, EE piglets displayed a signature consistent with a relative decrease in microglial activity compared to those in the B condition. These results confirm those from rodents, suggesting that EE may also confer neuronal health benefits in large mammal models, through a potential relative reduction in neuroinflammatory process and increase in neuroprotection driven by an enrichment-induced increase in behavioural activity. © 2018 The Authors | |
Scott, C. L.; T'Jonck, W.; Martens, L.; Todorov, H.; Sichien, D.; Soen, B.; Bonnardel, J.; Prijck, S. De; Vandamme, N.; Cannoodt, R.; Saelens, W.; Vanneste, B.; Toussaint, W.; Bleser, P. De; Takahashi, N.; Vandenabeele, P.; Henri, S.; Pridans, C.; Hume, D. A.; Lambrecht, B. N.; Baetselier, P. De; Milling, S. W. F.; Ginderachter, J. A. Van; Malissen, B.; Berx, G.; Beschin, A.; Saeys, Y.; Guilliams, M. The Transcription Factor ZEB2 Is Required to Maintain the Tissue-Specific Identities of Macrophages (Journal Article) In: Immunity, vol. 49, no. 2, pp. 312–325.e5, 2018, ISSN: 10747613, (Publisher: Cell Press). @article{scott_transcription_2018,Heterogeneity between different macrophage populations has become a defining feature of this lineage. However, the conserved factors defining macrophages remain largely unknown. The transcription factor ZEB2 is best described for its role in epithelial to mesenchymal transition; however, its role within the immune system is only now being elucidated. We show here that Zeb2 expression is a conserved feature of macrophages. Using Clec4f-cre, Itgax-cre, and Fcgr1-cre mice to target five different macrophage populations, we found that loss of ZEB2 resulted in macrophage disappearance from the tissues, coupled with their subsequent replenishment from bone-marrow precursors in open niches. Mechanistically, we found that ZEB2 functioned to maintain the tissue-specific identities of macrophages. In Kupffer cells, ZEB2 achieved this by regulating expression of the transcription factor LXRα removal of which recapitulated the loss of Kupffer cell identity and disappearance. Thus, ZEB2 expression is required in macrophages to preserve their tissue-specific identities. Scott et al. demonstrate that ZEB2 is critical for maintaining the tissue identities of macrophages. Loss of ZEB2 results in tissue-specific changes in different macrophage populations and their subsequent disappearance. In Kupffer cells, ZEB2 maintains LXRα expression, loss of which reproduces the change in Kupffer cell identity and their disappearance. © 2018 The Author(s) | |
Kaur, S.; Raggatt, L. J.; Millard, S. M.; Wu, A. C.; Batoon, L.; Jacobsen, R. N.; Winkler, I. G.; MacDonald, K. P.; Perkins, A. C.; Hume, D. A.; Levesque, J. -P.; Pettit, A. R. Self-repopulating recipient bone marrow resident macrophages promote long-term hematopoietic stem cell engraftment (Journal Article) In: Blood, vol. 132, no. 7, pp. 735–749, 2018, ISSN: 00064971, (Publisher: American Society of Hematology). @article{kaur_self-repopulating_2018,Distinct subsets of resident tissue macrophages are important in hematopoietic stem cell niche homeostasis and erythropoiesis. We used a myeloid reporter gene (Csf1r-eGFP) to dissect the persistence of bone marrow and splenic macrophage subsets following lethal irradiation and autologous hematopoietic stem cell transplantation in a mouse model. Multiple recipient bone marrow and splenic macrophage subsets survived after autologous hematopoietic stem cell transplantation with organ-specific persistence kinetics. Shortterm persistence (5 weeks) of recipient resident macrophages in spleen paralleled the duration of extramedullary hematopoiesis. In bone marrow, radiation-resistant recipient CD169+ resident macrophages and erythroid-island macrophages self-repopulated longterm after transplantation via