The draft genome sequence of the ferret (Mustela putorius furo) facilitates study of human respiratory disease (V体育ios版)

Xinxia Peng¹, Jessica Alföldi², Kevin Gori³, Amie J Eisfeld⁴, Scott R Tyler⁵, Jennifer Tisoncik-Go¹, David Brawand⁶, G Lynn Law¹, Nives Skunca⁷, Masato Hatta⁴, David J Gasper⁴, Sara M Kelly¹, Jean Chang¹, Matthew J Thomas¹, Jeremy Johnson², Aaron M Berlin², Marcia Lara⁶, Pamela Russell⁶, Ross Swofford², Jason Turner-Maier², Sarah Young², Thibaut Hourlier⁸, Bronwen Aken⁸, Steve Searle⁸, Xingshen Sun⁹, Yaling Yi⁹, M Suresh⁴, Terrence M Tumpey¹⁰, Adam Siepel¹¹, Samantha M Wisely¹², Christophe Dessimoz¹³, Yoshihiro Kawaoka¹⁴, Bruce W Birren², Kerstin Lindblad-Toh¹⁵, Federica Di Palma⁶, John F Engelhardt¹⁶, Robert E Palermo¹, Michael G Katze¹⁷

Affiliations

¹ Department of Microbiology, University of Washington, Seattle, Washington, USA.
² Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
³ European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, Cambridge, UK.
⁴ Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin, USA.
⁵ 1] Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA. . [2] Molecular and Cellular Biology Program, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
⁶ 1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2] MRC Functional Genomics Unit, University of Oxford, xford, UK (D.B.); Biogen Idec, Cambridge, Massachusetts, USA (M.L.); Division of Biology, California Institute of Technology, Pasadena, California, USA (P.R.); Vertebrate and Health Genomics, The Genome Analysis Center, Norwich, UK (F.D.P.).
⁷ 1] Department of Computer Science, Swiss Federal Institute of Technology (ETH Zurich), Zurich, Switzerland. [2] Swiss Institute of Bioinformatics, Zurich, Switzerland.
⁸ Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
⁹ Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA. .
¹⁰ Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
¹¹ Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York, USA.
¹² Department of Wildlife Ecology and Conservation, University of Florida, Gainesville, Florida, USA.
¹³ 1] European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, Cambridge, UK. [2] Department of Genetics, Evolution and Environment, University College London, London, UK. [3] Department of Computer Science, University College London, London, UK.
¹⁴ 1] Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin, USA. [2] ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama, Japan. [3] Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan. [4] Department of Special Pathogens, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan. [5] Laboratory of Bioresponses Regulation, Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto, Japan.
¹⁵ 1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2] Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
¹⁶ 1] Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA. . [2] Center for Gene Therapy, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
¹⁷ 1] Department of Microbiology, University of Washington, Seattle, Washington, USA. [2] Washington National Primate Research Center, Seattle, Washington, USA.

PMID: 25402615
PMCID: PMC4262547
DOI: 10.1038/nbt.3079

The draft genome sequence of the ferret (Mustela putorius furo) facilitates study of human respiratory disease (V体育2025版)

Xinxia Peng et al. Nat Biotechnol. 2014 Dec.

. 2014 Dec;32(12):1250-5.

doi: 10.1038/nbt.3079. Epub 2014 Nov 17.

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"VSports手机版" Affiliations

¹ Department of Microbiology, University of Washington, Seattle, Washington, USA.
² Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
³ European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, Cambridge, UK.
⁴ Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin, USA.
⁵ 1] Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA. . [2] Molecular and Cellular Biology Program, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
⁶ 1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2] MRC Functional Genomics Unit, University of Oxford, xford, UK (D.B.); Biogen Idec, Cambridge, Massachusetts, USA (M.L.); Division of Biology, California Institute of Technology, Pasadena, California, USA (P.R.); Vertebrate and Health Genomics, The Genome Analysis Center, Norwich, UK (F.D.P.).
⁷ 1] Department of Computer Science, Swiss Federal Institute of Technology (ETH Zurich), Zurich, Switzerland. [2] Swiss Institute of Bioinformatics, Zurich, Switzerland.
⁸ Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
⁹ Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA. .
¹⁰ Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
¹¹ Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York, USA.
¹² Department of Wildlife Ecology and Conservation, University of Florida, Gainesville, Florida, USA.
¹³ 1] European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, Cambridge, UK. [2] Department of Genetics, Evolution and Environment, University College London, London, UK. [3] Department of Computer Science, University College London, London, UK.
¹⁴ 1] Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin, USA. [2] ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama, Japan. [3] Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan. [4] Department of Special Pathogens, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan. [5] Laboratory of Bioresponses Regulation, Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto, Japan.
¹⁵ 1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2] Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
¹⁶ 1] Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA. . [2] Center for Gene Therapy, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
¹⁷ 1] Department of Microbiology, University of Washington, Seattle, Washington, USA. [2] Washington National Primate Research Center, Seattle, Washington, USA.

