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Ferret Genome Enables Deeper Study of Influenza, Cystic Fibrosis

Sable ferret

NEW YORK (GenomeWeb) – An international team of researchers has sequenced the ferret genome, which they say will bolster its use as a model organism to study human respiratory diseases such as influenza and cystic fibrosis.

The team led by the University of Washington's Michael Katze put together a 2.41 gigabase draft assembly of the Mustela putorius furo genome, which they then annotated using RNA sequencing data from 21 ferret tissues, as they reported in Nature Biotechnology today.

The researchers additionally examined the ferret's gene expression response to infection with pandemic influenza strains over time as well as investigated how closely a ferret model of cystic fibrosis mirrors disease progression in humans.

"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," co-author Federica Di Palma from The Genome Analysis Centre said in a statement.

The team performed whole-genome sequencing on a female sable ferret and assembled the reads they generated using ALLPATHS-LG into a 2.41 Gb assembly, including gaps. They then annotated the ferret genome using Ensembl and RNA-seq data from 24 samples of 21 tissues from both male and female ferrets. The researchers further annotated protein-coding gene models by combining Uniprot mammal and other vertebrate proteins sequenced with the RNA-seq data they generated.

Based on those annotated ferret protein sequences, the team constructed a phylogenetic tree that placed ferrets within the carnivore suborder Caniformia. While the ferret lineage diverged from what was to become the primate lineage before rodents did, ferrets are more similar to humans than rodents are because of the rapid evolution rodents underwent after their split from the primate lineage.

For three-quarters of orthologous triplets, ferret proteins were more similar to human proteins than were mouse proteins, Katze and his team reported. For instance, the ferret cystic fibrosis transmembrane conductance regulator (CFTR) protein has a PAM distance of 92 percent to the human CFTR, while the mouse has one of 79 percent. This, the researchers noted, suggests that many ferret proteins have evolved to conserve functions similar to the human protein orthologs.

Indeed, by comparing relative transcript abundance in seven tissues from ferrets and humans, the researchers found broad similarities in tissue-specific gene expression.

As the ferret is a common model organism to study human influenza virus infection, the team used the genomic profile it developed to enhance its examination of how ferret gene transcription changes in response to viral infection.

They infected ferrets with either the H1N1 2009 pandemic virus A/CA/04/2009 or the reconstructed H1N1 1918 pandemic virus and collected samples from their upper and lower respiratory tracts at various time points after infection. They then performed RNA-seq on those samples, finding that host transcriptional changes were more extensive in the infected trachea — they noted more than 9,800 differentially expressed genes there — as compared to the lung.

The different viruses also had a varying effect on host gene expression in the trachea. Infection with the 1918 virus kicked off differential expression of a number of genes at day one post-infection that was sustained through eight days after infection. The 2004 virus, meanwhile, led to gradual transcription changes — mostly affecting the same genes as the older virus — that peaked eight days after infection.

Xinxia Peng, a research assistant professor in the Katze lab, noted that the two flu viruses result in different trajectories. "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 added.

The team also investigated how cystic fibrosis progresses in a ferret model as compared to samples from humans. Using microarray-based analysis, the team examined gene expression changes in ferret knockouts of CFTR and normal ferrets, which they also compared to human cystic fibrosis datasets.

In newborn ferrets, they noted, there were some 470 genes that differentially expressed between the CFTR knockout ferrets and non-CF ferrets. Functional analysis of these genes indicated that they were mostly involved in coagulation, immune, and serotonin signaling pathways.

Older animals, they added, had more extensive differences in gene expression, affecting pathways like cholesterol biosynthesis, eicosanoid, and IL8 signaling and regulation.

Broadly, the team noted, these changes are similar to what's observed in humans with disease.

"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," Peng said. "The findings suggest that some of the disease processes responsible for the lung damage seen in cystic fibrosis begin very early in life."

Based on their use of the ferret genome sequence to examine host response to influenza and cystic fibrosis disease progression, the researchers argued that having the ferret genome can enhance the use of ferrets as model organisms.