autonomous cell division. Posttransplant peak expansion of recipient CD169+ resident macrophage number in bone marrow aligned with the persistent engraftment of phenotypic long-term reconstituting hematopoietic stem cells within bone marrow. Selective depletion of recipient CD169+ macrophages significantly compromised the engraftment of phenotypic long-term reconstituting hematopoietic stem cells and consequently impaired hematopoietic reconstitution. Recipient bone marrow resident macrophages are essential for optimal hematopoietic stem cell transplantation outcomes and could be an important consideration in the development of pretransplant conditioning therapies and/or chemoresistance approaches. © 2018 by The American Society of Hematology. | |
Bush, S. J.; Freem, L.; MacCallum, A. J.; O'Dell, J.; Wu, C.; Afrasiabi, C.; Psifidi, A.; Stevens, M. P.; Smith, J.; Summers, K. M.; Hume, D. A. Combination of novel and public RNA-seq datasets to generate an mRNA expression atlas for the domestic chicken (Journal Article) In: BMC Genomics, vol. 19, no. 1, 2018, ISSN: 14712164, (Publisher: BioMed Central Ltd.). @article{bush_combination_2018,Background: The domestic chicken (Gallus gallus) is widely used as a model in developmental biology and is also an important livestock species. We describe a novel approach to data integration to generate an mRNA expression atlas for the chicken spanning major tissue types and developmental stages, using a diverse range of publicly-archived RNA-seq datasets and new data derived from immune cells and tissues. Results: Randomly down-sampling RNA-seq datasets to a common depth and quantifying expression against a reference transcriptome using the mRNA quantitation tool Kallisto ensured that disparate datasets explored comparable transcriptomic space. The network analysis tool Graphia was used to extract clusters of co-expressed genes from the resulting expression atlas, many of which were tissue or cell-type restricted, contained transcription factors that have previously been implicated in their regulation, or were otherwise associated with biological processes, such as the cell cycle. The atlas provides a resource for the functional annotation of genes that currently have only a locus ID. We cross-referenced the RNA-seq atlas to a publicly available embryonic Cap Analysis of Gene Expression (CAGE) dataset to infer the developmental time course of organ systems, and to identify a signature of the expansion of tissue macrophage populations during development. Conclusion: Expression profiles obtained from public RNA-seq datasets - despite being generated by different laboratories using different methodologies - can be made comparable to each other. This meta-analytic approach to RNA-seq can be extended with new datasets from novel tissues, and is applicable to any species. © 2018 The Author(s). | |
Jubb, A. W.; Hofer, T. P.; Hume, D. A.; Ziegler-Heitbrock, L. The preterm labor associated ADAMTS2 gene is induced by glucocorticoids (Journal Article) In: American Journal of Obstetrics and Gynecology, vol. 219, no. 1, pp. 122–123, 2018, ISSN: 00029378, (Publisher: Mosby Inc.). @article{jubb_preterm_2018, | |
Pandit, R. J.; Hinsu, A. T.; Patel, N. V.; Koringa, P. G.; Jakhesara, S. J.; Thakkar, J. R.; Shah, T. M.; Limon, G.; Psifidi, A.; Guitian, J.; Hume, D. A.; Tomley, F. M.; Rank, D. N.; Raman, M.; Tirumurugaan, K. G.; Blake, D. P.; Joshi, C. G. Microbial diversity and community composition of caecal microbiota in commercial and indigenous Indian chickens determined using 16s rDNA amplicon sequencing (Journal Article) In: Microbiome, vol. 6, no. 1, 2018, ISSN: 20492618, (Publisher: BioMed Central Ltd.). @article{pandit_microbial_2018,Background: The caecal microbiota plays a key role in chicken health and performance, influencing