Mammals express the sialic acids N-acetylneuraminic acid (Neu5Ac) and 
N-glycolylneuraminic acid (Neu5Gc) on cell surfaces, where they act as receptors 
for pathogens, including influenza A virus (IAV). Neu5Gc is synthesized from 
Neu5Ac by the enzyme cytidine monophosphate-N-acetylneuraminic acid hydroxylase 
(CMAH). In humans, this enzyme is inactive and only Neu5Ac is produced. Ferrets 
are susceptible to human-adapted IAV strains and have been the dominant animal 
model for IAV studies. Here we show that ferrets, like humans, do not synthesize 
Neu5Gc. Genomic analysis reveals an ancient, nine-exon deletion in the ferret 
CMAH gene that is shared by the Pinnipedia and Musteloidia members of the 
Carnivora. Interactions between two human strains of IAV with the sialyllactose 
receptor (sialic acid--α2,6Gal) confirm that the type of terminal sialic acid 
contributes significantly to IAV receptor specificity. Our results indicate that 
exclusive expression of Neu5Ac contributes to the susceptibility of ferrets to 
human-adapted IAV strains.