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The draft genome sequence of the ferret (Mustela putorius furo) facilitates study of human respiratory disease.

Peng X, Alföldi J, Gori K, Eisfeld AJ, Tyler SR, Tisoncik-Go J, Brawand D, Law GL, Skunca N, Hatta M, Gasper DJ, Kelly SM, Chang J, Thomas MJ, Johnson J, Berlin AM, Lara M, Russell P, Swofford R, Turner-Maier J, Young S, Hourlier T, Aken B, Searle S, Sun X, Yi Y, Suresh M, Tumpey TM, Siepel A, Wisely SM, Dessimoz C, Kawaoka Y, Birren BW, Lindblad-Toh K, Di Palma F, Engelhardt JF, Palermo RE, Katze MG - Nat. Biotechnol. (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, University of Washington, Seattle, Washington, USA.

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. 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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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.
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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.

Mentions: Using the annotated ferret protein sequences, we constructed a highly resolved phylogenetic tree (Supplementary Fig. 2). As expected, ferret falls within the Caniformia suborder of the Carnivores, as represented by the domestic dog, cat, giant panda and walrus, and the support values are high for most clades (Supplementary Tables 2 and 3, Methods). Although the clade containing the ferret diverged from a common ancestor before the divergence of the rodent and human/primate lineages, branch lengths in the tree indicate rapid evolution in the rodent clade, which has resulted in less genetic divergence between humans and ferrets than between humans and mice. Indeed, in comparing protein sequences between the species, we found that for 75% of all orthologous triplets, ferret proteins are closer than mouse proteins to human proteins (Figure 1a, Supplementary Table 4). For example, the ferretcystic fibrosis trans membrane conductance regulator (CFTR) protein is considerably closer to the human than is its mouse counterpart (%-identities [PAM distance] for ferret to human = 92% [8.1]; mouse to human = 79% [23.3]). Overall, basic cell physiology related Gene Ontology (GO) terms tend to be enriched among the genes residing in the angular sector representing the top 25% of genes where the ferret sequence is closer to human than the mouse ortholog. The enriched GO terms include nucleic acid metabolism, nuclear division, regulation of expression, and protein modification and localization (Supplementary Fig. 3, Supplementary Tables 5 and 6). Extending this comparison from CFTR to 106 CFTR-interacting proteins, we found that the ferret-to-human protein sequence similarity is significantly greater than the corresponding mouse ortholog (Wilcoxon test p-value = 3.1×10−6, Figure 1b). In additional comparisons, we examined gene sets pertinent to CF disease processes including inflammation, lung and pancreatic remodeling, and the regulation of insulin and diabetes, and in all cases found the encoded human proteins to be better conserved in ferret than in mouse (Figure 1b, Supplementary Fig. 4). In contrast, proteins encoded by some nervous system related genes appear to be more divergent from human in ferrets than mouse (Figure 1b). In summary, the overall high sequence similarity between ferret and human proteins shown by these genome-level analyses indicates many ferret proteins have likely evolved to conserve similar molecular functions as their human protein orthologs.


The draft genome sequence of the ferret (Mustela putorius furo) facilitates study of human respiratory disease.

Peng X, Alföldi J, Gori K, Eisfeld AJ, Tyler SR, Tisoncik-Go J, Brawand D, Law GL, Skunca N, Hatta M, Gasper DJ, Kelly SM, Chang J, Thomas MJ, Johnson J, Berlin AM, Lara M, Russell P, Swofford R, Turner-Maier J, Young S, Hourlier T, Aken B, Searle S, Sun X, Yi Y, Suresh M, Tumpey TM, Siepel A, Wisely SM, Dessimoz C, Kawaoka Y, Birren BW, Lindblad-Toh K, Di Palma F, Engelhardt JF, Palermo RE, Katze MG - Nat. Biotechnol. (2014)

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.
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Related In: Results  -  Collection

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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.
Mentions: Using the annotated ferret protein sequences, we constructed a highly resolved phylogenetic tree (Supplementary Fig. 2). As expected, ferret falls within the Caniformia suborder of the Carnivores, as represented by the domestic dog, cat, giant panda and walrus, and the support values are high for most clades (Supplementary Tables 2 and 3, Methods). Although the clade containing the ferret diverged from a common ancestor before the divergence of the rodent and human/primate lineages, branch lengths in the tree indicate rapid evolution in the rodent clade, which has resulted in less genetic divergence between humans and ferrets than between humans and mice. Indeed, in comparing protein sequences between the species, we found that for 75% of all orthologous triplets, ferret proteins are closer than mouse proteins to human proteins (Figure 1a, Supplementary Table 4). For example, the ferretcystic fibrosis trans membrane conductance regulator (CFTR) protein is considerably closer to the human than is its mouse counterpart (%-identities [PAM distance] for ferret to human = 92% [8.1]; mouse to human = 79% [23.3]). Overall, basic cell physiology related Gene Ontology (GO) terms tend to be enriched among the genes residing in the angular sector representing the top 25% of genes where the ferret sequence is closer to human than the mouse ortholog. The enriched GO terms include nucleic acid metabolism, nuclear division, regulation of expression, and protein modification and localization (Supplementary Fig. 3, Supplementary Tables 5 and 6). Extending this comparison from CFTR to 106 CFTR-interacting proteins, we found that the ferret-to-human protein sequence similarity is significantly greater than the corresponding mouse ortholog (Wilcoxon test p-value = 3.1×10−6, Figure 1b). In additional comparisons, we examined gene sets pertinent to CF disease processes including inflammation, lung and pancreatic remodeling, and the regulation of insulin and diabetes, and in all cases found the encoded human proteins to be better conserved in ferret than in mouse (Figure 1b, Supplementary Fig. 4). In contrast, proteins encoded by some nervous system related genes appear to be more divergent from human in ferrets than mouse (Figure 1b). In summary, the overall high sequence similarity between ferret and human proteins shown by these genome-level analyses indicates many ferret proteins have likely evolved to conserve similar molecular functions as their human protein orthologs.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, University of Washington, Seattle, Washington, USA.

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. 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.

Show MeSH
Related in: MedlinePlus