digestion and absorption of nutrients, and contributing to defence against colonisation by invading pathogens. Measures of productivity and resistance to pathogen colonisation are directly influenced by chicken genotype, but host driven variation in microbiome structure is also likely to exert a considerable indirect influence. Methods: Here, we define the caecal microbiome of indigenous Indian Aseel and Kadaknath chicken breeds and compare them with the global commercial broiler Cobb400 and Ross 308 lines using 16S rDNA V3-V4 hypervariable amplicon sequencing. Results: Each caecal microbiome was dominated by the genera Bacteroides, unclassified bacteria, unclassified Clostridiales, Clostridium, Alistipes, Faecalibacterium, Eubacterium and Blautia. Geographic location (a measure recognised to include variation in environmental and climatic factors, but also likely to feature varied management practices) and chicken line/breed were both found to exert significant impacts (p textless 0.05) on caecal microbiome composition. Linear discriminant analysis effect size (LEfSe) revealed 42 breed-specific biomarkers in the chicken lines reared under controlled conditions at two different locations. Conclusion: Chicken breed-specific variation in bacterial occurrence, correlation between genera and clustering of operational taxonomic units indicate scope for quantitative genetic analysis and the possibility of selective breeding of chickens for defined enteric microbiota. © 2018 The Author(s). | |
Dunning, J.; Blankley, S.; Hoang, L. T.; Cox, M.; Graham, C. M.; James, P. L.; Bloom, C. I.; Chaussabel, D.; Banchereau, J.; Brett, S. J.; Habibi, M. S.; Johnston, S. L.; Hansel, T. T.; Levin, M.; Thwaites, R. S.; Warner, J. O.; Cookson, W. O.; Gazzard, B. G.; Hay, A.; McCauley, J.; Aylin, P.; Ashby, D.; Barclay, W. S.; Elderfield, R. A.; Nadel, S.; Herberg, J. A.; Drumright, L. N.; Garcia-Alvarez, L.; Holmes, A. H.; Kon, O. M.; Aston, S. J.; Gordon, S. B.; Hussell, T.; Thompson, C.; Zambon, M. C.; Baillie, K. J.; Hume, D. A.; Simmonds, P.; Hayward, A.; Smyth, R. L.; McNamara, P. S.; Semple, M. G.; Nguyen-Van-Tam, J. S.; Ho, L. -P.; McMichael, A. J.; Kellam, P.; Adamson, W. E.; Carman, W. F.; Griffiths, M. J.; Moffatt, M. F.; O'Garra, A.; Openshaw, P. J. M. Progression of whole-blood transcriptional signatures from interferon-induced to neutrophil-associated patterns in severe influenza (Journal Article) In: Nature Immunology, vol. 19, no. 6, pp. 625–635, 2018, ISSN: 15292908, (Publisher: Nature Publishing Group). @article{dunning_progression_2018,Transcriptional profiles and host-response biomarkers are used increasingly to investigate the severity, subtype and pathogenesis of disease. We now describe whole-blood mRNA signatures and concentrations of local and systemic immunological mediators in 131 adults hospitalized with influenza, from whom extensive clinical and investigational data were obtained by MOSAIC investigators. Signatures reflective of interferon-related antiviral pathways were common up to day 4 of symptoms in patients who did not require mechanical ventilator support; in those who needed mechanical ventilation, an inflammatory, activated-neutrophil and cell-stress or death ('bacterial') pattern was seen, even early in disease. Identifiable bacterial co-infection was not necessary for this 'bacterial' signature but was able to enhance its development while attenuating the early 'viral' signature. Our findings emphasize the importance of timing and severity in the interpretation of host responses to acute viral infection and identify specific patterns of immune-system activation that might enable the development of novel diagnostic and therapeutic tools for severe influenza. © 2018 The Author(s). | |
