The research has been funded by the National Institute of Allergy and infectious Diseases (NIAID) coordinated by Michael Katze and Xinxia Peng at the University of Washington in Seattle and Federica Di Palma, formerly at the Broad Institute of MIT and Harvard and now at The Genome Analysis Centre (TGAC).
.“By creating a high quality genome and transcriptome resource for the ferret, we have demonstrated how studies in non-conventional model organisms can facilitate essential bioscience research underpinning health,” said Federica Di Palma, Director of Science (Vertebrate & Health Genomics) at TGAC.
Ferrets have long been considered the best animal model for studying a number of human diseases, particularly influenza, because the strains that infect humans also infect ferrets and spread from ferret to ferret much as they do from human to human.
In the study, scientists at Broad Institute of MIT and Harvard, led by Federica Di Palma and Jessica Alfoldi, first sequenced and annotated the genome of a domestic sable ferret, Mustela putorius furo, and then collaborated with the Katze group on the subsequent analysis. A technique called transcriptome analysis was used to reveal which genes were being turned on, or “expressed,” in ferret tissues when challenged by influenza and in a “knock out” model of cystic fibrosis.
“This is a big deal,” said Michael Katze, UW professor of Microbiology who led the research effort. “Every time you sequence a genome, it allows you to answer a wide range of questions you couldn’t before. Having the genome changes a field forever.”
In the influenza portion of the study, Yoshihiro Kawaoka’s group at the University of Wisconsin-Madison exposed ferrets to a reconstructed version of the virus that caused the deadly pandemic flu of 1918, the so-called “Spanish flu,” which killed 25 million people worldwide, and the so-called “swine-flu” virus that caused the worldwide pandemic of 2009-2010 and continues to cause disease today.
They then collected samples from the animals’ tracheas and lungs on the first, third and eighth day of the infection for transcriptome analysis.
The Katze team found that two viruses affected the ferret trachea and the lungs differently. The 1918 virus, for example, triggered a marked transcriptional response in the trachea on the first day of infection, a response that was sustained though day 8.
The 2009 strain, on the other hand, triggered a response that started slowly and grew gradually, peaking on day 8.
“The 1918 flu elicited a huge response on day one and that response was sustained,” says Xinxia Peng, a research assistant professor in the Katze lab and a specialist in computational biology who was lead author on the study. “The 2009 pandemic flu triggered a response that gradually grew over several days. They had very different trajectories.”
In the lung, however, gene transcription triggered by both viruses was roughly the same, but was different from that seen in the trachea. “This side by side comparison reveals that the host response to these two viruses differs primarily in the trachea and may explain the course of infection,” Peng said.
To better understand cystic fibrosis, John Engelhardt’s group at the University of Iowa genetically engineered a ferret lacking the gene for a membrane protein called the cystic fibrosis transmembrane conductance regulator (CFTR). Defects in the CFTR gene are responsible for this inherited disease, which affects 30,000 Americans.
In the cystic fibrosis model, analysis of the transcriptome of the gene “knock-out” ferrets revealed that changes in the expression of genes can be seen on the first day of life and increase significantly over the next 15 days.
“We found that there are transcriptional changes from day one, right out-of-the-gate, and many of the changes are very similar to those seen in humans,” says Peng. “The findings suggest that some of the disease processes responsible for the lung damage seen in cystic fibrosis begin very early in life.”
Katze said transcriptome responses seen in both the influenza studies and the cystic fibrosis studies closely resemble those seen in humans, suggesting that ferret models will not only help scientists understand these two diseases but a broader set of diseases including heart disease and diabetes.
The research paper, titled: “The draft genome sequence of the ferret (Mustela putorius furo) facilitates study of human respiratory disease” is published in leading science journal Nature Biotechnology.
About TGAC
The Genome Analysis Centre (TGAC) is a world-class research institute focusing on the development of genomics and computational biology. TGAC is based within the Norwich Research Park and receives strategic funding from the Biotechnology and Biological Science Research Council (BBSRC) - £7.4M in 2013/14 - as well as support from other research funders. TGAC is one of eight institutes that receive strategic funding from BBSRC. TGAC operates a National Capability to promote the application of genomics and bioinformatics to advance bioscience research and innovation.
TGAC offers state of the art DNA sequencing facility, unique by its operation of multiple complementary technologies for data generation. The Institute is a UK hub for innovative Bioinformatics through research, analysis and interpretation of multiple, complex data sets. It hosts one of the largest computing hardware facilities dedicated to life science research in Europe. It is also actively involved in developing novel platforms to provide access to computational tools and processing capacity for multiple academic and industrial users and promoting applications of computational Bioscience. Additionally, the Institute offers a Training programme through courses and workshops, and an Outreach programme targeting schools, teachers and the general public through dialogue and science communication activities. www.tgac.ac.uk
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