PMID: 25402615
PMCID: PMC4262547
DOI: VSports最新版本 - 10.1038/nbt.3079

Abstract

The domestic ferret (Mustela putorius furo) is an important animal model for multiple human respiratory diseases. It is considered the 'gold standard' for modeling human influenza virus infection and transmission. Here we describe the 2. 41 Gb draft genome assembly of the domestic ferret, constituting 2. 28 Gb of sequence plus gaps. We annotated 19,910 protein-coding genes on this assembly using RNA-seq data from 21 ferret tissues VSports手机版. We characterized the ferret host response to two influenza virus infections by RNA-seq analysis of 42 ferret samples from influenza time-course data and showed distinct signatures in ferret trachea and lung tissues specific to 1918 or 2009 human pandemic influenza virus infections. Using microarray data from 16 ferret samples reflecting cystic fibrosis disease progression, we showed that transcriptional changes in the CFTR-knockout ferret lung reflect pathways of early disease that cannot be readily studied in human infants with cystic fibrosis disease. .

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Conflict of interest statement

Competing Financial Interests The authors declare no competing financial interests.

"V体育安卓版" Figures

**Figure 1**
Cross-species comparisons show that ferret protein sequence and tissue-specific expression are similar to that of human. a. Scatter plot of human vs. mouse protein divergence in Point Accepted Mutation (PAM) metric (y-axis) against the corresponding human vs. ferret protein divergence (x-axis). Proteins appear above the 45° diagonal (grey dashes) when the ferret sequence is closer to the human sequence than the corresponding mouse sequence. The angle of the line to each protein from the origin is directly related to the ratio of mouse divergence from human sequence and ferret divergence from the human sequence. A greater angle from the origin indicates greater divergence. The quartiles of the distribution of these ratios are displayed in different colors (blue being the least conserved in ferret relative to mouse, and orange-brown being the most conserved). Hatched lines on the axes show the metric distributions for the individual species (Supplementary Table 4). b. Box plots of the angles represented in panel a for proteins in eight selected biological functions. For gene sets related to CF (light yellow), human protein sequence is better conserved in ferret than in mouse. For two nervous system related gene sets (blue), human protein sequence tended to be more conserved in mouse. Next to each function are the number of proteins in the function and the p-value from one-sided Wilcoxon signed rank test comparing the human-ferret (x-axis in a) vs. human-mouse (y-axis in a) divergence in PAM metric. c. K-means clustering of ferret-human orthologous genes by their tissue expression patterns reveals similarities in tissue-specificity. The color scale represents relative abundance across all tissues within each species and is saturated at 70%. Vertical partitions correspond to the seven clusters of genes from the optimal clustering, numbers of genes per cluster appearing on the top. Horizontal groupings are organized by tissue with ferret and human pairings denoted by the color bar at the side, and highlight the tissue-specificity of clusters 2 through 7.

**Figure 2**
Transcriptomic analyses of the host response to influenza virus infection and CF disease progression in ferrets. a. Heat map visualization shows distinct gene expression changes in lung and trachea samples from ferrets infected with either the 2009 pandemic H1N1 influenza A/CA/04/2009 virus (CA04) or the 1918 pandemic H1N1 influenza A/Brevig Mission/1/1918 virus (1918). Each row shows the log₂ (fold-change) for three infected animals relative to corresponding tissue from three mock-infected ferrets. The heat map is organized by the specificity of the changes with respect to tissue or virus. From left to right black bars at the top of the panel indicate four groups of genes: specific to trachea; distinct profiles in trachea and lung; similar profiles in trachea and lung; specific to lung (for additional details see Supplementary Fig. 18); within each group orange subsections differ between the virus strains, green subsections do not. b. Multidimensional scaling (MDS) representation of the distances among samples based on the indicated cluster of 2,592 genes from a that distinguish viruses in trachea but not in lung. Points show individual animals as indicated on the far right. The x- and y-axes represent a conceptual 2-dimensional space to which the MDS algorithm projected individual lung and trachea samples of high-dimensionality; i.e., the number of genes in the block associated with each sample, while preserving the distances/dissimilarities between samples as closely as possible. Double arrow illustrates that the gene signature distinguishes the two virus infections in trachea at 1 dpi, while lung samples show no separation (dotted rectangle). c. As in b, for the indicated cluster of 152 genes that is differentially regulated in lung but not trachea tissues and separates the two virus strains on 1 dpi. d and e. Differential transcriptional responses in an experiment comparing lung samples from 15-day-old CF ferrets (n=3) vs. non-CF ferrets (n=5). d. Similar pathways enriched in genes differentially expressed in 15-day-old CF ferret lung samples and CF human bronchial brushings, derived from Ingenuity Pathway Analysis. The values in parenthesis are the enrichment p-values for the corresponding pathways in the genes differentially expressed in CF human bronchial brushing. In brackets are genes which were differentially expressed in both ferret and human CF/non-CF comparisons. e. Network illustration of 32 genes of the function ‘inflammatory response’, which were differentially expressed in the same direction in ferret and human CF datasets (for additional details see Supplementary Fig. 20). Red and blue shading reflects the extent of increased or decreased expression, respectively, in CF relative to non-CF individuals. A solid line between two genes indicates direct interaction(s) among them and a dotted line for indirect interaction(s), as documented in the literature.

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References

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