Lisowski, Z. M.; Pirie, R. S.; Blikslager, A. T.; Lefebvre, D.; Hume, D. A.; Hudson, N. P. H. An update on equine post-operative ileus: Definitions, pathophysiology and management (Journal Article) In: Equine Veterinary Journal, vol. 50, no. 3, pp. 292–303, 2018, ISSN: 04251644, (Publisher: Equine Veterinary Journal Ltd). @article{lisowski_update_2018,Post-operative ileus (POI) is a serious condition which any horse undergoing abdominal surgery is at risk of developing, leading to increased hospitalisation time and resulting costs. Advances in the understanding of the development of equine POI are mainly based on human and rodent literature, where manipulation-induced inflammation has been identified as a trigger, with activation of resident muscularis externa macrophages playing a crucial role in the pathophysiology. Despite many pharmacological trials in all species, there is no single completely successful treatment for POI, highlighting that the condition is multifactorial in cause and requires a multimodal approach to minimise its incidence. © 2017 EVJ Ltd | |
Bush, S. J.; Muriuki, C.; McCulloch, M. E. B.; Farquhar, I. L.; Clark, E. L.; Hume, D. A. Cross-species inference of long non-coding RNAs greatly expands the ruminant transcriptome (Journal Article) In: Genetics Selection Evolution, vol. 50, no. 1, 2018, ISSN: 0999193X, (Publisher: BioMed Central Ltd.). @article{bush_cross-species_2018,Background: mRNA-like long non-coding RNAs (lncRNAs) are a significant component of mammalian transcriptomes, although most are expressed only at low levels, with high tissue-specificity and/or at specific developmental stages. Thus, in many cases lncRNA detection by RNA-sequencing (RNA-seq) is compromised by stochastic sampling. To account for this and create a catalogue of ruminant lncRNAs, we compared de novo assembled lncRNAs derived from large RNA-seq datasets in transcriptional atlas projects for sheep and goats with previous lncRNAs assembled in cattle and human. We then combined the novel lncRNAs with the sheep transcriptional atlas to identify co-regulated sets of protein-coding and non-coding loci. Results: Few lncRNAs could be reproducibly assembled from a single dataset, even with deep sequencing of the same tissues from multiple animals. Furthermore, there was little sequence overlap between lncRNAs that were assembled from pooled RNA-seq data. We combined positional conservation (synteny) with cross-species mapping of candidate lncRNAs to identify a consensus set of ruminant lncRNAs and then used the RNA-seq data to demonstrate detectable and reproducible expression in each species. In sheep, 20 to 30% of lncRNAs were located close to protein-coding genes with which they are strongly co-expressed, which is consistent with the evolutionary origin of some ncRNAs in enhancer sequences. Nevertheless, most of the lncRNAs are not co-expressed with neighbouring protein-coding genes. Conclusions: Alongside substantially expanding the ruminant lncRNA repertoire, the outcomes of our analysis demonstrate that stochastic sampling can be partly overcome by combining RNA-seq datasets from related species. This has practical implications for the future discovery of lncRNAs in other species. © 2018 The Author(s). | |
Regan, T.; Gill, A. C.; Clohisey, S. M.; Barnett, M. W.; Pariante, C. M.; Harrison, N. A.; Hume, D. A.; Bullmore, E. T.; Freeman, T. C.; Consortium, MRC Immunopsychiatry Effects of anti-inflammatory drugs on the expression of tryptophan-metabolism genes by human macrophages (Journal Article) In: Journal of Leukocyte Biology, vol. 103, no. 4, pp. 681–692, 2018, ISSN: 07415400, (Publisher: John Wiley and Sons Inc.). @article{regan_effects_2018,Several lines of evidence link macrophage activation and inflammation with (monoaminergic) nervous systems in the etiology of depression. IFN treatment is associated with depressive symptoms, whereas anti-TNFα therapies elicit positive mood. This study describes the actions of 2 monoaminergic antidepressants (escitalopram, nortriptyline) and 3 anti-inflammatory drugs (indomethacin, prednisolone, and anti-TNFα antibody) on the response of human monocyte-derived macrophages (MDMs) from 6 individuals to LPS or IFN-α. Expression profiling revealed robust changes in the MDM transcriptome (3294 genes at P textless 0.001) following LPS challenge, whereas a more limited subset of genes (499) responded to IFNα. Contrary to published reports, administered at nontoxic doses, neither monoaminergic antidepressant significantly modulated the transcriptional response to either inflammatory challenge. Each anti-inflammatory drug had a distinct impact on the expression of inflammatory cytokines and on the profile of inducible gene expression—notably on the regulation of enzymes involved in metabolism of tryptophan. Inter alia, the effect of anti-TNFα antibody confirmed a predicted autocrine stimulatory loop in human macrophages. The transcriptional changes were predictive of tryptophan availability and kynurenine synthesis, as analyzed by targeted metabolomic studies on cellular supernatants. We suggest that inflammatory processes in the brain or periphery could impact on depression by altering the availability of tryptophan for serotonin synthesis and/or by increasing production of neurotoxic kynurenine. ©2018 Society for Leukocyte Biology | |
Hawley, C. A.; Rojo, R.; Raper, A.; Sauter, K. A.; Lisowski, Z. M.; Grabert, K.; Bain, C. C.; Davis, G. M.; Louwe, P. A.; Ostrowski, M. C.; Hume, D. A.; Pridans, C.; Jenkins, S. J. Csf1r-mApple transgene expression and ligand binding in vivo reveal dynamics of CSF1R expression within the mononuclear phagocyte system (Journal Article) In: Journal of Immunology, vol. 200, no. 6, pp. 2209–2223, 2018, ISSN: 00221767, (Publisher: American Association of Immunologists). @article{hawley_csf1r-mapple_2018,CSF1 is the primary growth factor controlling macrophage numbers, but whether expression of the CSF1 receptor differs between discrete populations of mononuclear phagocytes remains unclear. We have generated a Csf1r-mApple transgenic fluorescent reporter mouse that, in combination with lineage tracing, Alexa Fluor 647-labeled CSF1-Fc and CSF1, and a modified ΔCsf1- enhanced cyan fluorescent protein (ECFP) transgene that lacks a 150 bp segment of the distal promoter, we have used to dissect the differentiation and CSF1 responsiveness of mononuclear phagocyte populations in situ. Consistent with previous Csf1r-driven reporter lines, Csf1r-mApple was expressed in blood monocytes and at higher levels in tissue macrophages, and was readily detectable in whole mounts or with multiphoton microscopy. In the liver and peritoneal cavity, uptake of labeled CSF1 largely reflected transgene expression, with greater receptor activity in mature macrophages than monocytes and tissue-specific expression in conventional dendritic cells. However, CSF1 uptake also differed between subsets of monocytes and discrete populations of tissue macrophages, which in macrophages correlated with their level of dependence on CSF1 receptor signaling for survival rather than degree of transgene expression. A double DCsf1r-ECFP-Csf1r-mApple transgenic mouse distinguished subpopulations of microglia in the brain, and permitted imaging of interstitial macrophages distinct from alveolar macrophages, and pulmonary monocytes and conventional dendritic cells. The Csf1r-mApple mice and fluorescently labeled CSF1 will be valuable resources for the study of macrophage and CSF1 biology, which are compatible with existing EGFP-based reporter lines. © 2018 by The American Association of Immunologists, Inc. | |
2020 |
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Regulation and function of macrophage colony-stimulating factor (CSF1) in the chicken immune system (Journal Article) In: Developmental and Comparative Immunology, vol. 105, 2020, ISSN: 0145305X, (Publisher: Elsevier Ltd). | |
Functional Annotation of the Transcriptome of the Pig, Sus scrofa, Based Upon Network Analysis of an RNAseq Transcriptional Atlas (Journal Article) In: Frontiers in Genetics, vol. 10, 2020, ISSN: 16648021, (Publisher: Frontiers Media S.A.). | |
Phenotypic impacts of CSF1R deficiencies in humans and model organisms (Journal Article) In: Journal of Leukocyte Biology, vol. 107, no. 2, pp. 205–219, 2020, ISSN: 07415400, (Publisher: John Wiley and Sons Inc.). | |
Functional evolution of the colony-stimulating factor 1 receptor (CSF1R) and its ligands in birds (Journal Article) In: Journal of Leukocyte Biology, vol. 107, no. 2, pp. 237–250, 2020, ISSN: 07415400, (Publisher: John Wiley and Sons Inc.). | |
The geometry of generalized loxodromic elements (Journal Article) In: Annales de l'Institut Fourier, vol. 70, no. 4, pp. 1689–1713, 2020, ISSN: 03730956, (Publisher: Association des Annales de l'Institut Fourier). | |
An improved pig reference genome sequence to enable pig genetics and genomics research (Journal Article) In: GigaScience, vol. 9, no. 6, 2020, ISSN: 2047217X, (Publisher: Oxford University Press). | |
2019 |
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Deletion of a Csf1r enhancer selectively impacts CSF1R expression and development of tissue macrophage populations (Journal Article) In: Nature Communications, vol. 10, no. 1, 2019, ISSN: 20411723, (Publisher: Nature Publishing Group). | |
Chromosome-level assembly of the water buffalo genome surpasses human and goat genomes in sequence contiguity (Journal Article) In: Nature Communications, vol. 10, no. 1, 2019, ISSN: 20411723, (Publisher: Nature Publishing Group). | |
Analysis of the Progeny of Sibling Matings Reveals Regulatory Variation Impacting the Transcriptome of Immune Cells in Commercial Chickens (Journal Article) In: Frontiers in Genetics, vol. 10, 2019, ISSN: 16648021, (Publisher: Frontiers Media S.A.). | |
A Mini-Atlas of Gene Expression for the Domestic Goat (Capra hircus) (Journal Article) In: Frontiers in Genetics, vol. 10, 2019, ISSN: 16648021, (Publisher: Frontiers Media S.A.). | |
Genetic and genomic analyses underpin the feasibility of concomitant genetic improvement of milk yield and mastitis resistance in dairy sheep (Journal Article) In: PLoS ONE, vol. 14, no. 11, 2019, ISSN: 19326203, (Publisher: Public Library of Science). | |
Developmental Stage-Specific Distribution of Macrophages in Mouse Mammary Gland (Journal Article) In: Frontiers in Cell and Developmental Biology, vol. 7, 2019, ISSN: 2296634X, (Publisher: Frontiers Media S.A.). | |
Elimination of Reference Mapping Bias Reveals Robust Immune Related Allele-Specific Expression in Crossbred Sheep (Journal Article) In: Frontiers in Genetics, vol. 10, 2019, ISSN: 16648021, (Publisher: Frontiers Media S.A.). | |
Examining the impact of imputation errors on fine-mapping using DNA methylation QTL as a model trait (Journal Article) In: Genetics, vol. 212, no. 3, pp. 577–586, 2019, ISSN: 00166731, (Publisher: Genetics Society of America). | |
In: Journal of Immunology, vol. 202, no. 11, pp. 3334–3335, 2019, ISSN: 00221767, (Publisher: American Association of Immunologists). | |
The Effect of Race Training on the Basal Gene Expression of Alveolar Macrophages Derived From Standardbred Racehorses (Journal Article) In: Journal of Equine Veterinary Science, vol. 75, pp. 48–54, 2019, ISSN: 07370806, (Publisher: W.B. Saunders). | |
Measurement of serum macrophage migration inhibitory factor (MIF) and correlation with severity and pruritus scores in client owned dogs with atopic dermatitis (Journal Article) In: Veterinary Dermatology, vol. 30, no. 2, pp. 115–e32, 2019, ISSN: 09594493, (Publisher: Blackwell Publishing Ltd). | |
Linked Mutations at Adjacent Nucleotides Have Shaped Human Population Differentiation and Protein Evolution (Journal Article) In: Genome Biology and Evolution, vol. 11, no. 3, pp. 759–775, 2019, ISSN: 17596653, (Publisher: Oxford University Press). | |
In: Nature Immunology, vol. 20, no. 3, pp. 373, 2019, ISSN: 15292908, (Publisher: Nature Publishing Group). | |
Relatively hyperbolic groups with fixed peripherals (Journal Article) In: Israel Journal of Mathematics, vol. 230, no. 1, pp. 443–470, 2019, ISSN: 00212172, (Publisher: Springer New York LLC). | |
CD169+ macrophages are critical for osteoblast maintenance and promote intramembranous and endochondral ossification during bone repair (Journal Article) In: Biomaterials, vol. 196, pp. 51–66, 2019, ISSN: 01429612, (Publisher: Elsevier Ltd). | |
Assembly of a parts list of the human mitotic cell cycle machinery (Journal Article) In: Journal of Molecular Cell Biology, vol. 11, no. 8, pp. 703–718, 2019, ISSN: 16742788, (Publisher: Oxford University Press). | |
Characterization of subpopulations of chicken mononuclear phagocytes that express TIM4 and CSF1R (Journal Article) In: Journal of Immunology, vol. 202, no. 4, pp. 1186–1199, 2019, ISSN: 00221767, (Publisher: American Association of Immunologists). | |
In: G3: Genes, Genomes, Genetics, vol. 9, no. 2, pp. 359–373, 2019, ISSN: 21601836, (Publisher: Genetics Society of America). | |
The Mononuclear Phagocyte System: The Relationship between Monocytes and Macrophages (Journal Article) In: Trends in Immunology, vol. 40, no. 2, pp. 98–112, 2019, ISSN: 14714906, (Publisher: Elsevier Ltd). | |
Increased ultra-rare variant load in an isolated Scottish population impacts exonic and regulatory regions (Journal Article) In: PLoS Genetics, vol. 15, no. 11, 2019, ISSN: 15537390, (Publisher: Public Library of Science). | |
Antigen sampling csf1r-expressing epithelial cells are the functional equivalents of mammalian m cells in the avian follicle-associated epithelium (Journal Article) In: Frontiers in Immunology, vol. 10, no. OCT, 2019, ISSN: 16643224, (Publisher: Frontiers Media S.A.). | |
A gene expression atlas of the domestic water buffalo (Bubalus bubalis) (Journal Article) In: Frontiers in Genetics, vol. 10, no. JUN, 2019, ISSN: 16648021, (Publisher: Frontiers Media S.A.). | |
Negative curvature in graphical small cancellation groups (Journal Article) In: Groups, Geometry, and Dynamics, vol. 13, no. 2, pp. 579–632, 2019, ISSN: 16617207, (Publisher: European Mathematical Society Publishing House). | |
Corrigendum: Causes and consequences of innate immune dysfunction in cirrhosis (Frontiers in Immunology (2019) 10 (293) DOI: 10.3389/fimmu.2019.00293) (Journal Article) In: Frontiers in Immunology, vol. 10, no. APR, 2019, ISSN: 16643224, (Publisher: Frontiers Media S.A.). | |
Casuses and consequences of innate immune dysfucntion in cirrhosis (Journal Article) In: Frontiers in Immunology, vol. 10, no. FEB, 2019, ISSN: 16643224, (Publisher: Frontiers Media S.A.). | |
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The role of CSF1R-dependent macrophages in control of the intestinal stem-cell niche (Journal Article) In: Nature Communications, vol. 9, no. 1, pp. 1272, 2018, ISSN: 2041-1723. | |
Development of in vitro enteroids derived from bovine small intestinal crypts (Journal Article) In: Veterinary Research, vol. 49, no. 1, pp. 54, 2018, ISSN: 1297-9716. | |
The role of CSF1R-dependent macrophages in control of the intestinal stem-cell niche (Journal Article) In: Nature Communications, vol. 9, no. 1, pp. 1272, 2018, ISSN: 2041-1723. | |
A chicken bioreactor for efficient production of functional cytokines (Journal Article) In: BMC Biotechnology, vol. 18, no. 1, 2018, ISSN: 14726750, (Publisher: BioMed Central Ltd.). | |
Phenotypic and genetic variation in the response of chickens to Eimeria tenella induced coccidiosis (Journal Article) In: Genetics Selection Evolution, vol. 50, no. 1, 2018, ISSN: 0999193X, (Publisher: BioMed Central Ltd.). | |
Immune cell gene signatures for profiling the microenvironment of solid tumors (Journal Article) In: Cancer Immunology Research, vol. 6, no. 11, pp. 1388–1400, 2018, ISSN: 23266066, (Publisher: American Association for Cancer Research Inc.). | |
Pleiotropic Impacts of Macrophage and Microglial Deficiency on Development in Rats with Targeted Mutation of the Csf1r Locus (Journal Article) In: Journal of Immunology, vol. 201, no. 9, pp. 2683–2699, 2018, ISSN: 00221767, (Publisher: American Association of Immunologists). | |
ADGRE1 (EMR1, F4/80) is a rapidly-evolving gene expressed in mammalian monocyte-macrophages (Journal Article) In: Frontiers in Immunology, vol. 9, no. OCT, 2018, ISSN: 16643224, (Publisher: Frontiers Media S.A.). | |
Environmentally enriched pigs have transcriptional profiles consistent with neuroprotective effects and reduced microglial activity (Journal Article) In: Behavioural Brain Research, vol. 350, pp. 6–15, 2018, ISSN: 01664328, (Publisher: Elsevier B.V.). | |
The Transcription Factor ZEB2 Is Required to Maintain the Tissue-Specific Identities of Macrophages (Journal Article) In: Immunity, vol. 49, no. 2, pp. 312–325.e5, 2018, ISSN: 10747613, (Publisher: Cell Press). | |
Self-repopulating recipient bone marrow resident macrophages promote long-term hematopoietic stem cell engraftment (Journal Article) In: Blood, vol. 132, no. 7, pp. 735–749, 2018, ISSN: 00064971, (Publisher: American Society of Hematology). | |
Combination of novel and public RNA-seq datasets to generate an mRNA expression atlas for the domestic chicken (Journal Article) In: BMC Genomics, vol. 19, no. 1, 2018, ISSN: 14712164, (Publisher: BioMed Central Ltd.). | |
The preterm labor associated ADAMTS2 gene is induced by glucocorticoids (Journal Article) In: American Journal of Obstetrics and Gynecology, vol. 219, no. 1, pp. 122–123, 2018, ISSN: 00029378, (Publisher: Mosby Inc.). | |
Microbial diversity and community composition of caecal microbiota in commercial and indigenous Indian chickens determined using 16s rDNA amplicon sequencing (Journal Article) In: Microbiome, vol. 6, no. 1, 2018, ISSN: 20492618, (Publisher: BioMed Central Ltd.). | |
Progression of whole-blood transcriptional signatures from interferon-induced to neutrophil-associated patterns in severe influenza (Journal Article) In: Nature Immunology, vol. 19, no. 6, pp. 625–635, 2018, ISSN: 15292908, (Publisher: Nature Publishing Group). | |
An update on equine post-operative ileus: Definitions, pathophysiology and management (Journal Article) In: Equine Veterinary Journal, vol. 50, no. 3, pp. 292–303, 2018, ISSN: 04251644, (Publisher: Equine Veterinary Journal Ltd). | |
Cross-species inference of long non-coding RNAs greatly expands the ruminant transcriptome (Journal Article) In: Genetics Selection Evolution, vol. 50, no. 1, 2018, ISSN: 0999193X, (Publisher: BioMed Central Ltd.). | |
Effects of anti-inflammatory drugs on the expression of tryptophan-metabolism genes by human macrophages (Journal Article) In: Journal of Leukocyte Biology, vol. 103, no. 4, pp. 681–692, 2018, ISSN: 07415400, (Publisher: John Wiley and Sons Inc.). | |
Csf1r-mApple transgene expression and ligand binding in vivo reveal dynamics of CSF1R expression within the mononuclear phagocyte system (Journal Article) In: Journal of Immunology, vol. 200, no. 6, pp. 2209–2223, 2018, ISSN: 00221767, (Publisher: American Association of Immunologists). | |